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WATANABE Yasuyoshi
Graduate School of Science, Technology and Innovation / Department of Science, Technology and Innovation
Professor

Researcher basic information

■ Research Areas
  • Life sciences / Pathobiochemistry
  • Life sciences / Medical biochemistry
  • Life sciences / Clinical pharmacy
  • Life sciences / Physiology
■ Committee History
  • 2008, 国際分子イメージング学会, council, 国際分子イメージング学会
  • 2006, 日本分子イメージング学会, 運営委員, 日本分子イメージング学会
  • 2005, 日本疲労学会, 理事, 日本疲労学会
  • 2002, 日本神経化学会, 評議員, 日本神経化学会
  • 2000, 日本生理学会, 評議員, 日本生理学会
  • 1992, 日本ビタミン学会, 評議員, 日本ビタミン学会
  • 1991, 国際プテリジンと関連生体アミン学会, International Advisary Board Member, 国際プテリジンと関連生体アミン学会
  • 1988, 日本生化学会, 評議員, 日本生化学会
  • 1986, ビタミンB研究委員会, 委員, ビタミンB研究委員会

Research activity information

■ Award
  • 2010 文部科学大臣表彰科学技術賞研究部門

  • 2008 大阪市立大学学友会顕彰

  • 2007 エルウィン・フォン・ベルツ賞 1等賞

  • 1987 エルウィン・フォン・ベルツ賞 2等賞

■ Paper
  • Feng Zhu, Hirosato Kanda, Hiroyuki Neyama, Yuping Wu, Shigeki Kato, Di Hu, Shaoqi Duan, Koichi Noguchi, Yasuyoshi Watanabe, Kazuto Kobayashi, Yi Dai, Yilong Cui
    Springer Science and Business Media LLC, Jun. 2024, Neuroscience Bulletin
    Scientific journal

  • Di Hu, Shigeru Kabayama, Yasuyoshi Watanabe, Yilong Cui
    Molecular hydrogen, the smallest and lightest molecule, serves as an intense reducing agent. Its distinct characteristics, including minimal size and neutral charge, enhance bioavailability and facilitate significant biological effects. Previously considered physiologically inert, hydrogen has gained recognition as a powerful therapeutic agent, known for its antioxidative and anti-inflammatory properties. Electrolyzed hydrogen water (EHW), enriched with molecular hydrogen, demonstrates remarkable antioxidative capabilities, indicating potential benefits for various diseases. Inflammation-induced reactive oxygen species (ROS) amplify inflammation, leading to secondary oxidative stress and creating a crosstalk between ROS and inflammatory responses. This crosstalk contributes to the pathogenesis and progression of chronic diseases. EHW interrupts this crosstalk, reducing inflammatory cytokines and oxidative stress across various disease models, suggesting therapeutic potential. EHW is also known for its anti-inflammatory effects, extending to pain management, as evidenced in models like sciatic nerve ligation and inflammatory pain. In an inflammatory bowel disease (IBD) model, EHW effectively alleviates abdominal pain, mitigating 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced inflammation and oxidative stress, offering insights for clinical applications. Additionally, hydrogen selectively targets harmful radicals, and EHW intake helps balance stress-induced hormonal dysregulation, potentially easing disorders associated with chronic stress.
    MDPI AG, Mar. 2024, Antioxidants, 13(3) (3), 313 - 313
    Scientific journal

  • 脳膠芽腫のコンパニオン診断用PETトレーサーとしての[11C]エリブリンの合成
    丹羽 節, 田原 強, Chase Charles E., Fang Francis G., 中岡 貴義, 入江 さつき, 林中 恵美, 和田 康弘, 向井 英史, 増富 健吉, 渡辺 恭良, 崔 翼龍, 細谷 孝充
    エリブリンは局所再発性・転移性乳がん、および悪性軟部腫瘍に対する治療薬である。近年、エリブリンの膠芽腫に対する有効性を示唆する結果が報告されたことから、その患部への送達を陽電子放射断層撮像(PET)法で可視化するため、エリブリンの炭素11による標識を行った。検討の結果、エリブリンの主要骨格を持つ入手可能なアルデヒドに対し、[11C]ニトロメタンを用いたニトロアルドール反応とニトロ基の還元を行うことで、エリブリンの側鎖35位に炭素11を導入したPETプローブの合成に成功した。これを脳腫瘍モデルマウスに投与しPET撮像を行ったところ、エリブリンが代謝されることなく、腫瘍部位に特異的に集積することを示す結果が得られた。この結果は、11Cで標識されたエリブリンが生体内動態の定量評価および腫瘍イメージングにおいて有用なPETプローブとなる可能性を示唆している。(著者抄録)
    日本分子イメージング学会, Feb. 2024, JSMI Report, 17(1) (1), 30 - 33, Japanese

  • 脳膠芽腫のコンパニオン診断用PETトレーサーとしての[11C]エリブリンの合成
    丹羽 節, 田原 強, Chase Charles E., Fang Francis G., 中岡 貴義, 入江 さつき, 林中 恵美, 和田 康弘, 向井 英史, 増富 健吉, 渡辺 恭良, 崔 翼龍, 細谷 孝充
    日本分子イメージング学会, Feb. 2024, JSMI Report, 17(1) (1), 30 - 33, Japanese

  • Mei Tian, Chuantao Zuo, Ali Cahid Civelek, Ignasi Carrio, Yasuyoshi Watanabe, Keon Wook Kang, Koji Murakami, Valentina Garibotto, John O Prior, Henryk Barthel, Yihui Guan, Jiaying Lu, Rui Zhou, Chentao Jin, Shuang Wu, Xiaohui Zhang, Yan Zhong, Hong Zhang
    Alzheimer's disease (AD) is the main cause of dementia, with its diagnosis and management remaining challenging. Amyloid positron emission tomography (PET) has become increasingly important in medical practice for patients with AD. To integrate and update previous guidelines in the field, a task group of experts of several disciplines from multiple countries was assembled, and they revised and approved the content related to the application of amyloid PET in the medical settings of cognitively impaired individuals, focusing on clinical scenarios, patient preparation, administered activities, as well as image acquisition, processing, interpretation and reporting. In addition, expert opinions, practices, and protocols of prominent research institutions performing research on amyloid PET of dementia are integrated. With the increasing availability of amyloid PET imaging, a complete and standard pipeline for the entire examination process is essential for clinical practice. This international consensus and practice guideline will help to promote proper clinical use of amyloid PET imaging in patients with AD.
    Aug. 2023, Phenomics (Cham, Switzerland), 3(4) (4), 375 - 389, English, International magazine
    Scientific journal

  • Sachiko Horie, Yasuhiro Suzuki, Tsuyoshi Yamamoto, Satoshi Obika, Kohta Mohri, Chizuru Kiyota, Qin Ren, Shota Warashina, Yasuhiro Wada, Yasuyoshi Watanabe, Hidefumi Mukai, Yasufumi Sato
    Vasohihibin-2 (VASH2) is a homolog of vasohibin-1 (VASH1) and is overexpressed in various cancers. Vasohihibin-2 acts on both cancer cells and cancer microenvironmental cells. Previous analyses have shown that VASH2 promotes cancer progression and abrogation of VASH2 results in significant anticancer effects. We therefore propose VASH2 to be a practical molecular target for cancer treatment. Modifications of antisense oligonucleotide (ASO) such as bridged nucleic acids (BNA)-based modification increases the specificity and stability of ASO, and are now applied to the development of a number of oligonucleotide-based drugs. Here we designed human VASH2-ASOs, selected an optimal one, and developed 2',4'-BNA-based VASH2-ASO. When systemically administered, naked 2',4'-BNA-based VASH2-ASO accumulated in the liver and showed its gene-silencing activity. We then examined the effect of 2',4'-BNA-based VASH2-ASO in liver cancers. Intraperitoneal injection of naked 2',4'-BNA-based VASH2-ASO exerted a potent antitumor effect on orthotopically inoculated human hepatocellular carcinoma cells. The same manipulation also showed potent antitumor activity on the splenic inoculation of human colon cancer cells for liver metastasis. These results provide a novel strategy for the treatment of primary as well as metastatic liver cancers by using modified ASOs targeting VASH2.
    Jul. 2023, Cancer science, English, International magazine
    Scientific journal

  • 小型細胞外小胞の肝臓・脾臓取り込み機序解明のためのPET動態解析
    藁科 翔太, 毛利 浩太, 前田 和哉, 和田 康弘, 渡辺 恭良, 向井 英史
    日本DDS学会, Jul. 2023, 日本DDS学会学術集会プログラム予稿集, 39回, 176 - 176, Japanese

  • 肝蔵デリバリーに向けたmRNA封入脂質ナノ粒子の遺伝子発現とPET体内動態評価
    毛利 浩太, 宮崎 崇之, 藁科 翔太, 高橋 麻衣子, 仁 欽, 和田 康弘, 渡辺 恭良, 鈴木 裕太, 向井 英史
    日本DDS学会, Jul. 2023, 日本DDS学会学術集会プログラム予稿集, 39回, 181 - 181, Japanese

  • Takahito Yoshizaki, Shinobu Minatani, Hiroto Namba, Akitoshi Takeda, Joji Kawabe, Hideko Mizuta, Yasuhiro Wada, Aya Mawatari, Yasuyoshi Watanabe, Hitoshi Shimada, Makoto Higuchi, Yoshiaki Itoh
    Background: Heterogeneity in Alzheimer's disease (AD) has been reported on the basis of clinical, neuropathological, and neuroimaging data. However, most of the indices, including cerebral atrophy evaluated using magnetic resonance imaging and amyloid b (Ab) accumulation detected using positron emission tomography (PET), lack sensitivity, and specificity for categorization. Aim: Herein, we used a novel PET ligand for tau to estimate the differential distribution of tau in the subtypes of AD. Methods: Patients with posterior cortical atrophy (PCA; n = 3), frontal variant of AD (FAD; n = 1), logopenic variant primary progressive aphasia (LPPA; n = 2), typical AD (TAD; n = 6), and healthy controls (HC; n = 12) were studied. Ab and tau accumulation were evaluated using [C-11]PiB and [C-11]PBB3, respectively. Results: Amyloid b accumulation was confirmed in all PCA, FAD, LPPA, and TAD cases. Tau accumulation was dominantly high in the occipital lobes in the PCA, strikingly high in the frontal lobes in the FAD, and moderately high in the angular gyrus of the dominant hemisphere in the LPPA. Tau accumulation in TAD cases was significantly higher than age-dependent tau accumulation in HC in these subtype-specific regions as well as in AD signature regions. Glucose utilization was reversely correlated with PBB3 accumulation in the subtype-specific regions. Conclusions: Tau accumulates differently in the four subtypes of AD, suggesting that tau pathology may be closely associated with unique clinical features.
    WILEY, Jul. 2023, NEUROLOGY AND CLINICAL NEUROSCIENCE, 11(4) (4), 231 - 238, English
    Scientific journal

  • Hiroyuki Neyama, Yuping Wu, Yuka Nakaya, Shigeki Kato, Tomoko Shimizu, Tsuyoshi Tahara, Mika Shigeta, Michiko Inoue, Kazunari Miyamichi, Natsuki Matsushita, Tomoji Mashimo, Yoshiki Miyasaka, Yasuyoshi Watanabe, Masayuki Kobayashi, Kazuto Kobayashi, Yilong Cui
    Abstract Placebo analgesia is caused by inactive treatment, implicating endogenous brain function involvement. However, the underlying neurobiological mechanisms remain unclear. We found that μ-opioid signals in the medial prefrontal cortex (mPFC) activate the descending pain inhibitory system to initiate placebo analgesia in neuropathic pain rats. Chemogenetic manipulation demonstrated that specific activation of μ-opioid receptor-positive (MOR+) neurons in the mPFC or suppression of the mPFC-ventrolateral periaqueductal gray (vlPAG) circuit inhibited placebo analgesia in rats. MOR+neurons in the mPFC are monosynaptically connected and directly inhibit L5 pyramidal neurons that project to the vlPAG via GABAAreceptors. Thus, intrinsic opioid signaling in the mPFC disinhibits excitatory outflow to the vlPAG by suppressing MOR+neurons, leading to descending pain inhibitory system activation that initiates placebo analgesia. One Sentence Summary Sugar pills relieve pain by activating the intrinsic pain inhibitory system via opioidergic signals in the prefrontal cortex.
    Cold Spring Harbor Laboratory, Jun. 2023

  • Manon Dubol, Jana Immenschuh, My Jonasson, Kayo Takahashi, Takashi Niwa, Takamitsu Hosoya, Sara Roslin, Johan Wikström, Gunnar Antoni, Yasuyoshi Watanabe, Mark Lubberink, Anat Biegon, Inger Sundström-Poromaa, Erika Comasco
    BACKGROUND: Of interest to women's mental health, a wealth of studies suggests sex differences in nicotine addiction and treatment response, but their psychoneuroendocrine underpinnings remain largely unknown. A pathway involving sex steroids could indeed be involved in the behavioural effects of nicotine, as it was found to inhibit aromatase in vitro and in vivo in rodents and non-human primates, respectively. Aromatase regulates the synthesis of oestrogens and, of relevance to addiction, is highly expressed in the limbic brain. METHODS: The present study sought to investigate in vivo aromatase availability in relation to exposure to nicotine in healthy women. Structural magnetic resonance imaging and two [11C]cetrozole positron emission tomography (PET) scans were performed to assess the availability of aromatase before and after administration of nicotine. Gonadal hormones and cotinine levels were measured. Given the region-specific expression of aromatase, a ROI-based approach was employed to assess changes in [11C]cetrozole non-displaceable binding potential. RESULTS: The highest availability of aromatase was found in the right and left thalamus. Upon nicotine exposure, [11C]cetrozole binding in the thalamus was acutely decreased bilaterally (Cohen's d = -0.99). In line, cotinine levels were negatively associated with aromatase availability in the thalamus, although as non-significant trend. CONCLUSIONS: These findings indicate acute blocking of aromatase availability by nicotine in the thalamic area. This suggests a new putative mechanism mediating the effects of nicotine on human behaviour, particularly relevant to sex differences in nicotine addiction.
    May 2023, Comprehensive psychiatry, 123, 152381 - 152381, English, International magazine
    Scientific journal

  • Satoshi Nozaki, Yuka Nakatani, Aya Mawatari, William Ewan Hume, Hisashi Doi, Yasuyoshi Watanabe
    BACKGROUND: (S)-2-amino-3-[3-(2-18F-fluoroethoxy)-4-iodophenyl]-2-methylpropanoic acid (18F-FIMP) as a promising PET probe for imaging the tumor-specific L-type amino acid transporter (LAT) 1. Our previous study revealed that 18F-FIMP had a higher affinity for LAT1 than for LAT2 abundantly expressed even in normal cells. 18F-FIMP showed high accumulation in LAT1-positive tumor tissues and low accumulation in inflamed lesions in tumor-bearing mice. However, the affinity of 18F-FIMP for other amino acid transporters was not determined yet. Here, we aimed to determine whether 18F-FIMP has affinity for other tumor-related amino acid transporters, such as sodium- and chloride-dependent neutral and basic amino acid transporter B(0 +) (ATB0,+), alanine serine cysteine transporter 2 (ASCT2), and cystine/glutamate transporter (xCT). PROCEDURES: Cells overexpressing LAT1, ATB0,+, ASCT2, or xCT were established by the transfection of expression vectors for LAT1, ATB0,+, ASCT2, or xCT. Protein expression levels were determined by western blot and immunofluorescent analyses. Transport function was evaluated by a cell-based uptake assay using 18F-FIMP and 14C-labeled amino acids as substrates. RESULTS: Intense signals were observed only for expression vector-transfected cells on western blot and immunofluorescent analyses. These signals were strongly reduced by gene-specific small interfering ribonucleic acid treatment. The uptake values for each 14C-labeled substrate were significantly higher in the transfected cells than in the mock-transfected cells and were significantly inhibited by the corresponding specific inhibitors. The 18F-FIMP uptake values were significantly higher in the LAT1- and ATB0,+-overexpressing cells than in the corresponding mock cells, but no such increase was seen in the ASCT2- or xCT-overexpressing cells. These 18F-FIMP uptake values were significantly decreased by the specific inhibitors for LAT1- and ATB0,+. CONCLUSIONS: We demonstrated that 18F-FIMP has affinity not only for LAT1, but also for ATB0,+. Our results may be helpful for understanding the mechanisms of the whole-body distribution and tumor accumulation of 18F-FIMP.
    Apr. 2023, EJNMMI research, 13(1) (1), 36 - 36, English, International magazine
    Scientific journal

  • Shota Warashina, Hiroki Sato, Maki Zouda, Maiko Takahashi, Yasuhiro Wada, Toby Passioura, Hiroaki Suga, Yasuyoshi Watanabe, Kunio Matsumoto, Hidefumi Mukai
    Two-chain hepatocyte growth factor (tcHGF), the mature form of HGF, is associated with malignancy and anticancer drug resistance; therefore, its quantification is an important indicator for cancer diagnosis. In tumors, activated tcHGF hardly discharges into the systemic circulation, indicating that tcHGF is an excellent target for molecular imaging using positron emission tomography (PET). We recently discovered HGF-inhibitory peptide-8 (HiP-8) that binds specifically to human tcHGF with nanomolar affinity. The purpose of this study was to investigate the usefulness of HiP-8-based PET probes in human HGF knock-in humanized mice. 64Cu-labeled HiP-8 molecules were synthesized using a cross-bridged cyclam chelator, CB-TE1K1P. Radio-high-performance liquid chromatography-based metabolic stability analyses showed that more than 90% of the probes existed in intact form in blood at least for 15 min. In PET studies, significantly selective visualization of hHGF-overexpressing tumors versus hHGF-negative tumors was observed in double-tumor-bearing mice. The accumulation of labeled HiP-8 into the hHGF-overexpressing tumors was significantly reduced by competitive inhibition. In addition, the radioactivity and distribution of phosphorylated MET/HGF receptor were colocalized in tissues. These results demonstrate that the 64Cu-labeled HiP-8 probes are suitable for tcHGF imaging in vivo, and secretory proteins like tcHGF can be a target for PET imaging.
    Apr. 2023, Molecular pharmaceutics, 20(4) (4), 2029 - 2038, English, International magazine
    Scientific journal

  • Takashi Niwa, Tsuyoshi Tahara, Charles E. Chase, Francis G. Fang, Takayoshi Nakaoka, Satsuki Irie, Emi Hayashinaka, Yasuhiro Wada, Hidefumi Mukai, Kenkichi Masutomi, Yasuyoshi Watanabe, Yilong Cui, Takamitsu Hosoya
    The Chemical Society of Japan, Mar. 2023, Bulletin of the Chemical Society of Japan, 96(3) (3), 283 - 290, English
    Scientific journal

  • Tsuyoshi Tahara, Shuhei Takatani, Mieko Tsuji, Nina Shibata, Nami Hosaka, Michiko Inoue, Masahiro Ohno, Daiki Ozaki, Aya Mawatari, Yasuyoshi Watanabe, Hisashi Doi, Hirotaka Onoe
    Amino acid transporters are upregulated in many cancer cells, and system L amino acid transporters (LAT1-4), in particular, LAT1, which preferentially transports large, neutral, and branched side-chain amino acids, are considered a primary target for cancer positron emission tomography (PET) tracer development. Recently, we developed a 11C-labeled leucine analog, l-α-[5-11C]methylleucine ([5-11C]MeLeu), via a continuous two-step reaction of Pd0-mediated 11C-methylation and microfluidic hydrogenation. In this study, we evaluated the characteristics of [5-11C]MeLeu and also compared the sensitivity to brain tumors and inflammation with l-[11C]methionine ([11C]Met) to determine its potential for brain tumor imaging. Competitive inhibition experiments, protein incorporation, and cytotoxicity experiments of [5-11C]MeLeu were performed in vitro. Further, metabolic analyses of [5-11C]MeLeu were performed using a thin-layer chromatogram. The accumulation of [5-11C]MeLeu in tumor and inflamed regions of the brain was compared with [11C]Met and 11C-labeled (S)-ketoprofen methyl ester by PET imaging, respectively. Transporter assay with various inhibitors revealed that [5-11C]MeLeu is mainly transported via system L amino acid transporters, especially LAT1, into A431 cells. The protein incorporation assay and metabolic assay in vivo demonstrated that [5-11C]MeLeu was neither used for protein synthesis nor metabolized. These results indicate that MeLeu is very stable in vivo. Furthermore, the treatment of A431 cells with various concentrations of MeLeu did not change their viability, even at high concentrations (∼10 mM). In brain tumors, the tumor-to-normal ratio of [5-11C]MeLeu was more elevated than that of [11C]Met. However, the accumulation levels of [5-11C]MeLeu were lower than those of [11C]Met (the standardized uptake value (SUV) of [5-11C]MeLeu and [11C]Met was 0.48 ± 0.08 and 0.63 ± 0.06, respectively). In brain inflammation, no significant accumulation of [5-11C]MeLeu was observed at the inflamed brain area. These data suggested that [5-11C]MeLeu was identified as a stable and safe agent for PET tracers and could help detect brain tumors, which overexpress the LAT1 transporter.
    Mar. 2023, Molecular pharmaceutics, 20(3) (3), 1842 - 1849, English, International magazine
    Scientific journal

  • Satoshi Nozaki, Yuka Nakatani, Aya Mawatari, Nina Shibata, William E Hume, Emi Hayashinaka, Yasuhiro Wada, Hisashi Doi, Yasuyoshi Watanabe
    Several limitations of [18F]FDG have been reported, such as nonspecific uptake of inflammation foci. Moreover, [11C]MET has been found to accumulate in normal and inflammatory tissues as well as tumors. To increase specificity to tumor tissues, PET probes with tumor-specific molecular targets have been actively developed. [18F]FIMP was found to be highly accumulated in LAT1-positive tumors but not in inflamed tissue. The aim of this study was to explore whether [18F]FIMP can be used for the early-phase evaluation of radiotherapy accompanied by inflammation, and compare its effectiveness with those of [11C]MET and [18F]FDG. Tumor uptake of [18F]FIMP decreased at day 1 after irradiation, and remained low until day 14. Comparatively, that of [18F]FDG initially decreased at day 3 but was transiently elevated at day 7 and then decreased again at day 10. Decreased tumor uptake of [11C]MET was observed at day 10. In line with the uptake of [18F]FIMP, the ratio of Ki-67 immuno-positive cells in tumor tissues significantly decreased at day 1, 7, and 10 as compared with that in the control. These findings suggest that [18F]FIMP may be a PET probe involved in the early detection and prediction of radiotherapy efficacy, although further clarification is needed.
    Feb. 2023, Scientific reports, 13(1) (1), 1961 - 1961, English, International magazine
    Scientific journal

  • Maiko Takahashi, Erike Widyasari Sukowati, Shoko Nomura, Akari Kato, Kenji Mizuseki, Yasuyoshi Watanabe, Hidefumi Mukai
    Live bacterial therapeutics is gaining attention, especially for cancer therapy, because anaerobic bacteria selectively grow inside the solid tumours. However, the effect of tumour structure and bacterial characteristics on the pharmacokinetics of tumours is unclear; therefore, we aimed to elucidate the effects of tumour structure and types of bacteria on tumoral bacterial growth. Using six mouse xenograft models, including stroma-rich tumours similar to clinical tumours, and two models of live bacterial therapeutics, Salmonella typhimurium VNP20009 and Escherichia coli DH5α, we investigated bacterial growth and distribution in tumours after intravenous administration. Rapid growth of E. coli was observed in HCT116 and other tumours with few collagens, blood vessels not covered by mural cells, and a cancer cell area proliferated disorderly, whereas tumours with contrasting features, such as BxPC-3, showed lower bacterial growth and a limited intratumor distribution. Alternatively, Salmonella typhimurium VNP20009, when successfully proliferated (the probability was approximately 50%), grew to 108 colony forming units/g tissue even in BxPC-3 tumours, and its intratumor distribution was extensive. This study suggests that the development of new methods to modify tumour structure will be essential for the development of anti-tumour clinical therapies based on live bacterial therapeutics.
    Feb. 2023, Journal of drug targeting, 31(2) (2), 194 - 205, English, International magazine
    Scientific journal

  • Danxi Li, Di Hu, Yuta Ochi, Wakiko Arakaki, Aya Mawatari, Mika Shigeta, Yuping Wu, Emi Hayashinaka, Hiroyuki Neyama, Tsuyoshi Tahara, Yasuhiro Wada, Feng Li, Hisashi Doi, Yasuyoshi Watanabe, Yilong Cui
    INTRODUCTION: A series of symptoms, including fever, widespread pain, fatigue, and even ageusia, have frequently been reported in the context of various infections, such as COVID-19. Although the pathogenic mechanisms underlying an infection causing fever and pain have been well established, the mechanisms of fatigue induced by infection in specific brain regions remain unclear. METHODS: To elucidate whether and how the peripheral infection cause fatigue via regional neuroinflammation, we performed a brain-wide investigation of neuroinflammation in a peripheral pseudoinfection rat model using [18F]DPA-714 positron emission tomography (PET) imaging analysis, in which the polyriboinosinic: polyribocytidylic acid (poly I:C) was intraperitoneally injected. RESULTS: Transient fever lasting for several hours and subsequent suppression of spontaneous activity lasting a few days were induced by poly I:C treatment. Significant increase in plasma interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF)-α were observed at 2 and 4 h following poly I:C treatment. PET imaging analysis revealed that the brain uptake of [18F]DPA-714 was significantly increased in several brain regions one day after poly I:C treatment, such as the dorsal raphe (DR), parvicellular part of red nucleus (RPC), A5 and A7 noradrenergic nucleus, compared with the control group. The accumulation of [18F]DPA-714 in the DR, RPC and A5 was positively correlated with subsequent fatigue-like behavior, and that in the A7 tended to positively correlate with fever. DISCUSSION: These findings suggest that peripheral infection may trigger regional neuroinflammation, which may cause specific symptoms such as fatigue. A similar mechanism might be involved in COVID-19.
    2023, Frontiers in immunology, 14, 1261256 - 1261256, English, International magazine
    Scientific journal

  • Akane Yasuoka, Naoko Tsugawa, Chihiro Ura, Honami Ogasawara, Kiyoshi Tanaka, Kei Mizuno, Yasuyoshi Watanabe, Akiko Kuwabara
    Recent studies have described that vitamin D deficiency/insufficiency is associated with hypertension, insulin resistance, and dyslipidemia, which are major components of metabolic syndrome causing atherosclerosis. Therefore, we investigated the relationship between serum 25-hydroxyvitamin D [25(OH)D] concentration and atherosclerotic disease risk factors in healthy Japanese adults. In the present cross-sectional study, 1,177 subjects (348 males and 829 females) aged 20-72 y living in Japan (34.7-35.0ºN) were evaluated for vitamin D status by measuring serum 25(OH)D concentration. Atherosclerotic disease risk factors were defined as the presence of two or more of the following three risk factors: high blood pressure, dyslipidemia, and hyperglycemia. The percentages of vitamin D deficient and insufficient subjects were 33% and 46% in males and 59% and 32% in females, respectively. Subjects with atherosclerotic disease risk factors were significantly older and had higher BMI than those without it in both sexes. Male subjects with atherosclerotic disease risk factors had significantly lower physical activity and serum 25(OH)D concentration than those without it. In a logistic regression analysis adjusted for confounding factors, serum 25(OH)D concentration showed a significant inverse association with risk factors of atherosclerotic disease in males (OR=0.951, 95%CI: 0.906-0.998), but not in females. A covariance structure analysis also suggested that serum 25(OH)D level has a direct association with risk factors of atherosclerotic disease. In conclusion, we have demonstrated that low serum 25(OH)D level is a significant factor for increased atherosclerotic disease risk factors in males.
    2023, Journal of nutritional science and vitaminology, 69(3) (3), 176 - 183, English, Domestic magazine
    Scientific journal

  • Yilong Cui, Hiroyuki Neyama, Di Hu, Tianliang Huang, Emi Hayashinaka, Yasuhiro Wada, Yasuyoshi Watanabe
    Pain is an unpleasant subjective experience that is usually modified by complex multidimensional neuropsychological processes. Increasing numbers of neuroimaging studies in humans have characterized the hierarchical brain areas forming a pain matrix, which is involved in the different dimensions of pain components. Although mechanistic investigations have been performed extensively in rodents, the homologous brain regions involved in the multidimensional pain components have not been fully understood in the rodent brain. Herein, we successfully identified several brain regions activated in response to mechanical allodynia in neuropathic pain rat models using an alternative neuroimaging method based on 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography (FDG PET) scanning. Regions such as the medial prefrontal cortex, primary somatosensory cortex hindlimb region, and the centrolateral thalamic nucleus were identified. Moreover, brain activity in these regions was positively correlated with mechanical allodynia-related behavioral changes. These results suggest that FDG PET imaging in neuropathic pain model rats enables the evaluation of regional brain activity encoding the multidimensional pain aspect. It could thus be a fascinating tool to bridge the gap between preclinical and clinical investigations.
    MDPI AG, Dec. 2022, Biomedicines, 11(1) (1), 63 - 63, English, International magazine
    Scientific journal

  • Kohta Mohri, Kim Phuong Huynh Nhat, Maki Zouda, Shota Warashina, Yasuhiro Wada, Yasuyoshi Watanabe, Shunsuke Tagami, Hidefumi Mukai
    Microcin J25 (MccJ25), a lasso peptide, has a unique 3-D interlocked structure that provides high stability under acidic conditions, at high temperatures, and in the presence of proteases. In this study, we generated a positron emission tomography (PET) probe based on MccJ25 analog with an RGD motif and investigated their pharmacokinetics and utility for integrin αvβ3 imaging in tumors. The MccJ25 variant with an RGD motif in the loop region and a lysine substitution at the C-terminus (MccJ25(RGDF)GtoK) was produced in E. coli transfected with plasmid DNA containing the MccJ25 biosynthetic gene cluster (mcjABCD). [64Cu]Cu-MccJ25(RGDF)GtoK was synthesized using the C-terminal lysine labeled with copper-64 (t1/2 = 12.7 h) via a bifunctional chelator; it showed stability in 90% mouse plasma for 45 min. Using PET imaging for integrin αvβ3 positive U87MG tumor bearing mice, [64Cu]Cu-MccJ25(RGDF)GtoK could clearly distinguish the tumor, and its accumulation was significantly higher than that of MccJ25(GIGT)GtoK without the binding motif for integrin αvβ3. Furthermore, MccJ25(RGDF)GtoK enabled visualization of only U87MG tumors but not MCF-7 tumors with low integrin αvβ3 expression in double tumor-bearing mice. In ex vivo biodistribution analysis, the integrin αvβ3 non-specific accumulation of [64Cu]Cu-MccJ25(RGDF)GtoK was significantly lower in various tissues, except for the kidneys, as compared to the control probe ([64Cu]Cu-cyclic RGD peptide). These results of the present study indicate that 64Cu-labeling methods are appropriate for the synthesis of MccJ25-based PET probes, and [64Cu]Cu-MccJ25 variants are useful tools for cancer molecular imaging.
    Nov. 2022, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, 180, 106339 - 106339, English, International magazine
    [Refereed]
    Scientific journal

  • Kei Mizuno, Kyosuke Watanabe, Emi Yamano, Kyoko Ebisu, Kanako Tajima, Junzo Nojima, Yusuke Ohsaki, Shigeru Kabayama, Yasuyoshi Watanabe
    Chronic oxidative stress induces deterioration of health and a risk for the onset of various diseases. Previous clinical studies revealed that electrolyzed hydrogen water (EHW) is effective to reduce oxidative stress during hemodialysis in patients with chronic dialysis. In the present observational study, we investigated the antioxidant effects of a daily continuous intake of EHW in healthy adults. The concentrations of serum reactive oxygen metabolites-derived compounds (d-ROMs) and blood urea nitrogen in healthy volunteers (n = 64) who had a habit of intake over 500 mL/day of EHW at least 5 days a week for longer than 6 months were lower than those of age- and sex-matched controls (n = 470) without the habit of EHW intake. Oxidation stress index which the ratio between concentrations in d-ROMs and biological antioxidant potential was correlated with the serum concentration of high-sensitivity C-reactive protein or low-density lipoprotein cholesterol in the EHW group. These results suggest that the continuous intake of EHW induces antioxidant effects and may contribute to alleviate the risk of various oxidative stress-related dysfunctions and diseases in healthy adults.
    Nov. 2022, Heliyon, 8(11) (11), e11853, English, International magazine
    Scientific journal

  • Di Hu, Tianliang Huang, Mika Shigeta, Yuta Ochi, Shigeru Kabayama, Yasuyoshi Watanabe, Yilong Cui
    Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the digestive tract and is typically accompanied by characteristic symptoms, such as abdominal pain, diarrhea, and bloody stool, severely deteriorating the quality of the patient's life. Electrolyzed hydrogen water (EHW) has been shown to alleviate inflammation in several diseases, such as renal disease and polymyositis/dermatomyositis. To investigate whether and how daily EHW consumption alleviates abdominal pain, the most common symptom of IBD, we examined the antioxidative and anti-inflammatory effects of EHW in an IBD rat model, wherein colonic inflammation was induced by colorectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS). We found that EHW significantly alleviated TNBS-induced abdominal pain and tissue inflammation. Moreover, the production of proinflammatory cytokines in inflamed colon tissue was also decreased significantly. Meanwhile, the overproduction of reactive oxygen species (ROS), which is intricately involved in intestinal inflammation, was significantly suppressed by EHW. Additionally, expression of S100A9, an inflammatory biomarker of IBD, was significantly suppressed by EHW. These results suggest that the EHW prevented the overproduction of ROS due to its powerful free-radical scavenging ability and blocked the crosstalk between oxidative stress and inflammation, thereby suppressing colonic inflammation and alleviating abdominal pain.
    Oct. 2022, Nutrients, 14(21) (21), English, International magazine
    Scientific journal

  • Tatsuya Kida, Nobuaki Takahashi, Masayuki X Mori, Jiacheng H Sun, Hideto Oota, Kosuke Nishino, Takashi Okauchi, Yuta Ochi, Daisuke Kano, Ukihide Tateishi, Yasuyoshi Watanabe, Yilong Cui, Yasuo Mori, Hisashi Doi
    Transient receptor potential cation channel subfamily V member 1 (TRPV1)-targeted compounds were synthesized by modifying the structure of SB366791, a pharmaceutically representative TRPV1 antagonist. To avoid amide-iminol tautomerization, structurally supported N-methylated amides (i.e., 3-alkoxy-substitued N-meythylamide derivatives of SB366791) were evaluated using a Ca2+ influx assay, in which cells expressed recombinant TRPV1 in the presence of 1.0 μM capsaicin. The antagonistic activities of N-(3-methoxyphenyl)-N-methyl-4-chlorocinnamamide (2) (RLC-TV1004) and N-{3-(3-fluoropropoxy)phenyl}-N-methyl-4-chlorocinnamamide (4) (RLC-TV1006) were found to be approximately three-fold higher (IC50: 1.3 μM and 1.1 μM, respectively) than that of SB366791 (IC50: 3.7 μM). These results will help reinvigorate the potential of SB366791 in medicinal chemistry applications. The 3-methoxy and 3-fluoroalkoxy substituents were used to obtain radioactive [11C]methoxy- or [18F]fluoroalkoxy-incorporated tracers for in vivo positron emission tomography (PET). Using the 11C- or 18F-labeled derivatives, explorative PET imaging trials were performed in rats.
    Oct. 2022, RSC medicinal chemistry, 13(10) (10), 1197 - 1204, English, International magazine
    Scientific journal

  • Shota Warashina, Maki Zouda, Kohta Mohri, Yasuhiro Wada, Kazuya Maeda, Yasuyoshi Watanabe, Hidefumi Mukai
    We developed a method of labeling the surfaces of small extracellular vesicles (sEVs) with 64Cu using a cross-bridged, macrocyclic chelator (CB-TE1A1P) and applied to pharmacokinetics study with positron emission tomography (PET). After incubation in 20% plasma for 10 min, approximately a half of the 64Cu was desorbed from 64Cu-labeled sEVs purified by phosphate-buffered saline wash, suggesting partly weak interaction without coordinating to CB-TE1A1P. After subsequent purification with albumin, 64Cu desorption was greatly reduced, resulting in a radiochemical stability of 95.7%. Notably, labeling did not alter the physicochemical and biological properties of sEVs. After intravenous injection, 64Cu-labeled sEVs rapidly disappeared from the systemic blood circulation and accumulated mainly in the liver and spleen of macrophage-competent mice. In macrophage-depleted mice, 64Cu-labeled sEVs remained in the blood circulation for a longer period and gradually accumulated in the liver and spleen, suggesting mechanisms of hepatic and splenic accumulation other than macrophage-dependent phagocytosis. The comparison of tissue uptake clearance between macrophage-competent and macrophage-depleted mice suggests that macrophages contributed to 67% and 76% of sEV uptake in the liver and spleen, respectively. The application of this method in pharmacokinetics PET studies can be useful in preclinical and clinical research and the development of sEV treatment modalities.
    Aug. 2022, International journal of pharmaceutics, 624, 121968 - 121968, English, International magazine
    Scientific journal

  • Hiroyuki Neyama, Michiko Nishiyori, Yilong Cui, Yasuyoshi Watanabe, Hiroshi Ueda
    The intermittent cold stress-induced generalized pain response mimics the pathophysiological and pharmacotherapeutic features reported for fibromyalgia patients, including the presence of chronic generalized pain and female dominance. In addition, the intermittent cold stress-induced generalized pain is abolished in lysophosphatidic acid receptor type-1 knockout mice, as reported in many cases of neuropathic pain models. This study aimed to identify the brain loci involved in the intermittent cold stress generalized pain response and test their dependence on the lysophosphatidic acid receptor type-1. Positron emission tomography analyses using 2-deoxy-2-[18 F]fluoro-d-glucose in the presence of a pain stimulus showed that intermittent cold stress causes a significant increase in uptake in the ipsilateral regions, including the salience networking-related anterior cingulate cortex and insular cortex and the cognition-related hippocampus. A significant decrease was observed in the default mode network-related posterior cingulate cortex. Almost these intermittent cold stress-induced changes were abolished in lysophosphatidic acid receptor type-1 knockout mice. There results suggest that the intermittent cold stress-induced generalized pain response is mediated by the lysophosphatidic acid receptor type-1 in specific brain loci related to salience networking and cognition, which may lead to further developments in the treatment of fibromyalgia.
    Aug. 2022, The European journal of neuroscience, 56(3) (3), 4224 - 4233, English, International magazine
    [Refereed]
    Scientific journal

  • Yuta Ochi, Di Hu, Danxi Li, Wakiko Arakaki, Aya Mawatari, Mika Shigeta, Yuping Wu, Emi Hayashinaka, Hiroyuki Neyama, Tsuyoshi Tahara, Yasuhiro Wada, Feng Li, Hisashi Doi, Yasuyoshi Watanabe, Yilong Cui
    Abstract A series of symptoms, including fever, widespread pain, fatigue, and even ageusia, have frequently been reported in the context of various infections, such as COVID-19. Although the pathogenic mechanisms underlying an infection causing fever and pain have been well established, the mechanisms of fatigue induced by infection remain unclear. To elucidate whether and how the peripheral infection cause fatigue via regional neuroinflammation, we performed a brain-wide investigation of neuroinflammation in a peripheral pseudoinfection rat model using [18F]DPA-714 positron emission tomography (PET) imaging analysis, in which the polyriboinosinic: polyribocytidylic acid (poly I:C) was intraperitoneally injected. Consistent with previous reports, transient fever lasting for several hours and subsequent suppression of spontaneous activity lasting a few days were induced by poly I:C treatment. Significant increase in plasma interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF)-α were observed at 2 and 4 h following poly I:C treatment. PET imaging analysis revealed that the brain uptake of [18F]DPA-714 was significantly increased in several brain regions one day after poly I:C treatment, such as the dorsal raphe (DR), parvicellular part of red nucleus (RPC), A5 and A7 noradrenergic nucleus, compared with the control group. The accumulation of [18F]DPA-714 in the DR, RPC and A5 was positively correlated with the fatigue-like behavior, and that in the A7 tended to positively correlate with fever. These findings suggest that peripheral infection may trigger regional neuroinflammation, which may cause specific symptoms such as fatigue. A similar mechanism might be involved in COVID-19.
    Research Square Platform LLC, Jul. 2022

  • Tomonori Fukuchi, Takashi Niwa, Takamitsu Hosoya, Yasuyoshi Watanabe
    Physical Society of Japan, Jun. 2022, Journal of the Physical Society of Japan, 91(6) (6), English
    [Refereed]
    Scientific journal

  • 電解水素水の抗疲労・抗ストレス・抗酸化効果
    渡辺 恭良, 水野 敬, 崔 翼龍, 和田 智之, 高橋 佳代, 水間 広, 渡辺 恭介, 樺山 繁, 森澤 紳勝
    日本疲労学会, Jun. 2022, 日本疲労学会誌, 18(1) (1), 40 - 40, Japanese

  • 疲労の慢性化と神経・内分泌・免疫機能の破綻について
    崔 翼龍, 胡 迪, 渡辺 恭良
    日本疲労学会, Jun. 2022, 日本疲労学会誌, 18(1) (1), 42 - 42, Japanese

  • Takayoshi Nakaoka, Ken-Ichi Kaneko, Satsuki Irie, Aya Mawatari, Ami Igesaka, Yuta Uetake, Hidenori Ochiai, Takashi Niwa, Emi Yamano, Yasuhiro Wada, Masaaki Tanaka, Kohei Kotani, Hideki Kawahata, Joji Kawabe, Yukio Miki, Hisashi Doi, Takamitsu Hosoya, Maeda Kazuya, Hiroyuki Kusuhara, Yuichi Sugiyama, Yasuyoshi Watanabe
    It is widely accepted that uptake and efflux transporters on clearance organs play crucial roles in drug disposition. Although in vitro transporter assay system can identify the intrinsic properties of the target transporters, it is not so easy to precisely predict in vivo pharmacokinetic parameters from in vitro data. Positron emission tomography (PET) imaging is a useful tool to directly assess the activity of drug transporters in humans. We recently developed a practical synthetic method for fluorine-18-labeled pitavastatin ([18F]PTV) as a PET probe for quantitative evaluation of hepatobiliary transport. In the present study, we conducted clinical PET imaging with [18F]PTV and compared the pharmacokinetic properties of the probe for healthy subjects with or without rifampicin pretreatment. Rifampicin pretreatment significantly suppressed the hepatic maximum concentration and biliary excretion of the probe to 52% and 34% of the control values, respectively. Rifampicin treatment markedly decreased hepatic uptake clearance (21% of the control), and moderately canalicular efflux clearance with regard to hepatic concentration (52% of the control). These results demonstrate that [18F]PTV is a useful probe for clinical investigation of the activities of hepatobiliary uptake/efflux transporters in humans.
    Jun. 2022, Drug metabolism and pharmacokinetics, 44, 100449 - 100449, English, International magazine
    Scientific journal

  • Ken-Ichi Kaneko, Satsuki Irie, Aya Mawatari, Ami Igesaka, Di Hu, Takayoshi Nakaoka, Emi Hayashinaka, Yasuhiro Wada, Hisashi Doi, Yasuyoshi Watanabe, Yilong Cui
    BACKGROUND: Most antiepileptic drug therapies are symptomatic and adversely suppress normal brain function by nonspecific inhibition of neuronal activity. In recent times, growing evidence has suggested that neuroinflammation triggered by epileptic seizures might be involved in the pathogenesis of epilepsy. Although the potential effectiveness of anti-inflammatory treatment for curing epilepsy has been extensively discussed, the limited quantitative data regarding spatiotemporal characteristics of neuroinflammation after epileptic seizures makes it difficult to be realized. We quantitatively analyzed the spatiotemporal changes in neuroinflammation in the early phase after status epilepticus in rats, using translocator protein (TSPO) positron emission tomography (PET) imaging, which has been widely used for the quantitative evaluation of neuroinflammation in several animal models of CNS disease. METHODS: The second-generation TSPO PET probe, [18F]DPA-714, was used for brain-wide quantitative analysis of neuroinflammation in the brains of rats, when the status epilepticus was induced by subcutaneous injection of kainic acid (KA, 15 mg/kg) into those rats. A series of [18F]DPA-714 PET scans were performed at 1, 3, 7, and 15 days after status epilepticus, and the corresponding histological changes, including activation of microglia and astrocytes, were confirmed by immunohistochemistry. RESULTS: Apparent accumulation of [18F]DPA-714 was observed in several KA-induced epileptogenic regions, such as the amygdala, piriform cortex, ventral hippocampus, mediodorsal thalamus, and cortical regions 3 days after status epilepticus, and was reversibly displaced by unlabeled PK11195 (1 mg/kg). Consecutive [18F]DPA-714 PET scans revealed that accumulation of [18F]DPA-714 was focused in the KA-induced epileptogenic regions from 3 days after status epilepticus and was further maintained in the amygdala and piriform cortex until 7 days after status epilepticus. Immunohistochemical analysis revealed that activated microglia but not reactive astrocytes were correlated with [18F]DPA-714 accumulation in the KA-induced epileptogenic regions for at least 1 week after status epilepticus. CONCLUSIONS: These results indicate that the early spatiotemporal characteristics of neuroinflammation quantitatively evaluated by [18F]DPA-714 PET imaging provide valuable evidence for developing new anti-inflammatory therapies for epilepsy. The predominant activation of microglia around epileptogenic regions in the early phase after status epilepticus could be a crucial therapeutic target for curing epilepsy.
    Jun. 2022, European journal of nuclear medicine and molecular imaging, 49(7) (7), 2265 - 2275, English, International magazine
    Scientific journal

  • Kai Zhang, Hiroshi Mizuma, Yuka Nakatani, Yousuke Kanayama, Kayo Takahashi, Yoshino Matsumoto, Yasuhiro Wada, Kayo Onoe, Shino Owada, Emi Hayashinaka, Yuping Wu, Xiaohui Zhang, Mei Tian, Hong Zhang, Yasuyoshi Watanabe
    PURPOSE: To investigate the in vivo neurofunctional changes and therapeutic effects of young blood plasma (YBP) in aged mice, as well as the molecular mechanisms underlying the therapeutic effects of YBP ex vivo and in vitro. METHODS: Aged C57/BL6 mice received systemic administrations of phosphate-buffered saline (PBS) or YBP twice a week, for 4 weeks. In vivo 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG PET) under conscious state and cognitive behavioural tests were performed after 4-week treatment. In addition, an in vitro senescent model was established, and the expressions of key cognition-associated proteins and/or the alterations of key neuronal pathways were analysed in both brain tissues and cultured cells. RESULTS: Aged mice treated with YBP demonstrated higher glucose metabolism in the right hippocampus and bilateral somatosensory cortices, and lower glucose metabolism in the right bed nucleus of stria terminalis and left cerebellum. YBP treatment exerted beneficial effects on the spatial and long-term social recognition memory, and significantly increased the expressions of several cognition-related proteins and altered the key neuronal signalling pathways in the hippocampus and somatosensory cortex. Further in vitro studies suggested that YBP but not aged blood plasma significantly upregulated the expressions of several cognition-associated proteins. CONCLUSION: Our results highlight the role of the hippocampus and somatosensory cortex in YBP-induced beneficial effects on recognition memory in aged mice. 18F-FDG PET imaging under conscious state provides a new avenue for exploring the mechanisms underlying YBP treatment against age-related cognitive decline.
    SPRINGER, Apr. 2022, European journal of nuclear medicine and molecular imaging, 49(5) (5), 1456 - 1469, English, International magazine
    Scientific journal

  • Satoshi Nozaki, Yuka Nakatani, Aya Mawatari, William E Hume, Yasuhiro Wada, Akira Ishii, Masaaki Tanaka, Naohiro Tsuyuguchi, Hisashi Doi, Yasuyoshi Watanabe
    In the first-in-human PET study, we evaluated the biodistribution and tumor accumulation of the novel PET probe, (S)-2-amino-3-[3-(2-18F-fluoroethoxy)-4-iodophenyl]-2-methylpropanoic acid (18F-FIMP), which targets the tumor-related L-type amino acid transporter 1 (LAT1), and compared it with L-[methyl-11C]methionine (11C-MET) and 2-Deoxy-2-18F-fluoro-D-glucose (18F-FDG). 18F-FIMP biodistribution was revealed by whole-body and brain scans in 13 healthy controls. Tumor accumulation of 18F-FIMP was evaluated in 7 patients with a brain tumor, and compared with those of 11C-MET and 18F-FDG. None of the subjects had significant problems due to probe administration, such as adverse effects or abnormal vital signs. 18F-FIMP was rapidly excreted from the kidneys to the urinary bladder. There was no characteristic physiological accumulation in healthy controls. 18F-FIMP PET resulted in extremely clear images in patients with suspected glioblastoma compared with 11C-MET and 18F-FDG. 18F-FIMP could be a useful novel PET probe for LAT1-positive tumor imaging including glioblastoma.
    Mar. 2022, Biochemical and biophysical research communications, 596, 83 - 87, English, International magazine
    Scientific journal

  • Mei Tian, A Cahid Civelek, Ignasi Carrio, Yasuyoshi Watanabe, Keon Wook Kang, Koji Murakami, Valentina Garibotto, John O Prior, Henryk Barthel, Rui Zhou, Haifeng Hou, Xiaofeng Dou, Chentao Jin, Chuantao Zuo, Hong Zhang
    PURPOSE: Positron emission tomography (PET) with the first and only tau targeting radiotracer of 18F-flortaucipir approved by FDA has been increasingly used in depicting tau pathology deposition and distribution in patients with cognitive impairment. The goal of this international consensus is to help nuclear medicine practitioners procedurally perform 18F-flortaucipir PET imaging. METHOD: A multidisciplinary task group formed by experts from various countries discussed and approved the consensus for 18F-flortaucipir PET imaging in Alzheimer's disease (AD), focusing on clinical scenarios, patient preparation, and administered activities, as well as image acquisition, processing, interpretation, and reporting. CONCLUSION: This international consensus and practice guideline will help to promote the standardized use of 18F-flortaucipir PET in patients with AD. It will become an international standard for this purpose in clinical practice.
    Feb. 2022, European journal of nuclear medicine and molecular imaging, 49(3) (3), 895 - 904, English, International magazine
    Scientific journal

  • Kayo Takahashi, Takamitsu Hosoya, Kayo Onoe, Tomoko Mori, Shusaku Tazawa, Aya Mawatari, Yasuhiro Wada, Yumiko Watanabe, Hisashi Doi, Yasuyoshi Watanabe
    Aromatase is an estrogen synthetic enzyme that plays important roles in brain functions. To quantify aromatase expression in the brain by positron emission tomography (PET), we had previously developed [11C]cetrozole, which showed high specificity and affinity. To develop more efficient PET tracer(s) for aromatase imaging, we synthesized three analogs of cetrozole. We synthesized meta-cetrozole, nitro-cetrozole, and iso-cetrozole, and prepared the corresponding 11C-labeled tracers. The inhibitory activities of these three analogs toward aromatase were evaluated using marmoset placenta, and PET imaging of brain aromatase was performed using the 11C-labeled tracers in monkeys. The most promising analog in the monkey study, iso-cetrozole, was evaluated in the human PET study. The highest to lowest inhibitory activity of the analogs toward aromatase in the microsomal fraction from marmoset placenta was in the following order: iso-cetrozole, nitro-cetrozole, cetrozole, and meta-cetrozole. This order showed good agreement with the order of the binding potential (BP) of each 11C-labeled analog to aromatase in the rhesus monkey brain. A human PET study using [11C]iso-analog showed a similar distribution pattern of binding as that of [11C]cetrozole. The time-activity curves showed that elimination of [11C]iso-cetrozole from brain tissue was faster than that of 11C-cetrozole, indicating more rapid metabolism of [11C]iso-cetrozole. [11C]Cetrozole has preferable metabolic stability for brain aromatase imaging in humans, although [11C]iso-cetrozole might also be useful to measure aromatase level in living human brain because of its high binding potential.
    Dec. 2021, Scientific reports, 11(1) (1), 23623 - 23623, English, International magazine
    Scientific journal

  • Shuhei Takatani, Tsuyoshi Tahara, Mieko Tsuji, Daiki Ozaki, Nina Shibata, Yoshinobu Hashizume, Masaaki Suzuki, Hirotaka Onoe, Yasuyoshi Watanabe, Hisashi Doi
    The efficient synthesis of L-[5-11 C]leucine and L-α-[5-11 C]methylleucine has been investigated using a continuous two-step sequence of rapid reactions consisting of Pd0 -mediated 11 C-methylation and microfluidic hydrogenation. The synthesis of L-[5-11 C]leucine and L-α-[5-11 C]methylleucine was accomplished within 40 min with a decay-corrected radiochemical yield of 15-38 % based on [11 C]CH3 I, radiochemical purity of 95-99 %, and chemical purity of 95-99 %. The Pd impurities in the injectable solution measured using inductively coupled plasma mass spectrometry met the international criteria for human use. Positron emission tomography scanning after an intravenous injection of L-[5-11 C]leucine or L-α-[5-11 C]methyl leucine in A431 tumor-bearing mice was performed. As a result, L-α-[5-11 C]methylleucine was found to be a potentially useful probe for visualizing the tumor. Tissue distribution analysis showed that the accumulation value of L-α-[5-11 C]methylleucine in tumor tissue was high [12±3% injected dose/g tissue (%ID/g)].
    Nov. 2021, ChemMedChem, 16(21) (21), 3271 - 3279, English, International magazine
    Scientific journal

  • Kai Zhang, Hiroshi Mizuma, Xiaohui Zhang, Kayo Takahashi, Chentao Jin, Fahuan Song, Yuanxue Gao, Yousuke Kanayama, Yuping Wu, Yuting Li, Lijuan Ma, Mei Tian, Hong Zhang, Yasuyoshi Watanabe
    Normal brain aging is commonly associated with neural activity alteration, β-amyloid (Aβ) deposition, and tau aggregation, driving a progressive cognitive decline in normal elderly individuals. Positron emission tomography (PET) with radiotracers targeting these age-related changes has been increasingly employed to clarify the sequence of their occurrence and the evolution of clinically cognitive deficits. Herein, we reviewed recent literature on PET-based imaging of normal human brain aging in terms of neural activity, Aβ, and tau. Neural hypoactivity reflected by decreased glucose utilization with PET imaging has been predominately reported in the frontal, cingulate, and temporal lobes of the normal aging brain. Aβ PET imaging uncovers the pathophysiological association of Aβ deposition with cognitive aging, as well as the potential mechanisms. Tau-associated cognitive changes in normal aging are likely independent of but facilitated by Aβ as indicated by tau and Aβ PET imaging. Future longitudinal studies using multi-radiotracer PET imaging combined with other neuroimaging modalities, such as magnetic resonance imaging (MRI) morphometry, functional MRI, and magnetoencephalography, are essential to elucidate the neuropathological underpinnings and interactions in normal brain aging.
    SPRINGER, Nov. 2021, European journal of nuclear medicine and molecular imaging, 48(12) (12), 3859 - 3871, English, International magazine
    Scientific journal

  • Mei Tian, Yasuyoshi Watanabe, Keon Wook Kang, Koji Murakami, Arturo Chiti, Ignasi Carrio, A Cahid Civelek, Jianhua Feng, Yuankai Zhu, Rui Zhou, Shuang Wu, Junming Zhu, Yao Ding, Kai Zhang, Hong Zhang
    PURPOSE: Positron emission tomography (PET) with 18F-fluorodeoxyglucose ([18F]-FDG) has been increasingly applied in precise localization of epileptogenic focus in epilepsy patients, including pediatric patients. The aim of this international consensus is to provide the guideline and specific considerations for [18F]-FDG PET in pediatric patients affected by epilepsy. METHODS: An international, multidisciplinary task group is formed, and the guideline for brain [18F]-FDG PET/CT in pediatric epilepsy patients has been discussed and approved, which include but not limited to the clinical indications, patient preparation, radiopharmaceuticals and administered activities, image acquisition, image processing, image interpretation, documentation and reporting, etc. CONCLUSION: This is the first international consensus and practice guideline for brain [18F]-FDG PET/CT in pediatric epilepsy patients. It will be an international standard for this purpose in clinical practice.
    Nov. 2021, European journal of nuclear medicine and molecular imaging, 48(12) (12), 3827 - 3834, English, International magazine
    Scientific journal

  • 疲労の慢性化およびその分子神経メカニズムについて
    崔 翼龍, 胡 迪, 渡辺 恭良
    日本疲労学会, Jul. 2021, 日本疲労学会誌, 17(1) (1), 27 - 27, Japanese

  • 慢性疲労動物を用いた疲労の慢性化機序解析
    胡 迪, 李 丹渓, 重田 美香, 越智 祐太, 渡辺 恭良, 崔 翼龍
    日本疲労学会, Jul. 2021, 日本疲労学会誌, 17(1) (1), 30 - 30, Japanese

  • 抗疲労・健康と電解水素水
    樺山 繁, 中山 昌明, 崔 翼龍, 渡辺 恭良
    日本疲労学会, Jul. 2021, 日本疲労学会誌, 17(1) (1), 62 - 62, Japanese

  • 筋痛性脳脊髄炎/慢性疲労症候群の脳内炎症と病態関連バイオマーカー
    渡辺 恭良, 福田 早苗, 水野 敬, 田中 邦彦, 尾上 嘉代, 和田 康弘, 野島 順三, 中富 康仁, 山口 浩二, 倉恒 弘彦
    日本疲労学会, Jul. 2021, 日本疲労学会誌, 17(1) (1), 35 - 35, Japanese
    [Refereed]
    Scientific journal

  • 疲労の慢性化およびその分子神経メカニズムについて
    崔 翼龍, 胡 迪, 渡辺 恭良
    日本疲労学会, Jul. 2021, 日本疲労学会誌, 17(1) (1), 27 - 27, Japanese

  • 慢性疲労動物を用いた疲労の慢性化機序解析
    胡 迪, 李 丹渓, 重田 美香, 越智 祐太, 渡辺 恭良, 崔 翼龍
    日本疲労学会, Jul. 2021, 日本疲労学会誌, 17(1) (1), 30 - 30, Japanese

  • 抗疲労・健康と電解水素水
    樺山 繁, 中山 昌明, 崔 翼龍, 渡辺 恭良
    日本疲労学会, Jul. 2021, 日本疲労学会誌, 17(1) (1), 62 - 62, Japanese

  • Kai Zhang, Yujie Sun, Shuang Wu, Min Zhou, Xiaohui Zhang, Rui Zhou, Tingting Zhang, Yuanxue Gao, Ting Chen, Yao Chen, Xin Yao, Yasuyoshi Watanabe, Mei Tian, Hong Zhang
    Systematic imaging can be broadly defined as the systematic identification and characterization of biological processes at multiple scales and levels. In contrast to "classical" diagnostic imaging, systematic imaging emphasizes on detecting the overall abnormalities including molecular, functional, and structural alterations occurring during disease course in a systematic manner, rather than just one aspect in a partial manner. Concomitant efforts including improvement of imaging instruments, development of novel imaging agents, and advancement of artificial intelligence are warranted for achievement of systematic imaging. It is undeniable that scientists and radiologists will play a predominant role in directing this burgeoning field. This article introduces several recent developments in imaging modalities and nanoparticles-based imaging agents, and discusses how systematic imaging can be achieved. In the near future, systematic imaging which combines multiple imaging modalities with multimodal imaging agents will pave a new avenue for comprehensive characterization of diseases, successful achievement of image-guided therapy, precise evaluation of therapeutic effects, and rapid development of novel pharmaceuticals, with the final goal of improving human health-related outcomes.
    SPRINGER, Jun. 2021, European journal of nuclear medicine and molecular imaging, 48(6) (6), 1736 - 1758, English, International magazine
    Scientific journal

  • Yasuyoshi Watanabe, Aya Mawatari, Kazuki Aita, Yuzuru Sato, Yasuhiro Wada, Takayoshi Nakaoka, Kayo Onoe, Emi Yamano, Go Akamatsu, Akihito Ohnishi, Keiji Shimizu, Masahiro Sasaki, Hisashi Doi, Michio Senda
    UNLABELLED: Vitamine B1 thiamine is an essential component for glucose metabolism and energy production. The disulfide derivative, thiamine tetrahydrofurfuryl disulfide (TTFD), is more absorbent compared to readily-available water-soluble thiamine salts since it does not require the rate-limiting transport system required for thiamine absorption. However, the detailed pharmacokinetics of thiamine and TTFD under normal and pathological conditions were not clarified yet. Recently, 11C-labeled thiamine and TTFD were synthesized by our group, and their pharmacokinetics were investigated by PET imaging in normal rats. In this study, to clarify the whole body pharmacokinetics of [11C]TTFD in human healthy volunteers, we performed first-in-human PET imaging study with [11C]TTFD, along with radiation dosimetry of [11C]TTFD in humans. METHODS: Synthesis of [11C]TTFD was improved for clinical study. Dynamic whole-body PET images were acquired on three young male normal subjects after intravenous injection of [11C]TTFD. VOIs were defined for source organs on the PET images to measure time-course of [11C]TTFD uptake as percentage injected dose and the number of disintegrations for each organ. Radiation dosimetry was calculated with OLINDA/EXM. RESULTS: We succeeded in developing the improved synthetic method of [11C]TTFD for the first-in-human PET study. In the whole body imaging, uptake of [11C]TTFD by various tissues was almost plateaued at 10 min after intravenous injection, afterward gradually increased for the brain and urinary bladder (urine). %Injected dose was high in the liver, kidney, urinary bladder, heart, spine, brain, spleen, pancreas, stomach, and salivary glands, in this order. %Injected dose per gram of tissue was high also in the pituitary. By dosimetry, the effective radiation dose of [11C]TTFD calculated was 5.5 μSv/MBq (range 5.2-5.7). CONCLUSION: Novel synthetic method enabled clinical PET study with [11C]TTFD, which is a safe PET tracer with a dosimetry profile comparable to other common 11C-PET tracers. Pharmacokinetics of TTFD in the pharmacological dose and at different nutritional states could be further investigated by future quantitative PET studies. Noninvasive in vivo PET imaging for pathophysiology of thiamine-related function may provide diagnostic evidence of novel information about vitamin B1 deficiency in human tissues.
    May 2021, Biochemical and biophysical research communications, 555, 7 - 12, English, International magazine
    Scientific journal

  • Yasuyoshi Watanabe, Aya Mawatari, Kazuki Aita, Yuzuru Sato, Yasuhiro Wada, Takayoshi Nakaoka, Kayo Onoe, Emi Yamano, Go Akamatsu, Akihito Ohnishi, Keiji Shimizu, Masahiro Sasaki, Hisashi Doi, Michio Senda
    May 2021, Biochemical and biophysical research communications, 555, 215 - 215, English, International magazine

  • 擬似ウイルス感染モデルラットを用いた脳内炎症のPETイメージング
    崔 翼龍, 越智 祐太, 新垣 和貴子, 胡 迪, 李 丹渓, 重田 美香, 和田 康弘, 土居 久志, 渡辺 恭良
    日本分子イメージング学会, May 2021, JSMI Report, 14(2) (2), 126 - 126, Japanese

  • 擬似ウイルス感染モデルラットを用いた脳内炎症のPETイメージング
    崔 翼龍, 越智 祐太, 新垣 和貴子, 胡 迪, 李 丹渓, 重田 美香, 和田 康弘, 土居 久志, 渡辺 恭良
    日本分子イメージング学会, May 2021, JSMI Report, 14(2) (2), 126 - 126, Japanese

  • Kenward Vong, Tsuyoshi Tahara, Sayaka Urano, Igor Nasibullin, Kazuki Tsubokura, Yoichi Nakao, Almira Kurbangalieva, Hirotaka Onoe, Yasuyoshi Watanabe, Katsunori Tanaka
    This study presents the early framework of selective cell tagging (SeCT) therapy, which is the concept of preferentially labeling specific cells in vivo with chemical moieties that can elicit a therapeutic response. Using glycosylated artificial metalloenzyme (GArM)-based protein labeling, this study reports two separate functional strategies. In one approach, early tumor onset can be suppressed by tagging cancer cells in living mice with an integrin-blocking cyclic-Arg-Gly-Asp (cRGD) moiety, thereby disrupting cell adhesion onto the extracellular matrix. In another approach, tumor growth in mice can be reduced by tagging with a cytotoxic doxorubicin moiety. Subsequent cell death occurs following internalization and drug release. Overall, experiments have shown that mouse populations receiving the mixture of SeCT labeling reagents exhibited a significant delay/reduction in tumor onset and growth compared with controls. Highlighting its adaptability, this work represents a foundational step for further development of SeCT therapy and its potential therapeutic applications.
    AMER ASSOC ADVANCEMENT SCIENCE, Apr. 2021, Science advances, 7(17) (17), English, International magazine
    Scientific journal

  • Danxi Li, Di Hu, Mika Shigeta, Yuta Ochi, Yasuyoshi Watanabe, Feng Li, Yilong Cui
    Chronic fatigue syndrome (CFS) is characterized by long-lasting fatigue, and a range of symptoms, and is involved in homeostasis disruption. CFS patients frequently complain of low grade fever or chill even under normal body temperature indicating that thermosensory or thermoregulatory functions might be disturbed in CFS. However, little is known about the detailed mechanisms. To elucidate whether and how thermoregulatory function was altered during the development of chronic fatigue, we investigated temporal changes in body temperature with advance of fatigue accumulation in a chronic fatigue rat model using a wireless transponder. Our findings demonstrated that the body temperature was adaptively increased in response to fatigue loading in the early phase, but unable to retain in the late phase. The tail heat dissipation was often observed and the frequency of tail heat dissipation gradually increased initially, then decreased. In the late phase of fatigue loading, the body temperature for the tail heat dissipation phase decreased to a value lower than that for the non-dissipation phase. These results suggest that adaptive changes in thermoregulatory function occurred with fatigue progression, but this system might be disrupted by long-lasting fatigue, which may underlie the mechanism of fatigue chronification.
    Apr. 2021, Neuroscience research, 165, 45 - 50, English, International magazine
    [Refereed]
    Scientific journal

  • Emi Yamano, Yasuyoshi Watanabe, Yosky Kataoka
    Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a persistent and unexplained pathological state characterized by exertional and severely debilitating fatigue, with/without infectious or neuropsychiatric symptoms, and with a minimum duration of 6 consecutive months. Its pathogenesis is not fully understood. There are no firmly established diagnostic biomarkers or treatment, due to incomplete understanding of the etiology of ME/CFS and diagnostic uncertainty. Establishing a biomarker for the objective diagnosis is urgently needed to treat a lot of patients. Recently, research on ME/CFS using metabolome analysis methods has been increasing. Here, we overview recent findings concerning the metabolic features in patients with ME/CFS and the animal models which contribute to the development of diagnostic biomarkers for ME/CFS and its treatment. In addition, we discuss future perspectives of studies on ME/CFS.
    Mar. 2021, International journal of molecular sciences, 22(7) (7), English, International magazine
    Scientific journal

  • Di Hu, Danxi Li, Mika Shigeta, Yuta Ochi, Takashi Okauchi, Hiroyuki Neyama, Shigeru Kabayama, Yasuyoshi Watanabe, Yilong Cui
    Reactive oxygen species (ROS) are highly reactive and directly attack surrounding biomolecules to deteriorate cellular and tissue functions. Meanwhile, ROS also serve as signaling mediators to upregulate pro-inflammatory cytokine expression via activation of the nuclear factor kappa B signaling pathway, and the increased pro-inflammatory cytokines trigger respiratory burst of inflammatory cells that further accelerates ROS production in the inflamed tissue. Such crosstalk between ROS and inflammatory responses leads to a chain reaction of negativity, and cause progression of several chronic pathologies. Since molecular hydrogen is known to preferentially remove cytotoxic hydroxyl radicals and peroxynitrites, and to prevent cell and tissue damage, we here examined whether electrolyzed hydrogen water (EHW) enriched with molecular hydrogen and reactive hydrogen storing platinum nanoparticles dissolved from an electrode could alleviate oxidative stress and inflammation induced by continuous stress challenges. Five-day continuous stress loading to rats elevated reactive oxygen metabolites-derived compounds (d-ROMs), interleukin (IL)-1β, and adrenocorticotropic hormone (ACTH) levels and decreased the biological antioxidant potential (BAP) level. Drinking EHW during 5-day continuous stress loading significantly alleviated all of these changes. The results suggest that EHW could suppress stress-response-associated oxidative stress and IL-1β level elevation in vivo, and that drinking of EHW is effective for controlling stress responses via its antioxidant potential.
    Jan. 2021, Biochemical and biophysical research communications, 535, 1 - 5, English, International magazine
    Scientific journal

  • Hidefumi Mukai, Yasuyoshi Watanabe
    Recent progress in radiolabeling of macro- and middle-sized molecular probes has been extending possibilities to use PET molecular imaging for dynamic application to drug development and therapeutic evaluation. Theranostics concept also accelerated the use of macro- and middle-sized molecular probes for sharpening the contrast of proper target recognition even the cellular types/subtypes and proper selection of the patients who should be treated by the same molecules recognition. Here, brief summary of the present status of immuno-PET, and then further development of advanced technologies related to immuno-PET, peptidic PET probes, and nucleic acids PET probes are described.
    Jan. 2021, Nuclear medicine and biology, 92, 156 - 170, English, International magazine
    Scientific journal

  • Shunsuke Minusa, Kei Mizuno, Daichi Ojiro, Takeshi Tanaka, Hiroyuki Kuriyama, Emi Yamano, Hirohiko Kuratsune, Yasuyoshi Watanabe
    Increasing road crashes related to occupational drivers' deteriorating health has become a social problem. To prevent road crashes, warnings and predictions of increased crash risk based on drivers' conditions are important. However, in on-road driving, the relationship between drivers' physiological condition and crash risk remains unclear due to difficulties in the simultaneous measurement of both. This study aimed to elucidate the relationship between drivers' physiological condition assessed by autonomic nerve function (ANF) and an indicator of rear-end collision risk in on-road driving. Data from 20 male truck drivers (mean ± SD, 49.0±8.2 years; range, 35-63 years) were analyzed. Over a period of approximately three months, drivers' working behavior data, such as automotive sensor data, and their ANF data were collected during their working shift. Using the gradient boosting decision tree method, a rear-end collision risk index was developed based on the working behavior data, which enabled continuous risk quantification. Using the developed risk index and drivers' ANF data, effects of their physiological condition on risk were analyzed employing a logistic quantile regression method, which provides wider information on the effects of the explanatory variables, after hierarchical model selection. Our results revealed that in on-road driving, activation of sympathetic nerve activity and inhibition of parasympathetic nerve activity increased each quantile of the rear-end collision risk index. The findings suggest that acute stress-induced drivers' fatigue increases rear-end collision risk. Hence, in on-road driving, drivers' physiological condition monitoring and ANF-based stress warning and relief system can contribute to promoting the prevention of rear-end truck collisions.
    2021, PloS one, 16(10) (10), e0258892, English, International magazine
    Scientific journal

  • Shoko Nomura, Maiko Takahashi, Akari Hashiba Kato, Yasuhiro Wada, Yasuyoshi Watanabe, Fumiyoshi Yamashita, Hidefumi Mukai
    Biosorption-based bacterial 64Cu-labeling and its application in pharmacokinetic positron-emission tomography (PET) were investigated. Both gram-positive and gram-negative bacteria were efficiently labeled with [64Cu]Cu2+ ion in saline at room temperature within 5 min. The labeling ratio for Escherichia coli drastically decreased with trypsin pretreatment and the co-presence of excess Cu2+ ion, indicating the existence of specific Cu2+ binding sites on the E. coli cell surface. Washing with lysogeny broth medium was effective in purifying 64Cu-labeled E. coli for kinetic study; the labeling stability was approximately 90% in serum for 15 min. According to dynamic PET imaging in colon-26 tumor-bearing mice, 64Cu-labeled E. coli immediately disappeared from the blood circulation and primarily accumulated in the liver. In addition, transient pulmonary distribution was observed, being in a dose-dependently accelerated manner. Considering the simplicity and versatility of biosorption-based bacterial 64Cu-labeling without genetic modification, the early-phase pharmacokinetic PET with 64Cu-labeled bacteria is promising for assessing toxicological aspects of bacteria-mediated cancer therapy as well as a variety of bacterial pathogenicities in infectious diseases.
    Nov. 2020, International journal of pharmaceutics, 590, 119950 - 119950, English, International magazine
    Scientific journal

  • Toshimori Kitami, Sanae Fukuda, Tamotsu Kato, Kouzi Yamaguti, Yasuhito Nakatomi, Emi Yamano, Yosky Kataoka, Kei Mizuno, Yuuri Tsuboi, Yasushi Kogo, Harukazu Suzuki, Masayoshi Itoh, Masaki Suimye Morioka, Hideya Kawaji, Haruhiko Koseki, Jun Kikuchi, Yoshihide Hayashizaki, Hiroshi Ohno, Hirohiko Kuratsune, Yasuyoshi Watanabe
    Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex and debilitating disease with no molecular diagnostics and no treatment options. To identify potential markers of this illness, we profiled 48 patients and 52 controls for standard laboratory tests, plasma metabolomics, blood immuno-phenotyping and transcriptomics, and fecal microbiome analysis. Here, we identified a set of 26 potential molecular markers that distinguished ME/CFS patients from healthy controls. Monocyte number, microbiome abundance, and lipoprotein profiles appeared to be the most informative markers. When we correlated these molecular changes to sleep and cognitive measurements of fatigue, we found that lipoprotein and microbiome profiles most closely correlated with sleep disruption while a different set of markers correlated with a cognitive parameter. Sleep, lipoprotein, and microbiome changes occur early during the course of illness suggesting that these markers can be examined in a larger cohort for potential biomarker application. Our study points to a cluster of sleep-related molecular changes as a prominent feature of ME/CFS in our Japanese cohort.
    Nov. 2020, Scientific reports, 10(1) (1), 19933 - 19933, English, International magazine
    Scientific journal

  • My Jonasson, Patrik Nordeman, Jonas Eriksson, Helena Wilking, Johan Wikström, Kayo Takahashi, Takashi Niwa, Takamitsu Hosoya, Yasuyoshi Watanabe, Gunnar Antoni, Inger Sundström Poromaa, Mark Lubberink, Erika Comasco
    Aromatase, the enzyme that in the brain converts testosterone and androstenedione to estradiol and estrone, respectively, is a putative key factor in psychoneuroendocrinology. In vivo assessment of aromatase was performed to evaluate tracer kinetic models and optimal scan duration, for quantitative analysis of the aromatase positron emission tomography (PET) ligand [11 C]cetrozole. Anatomical magnetic resonance and 90-min dynamic [11 C]cetrozole PET-CT scans were performed on healthy women. Volume of interest (VOI)-based analyses with a plasma-input function were performed using the single-tissue and two-tissue (2TCM) reversible compartment models and plasma-input Logan analysis. Additionally, the simplified reference tissue model (SRTM), Logan reference tissue model (LRTM), and standardized uptake volume ratio model, with cerebellum as reference region, were evaluated. Parametric images were generated and regionally averaged voxel values were compared with VOI-based analyses of the reference tissue models. The optimal reference model was used for evaluation of a decreased scan duration. Differences between the plasma-input- and reference tissue-based methods and comparisons between scan durations were assessed by linear regression. The [11 C]cetrozole time-activity curves were best described by the 2TCM. SRTM nondisplaceable binding potential (BPND ), with cerebellum as reference region, can be used to estimate [11 C]cetrozole binding and generated robust and quantitatively accurate results for a reduced scan duration of 60 min. Receptor parametric mapping, a basis function implementation of SRTM, as well as LRTM, produced quantitatively accurate parametric images, showing BPND at the voxel level. As PET tracer, [11 C]cetrozole can be employed for relatively short brain scans to measure aromatase binding using a reference tissue-based approach.
    Nov. 2020, Journal of neuroscience research, 98(11) (11), 2208 - 2218, English, International magazine
    Scientific journal

  • Ivan Smirnov, Regina Sibgatullina, Sayaka Urano, Tsuyoshi Tahara, Peni Ahmadi, Yasuyoshi Watanabe, Ambara R Pradipta, Almira Kurbangalieva, Katsunori Tanaka
    Natural glycoconjugates that form glycocalyx play important roles in various biological processes based on cell surface recognition through pattern recognition mechanisms. This work represents a new synthesis-based screening strategy to efficiently target the cancer cells by higher-order glycan pattern recognition in both cells and intact animals (mice). The use of the very fast, selective, and effective RIKEN click reaction (6π-azaelectrocyclization of unsaturated imines) allows to synthesize and screen various structurally well-defined glycoalbumins containing two and eventually four different N-glycan structures in a very short time. The importance of glycan pattern recognition is exemplified in both cell- and mouse-based experiments. The use of pattern recognition mechanisms for cell targeting represents a novel and promising strategy for the development of diagnostic, prophylactic, and therapeutic agents for various diseases including cancers.
    Nov. 2020, Small (Weinheim an der Bergstrasse, Germany), 16(46) (46), e2004831, English, International magazine
    Scientific journal

  • 慢性疲労動物を用いた疲労の慢性化機序の解析
    胡 迪, 李 丹渓, 重田 美香, 岡内 隆, 越智 祐太, 渡辺 恭良, 崔 翼龍
    日本疲労学会, Nov. 2020, 日本疲労学会誌, 16(1) (1), 57 - 57, Japanese

  • Takanori Kawano, Junko Naito, Machiko Nishioka, Norihisa Nishida, Madoka Takahashi, Shinichi Kashiwagi, Tomohiro Sugino, Yasuyoshi Watanabe
    Euglena gracilis EOD-1, a kind of microalgae, is known to contain a high proportion of paramylon, a type of β-1,3-glucan. Paramylon derived from E. gracilis EOD-1 is presumed to suppress cellular oxidative injury and expected to reduce fatigue and fatigue sensation. Therefore, we aimed to examine whether food containing paramylon derived from E. gracilis EOD-1 (EOD-1PM) ingestion reduced fatigue and fatigue sensation in healthy adults. We conducted a randomized, double-blind, placebo-controlled, parallel-group comparison study in 66 healthy men and women who ingested a placebo or EOD-1PM daily for 4 weeks (daily life fatigue). Furthermore, at the examination days of 0 and 4 weeks, tolerance to fatigue load was evaluated using mental tasks (task-induced fatigue). We evaluated fatigue sensation using the Visual Analogue Scale, the work efficiency of the advanced trail making test and measured serum antioxidant markers. The EOD-1PM group showed significantly lower levels of physical and mental fatigue sensations and higher levels of work efficiency as well as serum biological antioxidant potential levels than the placebo group. These results indicate that EOD-1PM ingestion reduced fatigue and fatigue sensation, which may be due to an increase in antioxidant potential and maintenance of selective attention during work.
    Oct. 2020, Nutrients, 12(10) (10), English, International magazine
    Scientific journal

  • PETによるエクソソームの体内動態評価を指向した膜表面キレーター化学修飾による64Cu標識
    藁科 翔太, 造田 真希, 和田 康弘, 渡辺 恭良, 向井 英史
    (一社)日本核医学会, Oct. 2020, 核医学, 57(Suppl.) (Suppl.), S151 - S151, Japanese

  • 生物学的吸着に基づくバクテリア64Cu標識法の菌種適用範囲の検討
    野村 祥子, 高橋 麻衣子, 橋場 月, 和田 康弘, 渡辺 恭良, 向井 英史
    (一社)日本核医学会, Oct. 2020, 核医学, 57(Suppl.) (Suppl.), S151 - S151, Japanese

  • 悪性中皮腫特異的マーカーを標的とした抗体PETイメージング
    崔 翼龍, 田原 強, 辻 祥太郎, 仁 欽, 武 玉萍, 井上 美智子, 林中 恵美, 和田 康弘, 渡辺 恭良, 向井 英史, 今井 浩三
    (一社)日本核医学会, Oct. 2020, 核医学, 57(Suppl.) (Suppl.), S172 - S172, Japanese

  • 生物学的吸着を応用して64Cu標識した大腸菌の静脈内投与後の体内動態評価
    野村 祥子, 高橋 麻衣子, 橋場 月, 和田 康弘, 渡辺 恭良, 向井 英史
    日本DDS学会, Aug. 2020, 日本DDS学会学術集会プログラム予稿集, 36回, 147 - 147, Japanese

  • がん組織イメージングを目的とした64Cu標識lasso peptide MccJ25の作製と体内動態評価
    毛利 浩太, Kim Phuong Huynh Nhat, 造田 真希, 林中 恵美, 和田 康弘, 渡辺 恭良, 田上 俊輔, 向井 英史
    日本DDS学会, Aug. 2020, 日本DDS学会学術集会プログラム予稿集, 36回, 147 - 147, Japanese

  • Hiroyuki Shimada, Shinobu Minatani, Jun Takeuchi, Akitoshi Takeda, Joji Kawabe, Yasuhiro Wada, Aya Mawatari, Yasuyoshi Watanabe, Hitoshi Shimada, Makoto Higuchi, Tetsuya Suhara, Takami Tomiyama, Yoshiaki Itoh
    We previously identified a novel mutation in amyloid precursor protein from a Japanese pedigree of familial Alzheimer's disease, FAD (Osaka). Our previous positron emission tomography (PET) study revealed that amyloid β (Aβ) accumulation was negligible in two sister cases of this pedigree, indicating a possibility that this mutation induces dementia without forming senile plaques. To further explore the relationship between Aβ, tau and neurodegeneration, we performed tau and Aβ PET imaging in the proband of FAD (Osaka) and in patients with sporadic Alzheimer's disease (SAD) and healthy controls (HCs). The FAD (Osaka) patient showed higher uptake of tau PET tracer in the frontal, lateral temporal, and parietal cortices, posterior cingulate gyrus and precuneus than the HCs (>2.5 SD) and in the lateral temporal and parietal cortices than the SAD patients (>2 SD). Most noticeably, heavy tau tracer accumulation in the cerebellum was found only in the FAD (Osaka) patient. Scatter plot analysis of the two tracers revealed that FAD (Osaka) exhibits a distinguishing pattern with a heavy tau burden and subtle Aβ accumulation in the cerebral cortex and cerebellum. These observations support our hypothesis that Aβ can induce tau accumulation and neuronal degeneration without forming senile plaques.
    Jun. 2020, International journal of molecular sciences, 21(12) (12), English, International magazine

  • Kei Mizuno, Akihiro T Sasaki, Kyosuke Watanabe, Yasuyoshi Watanabe
    Our double-blind, placebo-controlled study evaluated effects of ubiquinol, the reduced form of coenzyme Q10, on mild fatigue in healthy individuals experiencing fatigue in daily life that had continued for more than 1 and less than 6 months. The participants received 100-mg/day (Ubq100; age 44.0 ± 9.8 years; 14 females and 6 males) or 150-mg/day ubiquinol (Ubq150; age 40.4 ± 11.8 years; 14 females and 8 males) or placebo (Plc; age 41.3 ± 13.4 years; 13 females and 7 males) daily for 12 weeks. Measurements of subjective and objective fatigue were conducted by using questionnaires-based fatigue scales/visual analogue scales and autonomic nerve function/biological oxidation index, respectively, prior to the first dosing and every 4 weeks thereafter. Serum ubiquinol level increased three- to four-fold after 4 weeks and remained significantly higher than that after Plc administration throughout the intake period. Although a higher blood level of ubiquinol was observed with Ubq150 than with Ubq100, the difference was not statistically significant. In both Ubq100 and Ubq150 groups, subjective levels of fatigue sensation and sleepiness after cognitive tasks, which consisted of the modified Advanced Trail Making Test, the modified Stroop Color-Word Test, and the Digit Symbol Substitution Test, improved significantly compared with those in the placebo group, suggesting an anti-fatigue effect. The Ubq150 group demonstrated significant improvement compared with the Plc group regarding subjective level of relaxation after task, sleepiness before and after task, motivation for task, and serum level of oxidative stress. Correlation analysis between blood level of ubiquinol and each evaluated effect suggested a positive relationship with relaxation after task, motivation for cognitive task, and parasympathetic activity. The results of the study suggest that ubiquinol intake relieves mild fatigue in healthy individuals.
    Jun. 2020, Nutrients, 12(6) (6), English, International magazine
    Scientific journal

  • Takayoshi Nakaoka, Yuta Uetake, Ken-ichi Kaneko, Takashi Niwa, Hidenori Ochiai, Satsuki Irie, Yoshie Suezaki, Natsumi Otsuka, Emi Hayashinaka, Yasuhiro Wada, Yilong Cui, Kazuya Maeda, Hiroyuki Kusuhara, Yuichi Sugiyama, Takamitsu Hosoya, Yasuyoshi Watanabe
    We developed a practical synthetic method for fluorine-18 (18F)-labeled pitavastatin ([18F]PTV) as a positron emission tomography (PET) tracer to assess hepatobiliary transporter activity and conducted a PET scan as a preclinical study for proof-of-concept in rats. This method is a one-pot synthesis involving aromatic 18F-fluorination of an arylboronic acid ester followed by deprotection under acidic conditions, which can be reproduced in general clinical sites equipped with a standard radiolabeling system due to the simplified procedure. PET imaging confirmed that intravenously administered [18F]PTV was rapidly accumulated in the liver and gradually transferred into the intestinal lumen through the bile duct. Radiometabolite analysis showed that [18F]PTV was metabolically stable, and 80% of the injected dose was detected as the unchanged form in both blood and bile. We applied integration plot analysis to assess tissue uptake clearance (CLuptake, liver and CLuptake, kidney) and canalicular efflux clearance (CLint, bile), and examined the effects of inhibitors on membrane transport. Treatment with rifampicin, an organic anion transporting polypeptide inhibitor, significantly reduced CLuptake, liver and CLuptake, kidney to 44% and 64% of control, respectively. In contrast, Ko143, a breast cancer resistance protein inhibitor, did not affect CLuptake, liver but significantly reduced CLint, bile to 39% of control without change in [18F]PTV blood concentration. In addition, we found decreased CLuptake, liver and increased CLint, bile in Eisai hyperbilirubinemic rats in response to altered expression levels of transporters. We expect that [18F]PTV can be translated into clinical application, as our synthetic method does not need special apparatus in the radiolabeling system and PET scan with [18F]PTV can quantitatively evaluate transporter activity in vivo.
    American Chemical Society (ACS), Jun. 2020, Molecular Pharmaceutics, 17(6) (6), 1884 - 1898, English, International magazine
    [Refereed]
    Scientific journal

  • がんプレシジョン診断を目的とした環状ペプチドプローブによる活性型HGF選択的PETイメージング
    藁科 翔太, 佐藤 拓輝, 造田 真希, 酒井 克也, Passioura Toby, 和田 康弘, 菅 裕明, 松本 邦夫, 渡辺 恭良, 向井 英史
    日本分子イメージング学会, May 2020, JSMI Report, 13(2) (2), 37 - 37, Japanese

  • Integrin αvβ3高発現がん組織イメージングを目的としたRGD配列を挿入したlasso peptide MccJ25のPETプローブとしての有用性評価
    毛利 浩太, Huynh Nhat Kim Phuong, 造田 真希, 林中 恵美, 和田 康弘, 渡辺 恭良, 田上 俊輔, 向井 英史
    日本分子イメージング学会, May 2020, JSMI Report, 13(2) (2), 30 - 30, Japanese

  • 銅(II)イオンの生物学的吸着を利用した細菌の64Cu標識
    野村 祥子, 高橋 麻衣子, 橋場 月, 和田 康弘, 渡辺 恭良, 向井 英史
    日本分子イメージング学会, May 2020, JSMI Report, 13(2) (2), 33 - 33, Japanese

  • Shogo Nomura, Yasuko Egawa, Sayaka Urano, Tsuyoshi Tahara, Yasuyoshi Watanabe, Katsunori Tanaka
    In the field of molecular imaging, selectivity for target cells is a key determinant of the degree of imaging contrast. Previously, we developed a pre-targeted method by which target cells could be selectively imaged using a labeled N-glycan that was ligated in situ with an integrin-targeted cyclic RGD peptide on the cell surface. Here we demonstrate the power of our method in discriminating various cancerous and non-cancerous cells that cannot be distinguished using conventional RGD ligands. Using four cyclic RGDyK peptides with various linker lengths with five N-glycans, we identify optimal combinations to discriminate six types of αvβ3 integrin-expressing cells on 96-well plates. The optimal combinations of RGD and N-glycan ligands for the target cells are fingerprinted on the plates, and then used to selectively image tumors in xenografted mouse models. Using this method, various N-glycan molecules, even those with millimolar affinities for their cognate lectins, could be used for selective cancer cell differentiation.
    Feb. 2020, Communications chemistry, 3(1) (1), 26 - 26, English, International magazine
    Scientific journal

  • Tomonori Fukuchi, Seiichi Yamamoto, Jun Kataoka, Kei Kamada, Akira Yoshikawa, Yasuyoshi Watanabe, Shuichi Enomoto
    PURPOSE: Beta-ray imaging systems are widely used for various biological objects to obtain a two-dimensional (2D) distribution of β-ray emitting radioisotopes. However, a conventional β-ray imaging system is unsuitable for multiple-tracer imaging, because the continuous energy distribution of β-rays complicates distinguishing among different tracers by energy information. Therefore, we developed a new type of β-ray imaging system, which is useful for multiple tracers by detecting coincidence γ-rays with β-rays, and evaluated its imaging performance. METHODS: Our system is composed of position-sensitive β-ray and γ-ray detectors. The former is a 35 × 35 × 1-mm3 Ce-Doped((La, Gd)2 Si2 O7 ) (La-GPS) scintillation detector, which has a 300-µm pitch of pixels. The latter is a 43 × 43 × 16-mm3 bismuth germanium oxide (BGO) scintillation detector. Both detectors are mounted on a flexible frame and placed in a user-selectable position. We experimentally evaluated the performance of the β-ray detector and the γ-ray efficiencies of the γ-ray detector with different energies, positions, and distances. We also conducted point sources and phantom measurements with dual isotopes to evaluate the system performance of multiple-tracer imaging. RESULTS: For the β-ray detector, the β-ray detection efficiencies for 45 Ca (245-keV maximum energy) and 90 Sr/90 Y (545 and 2280-keV maximum energy) were 14.3% and 21.9%, respectively. The total γ-ray detection efficiency of the γ-ray detector for all γ-rays from 22 Na (511-keV annihilation γ-rays and a 1275-keV γ-ray) in the center position with a detector distance of 20 mm was 17.5%. From a point-source measurement using 22 Na and 90 Sr/90 Y, we successfully extracted the position of a positron-γ emitter 22 Na. Furthermore, for a phantom experiment using 45 Ca and 18 F or 18 F and 22 Na, we successfully extracted the distribution of the second tracer using the annihilation γ-ray or de-excitation γ-ray coincidence. In all the imaging experiments, the event counts of the extracted images were consistent with the counts estimated by the measured γ-ray efficiencies. CONCLUSIONS: We successfully demonstrated the feasibility of our β-ray autoradiography system for imaging multiple isotopes. Since our system can identify not only a β-γ emitter but also a positron emitter using the coincidence detection of annihilation γ-rays, it is useful for PET tracers and various new applications that are otherwise impractical.
    Feb. 2020, Medical physics, 47(2) (2), 587 - 596, English, International magazine
    Scientific journal

  • Kei Mizuno, Daichi Ojiro, Takeshi Tanaka, Shunsuke Minusa, Hiroyuki Kuriyama, Emi Yamano, Hirohiko Kuratsune, Yasuyoshi Watanabe
    The fatigue of truck, bus, and taxi drivers has been a causal trigger for road accidents. However, the relationship between collision risk and the extent of objective fatigue has yet to be confirmed. In this study, we aimed to identify the relationship between autonomic nerve function as an objective parameter of fatigue and the extent of rear-end collision risk, which includes not only objectively risky events but also situations in which truck drivers require safety guidance from safety transport managers. Data of 33 truck driver participants (2 females, 31 males, 46.0 ± 9.1 years old, min-max: 24-65 years old) were analyzed. Drive recorder and automotive sensor data were collected over an eight-month period, and the autonomic nerve function during resting state in drivers was evaluated daily, pre- and post-shift, using pulse waves and electrocardiographic waveform measurement. The rear-end collision risk Index was developed using decision tree analysis of the audiovisual drive recorder data and distance data from the front automotive sensors. The rear-end collision risk index of shift-day was positively correlated with the sympathetic nerve activity index of post-shift condition on the previous day. This suggests that fatigue-related sympathetic nerve overactivity of post-shift condition increases the rear-end collision risk in the following day. Measures, such as actively seeking rest and undertaking fatigue recovery according to the degree of sympathetic nerve activity of post-shift condition, are necessary in order to prevent truck drivers' rear-end collisions.
    2020, PloS one, 15(9) (9), e0238738, English, International magazine
    Scientific journal

  • Tianliang Huang, Takashi Okauchi, Di Hu, Mika Shigeta, Yuping Wu, Yasuhiro Wada, Emi Hayashinaka, Shenglan Wang, Yoko Kogure, Koichi Noguchi, Yasuyoshi Watanabe, Yi Dai, Yilong Cui
    Inflammatory bowel disease (IBD), mainly comprising Crohn's disease and ulcerative colitis, is characterized by chronic inflammation in the digestive tract. Approximately 60% of the patients experience abdominal pain during acute IBD episodes, which severely impairs their quality of life. Both peripheral and central mechanisms are thought to be involved in such abdominal pain in IBD. Although much attention has been paid to peripheral mechanisms of abdominal pain in IBD pathophysiology, the involvement of supraspinal mechanisms remains poorly understood. To address this issue, we investigated regional brain activity in response to colorectal distension in normal and IBD model rats using voxel-based statistical analysis of 2-deoxy-2-[18F]fluoro-(D)-glucose positron emission tomography imaging. The rat IBD model was generated by colorectal administration of 2,4,6-trinitrobenzene sulfonic acid, a chemical compound widely used to generate colitis. Tissue damage and inflammation were induced and dynamically changed with time after 2,4,6-trinitrobenzene sulfonic acid injection, while colorectal distension-induced visceromotor response showed corresponding temporal changes. We found that characteristic brain activations were observed in response to visceral innocuous and noxious colorectal distension and supraspinal nociception shared some physiological sensory pathway. Moreover, widespread brain regions were activated, and the functional coupling between the central medial thalamic nucleus and anterior cingulate cortex was enhanced after noxious colorectal distension in IBD model of rats. Increased brain activity in the anterior insular cortex and anterior cingulate cortex was positively correlated with noxious colorectal distension-induced pain severity in normal and IBD rats, respectively. These findings suggest that the pain matrix was shifted following persistent colonic inflammation, and thalamocortical sensitization in the pathway from the central medial thalamic nucleus to anterior cingulate cortex might be a central mechanism of the visceral hyperalgesia in IBD pathophysiology.
    SAGE PUBLICATIONS INC, Nov. 2019, MOLECULAR PAIN, 15, 1744806919891327 - 1744806919891327, English, International magazine
    [Refereed]
    Scientific journal

  • Eguchi A, Fukuda S, Kuratsune H, Nojima J, Nakatomi Y, Watanabe Y, Feldstein AE
    Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious, debilitating disorder with a wide spectrum of symptoms, including pain, depression, and neurocognitive deterioration. Over 17 million people around the world have ME/CFS, predominantly women with peak onset at 30-50 years. Given the wide spectrum of symptoms and unclear etiology, specific biomarkers for diagnosis and stratification of ME/CFS are lacking. Here we show that actin network proteins in circulating extracellular vesicles (EVs) offer specific non-invasive biomarkers for ME/CFS. We found that circulating EVs were significantly increased in ME/CFS patients correlating to C-reactive protein, as well as biological antioxidant potential. Area under the receiver operating characteristic curve for circulating EVs was 0.80, allowing correct diagnosis in 90-94% of ME/CFS cases. From two independent proteomic analyses using circulating EVs from ME/CFS, healthy controls, idiopathic chronic fatigue, and depression, proteins identified from ME/CFS patients are involved in focal adhesion, actin skeletal regulation, PI3K-Akt signaling pathway, and Epstein-Barr virus infection. In particular, talin-1, filamin-A, and 14-3-3 family proteins were the most abundant proteins, representing highly specific ME/CFS biomarkers. Our results identified circulating EV number and EV-specific proteins as novel biomarkers for diagnosing ME/CFS, providing important information on the pathogenic mechanisms of ME/CFS.
    Nov. 2019, Brain, behavior, and immunity, 84, 106 - 114, English, International magazine
    [Refereed]
    Scientific journal

  • Satoshi Nozaki, Yuka Nakatani, Aya Mawatari, Nina Shibata, William E Hume, Emi Hayashinaka, Yasuhiro Wada, Hisashi Doi, Yasuyoshi Watanabe
    Positron emission tomography (PET) imaging can assist in the early-phase diagnostic and therapeutic evaluation of tumors. Here, we report the radiosynthesis, small animal PET imaging, and biological evaluation of a L-type amino acid transporter 1 (LAT1)-specific PET probe, 18F-FIMP. This probe demonstrates increased tumor specificity, compared to existing tumor-specific PET probes (18F-FET, 11C-MET, and 18F-FDG). Evaluation of probes by in vivo PET imaging, 18F-FIMP showed intense accumulation in LAT1-positive tumor tissues, but not in inflamed lesions, whereas intense accumulation of 18F-FDG was observed in both tumor tissues and in inflamed lesions. Metabolite analysis showed that 18F-FIMP was stable in liver microsomes, and mice tissues (plasma, urine, liver, pancreas, and tumor). Investigation of the protein incorporation of 18F-FIMP showed that it was not incorporated into protein. Furthermore, the expected mean absorbed dose of 18F-FIMP in humans was comparable or slightly higher than that of 18F-FDG and indicated that 18F-FIMP may be a safe PET probe for use in humans. 18F-FIMP may provide improved specificity for tumor diagnosis, compared to 18F-FDG, 18F-FET, and 11C-MET. This probe may be suitable for PET imaging for glioblastoma and the early-phase monitoring of cancer therapy outcomes.
    Oct. 2019, Scientific reports, 9(1) (1), 15718 - 15718, English, International magazine
    Scientific journal

  • Yasuyoshi Watanabe, Masaaki Tanaka, Akira Ishii, Kei Mizuno, Akihiro Sasaki, Emi Yamano, Yilong Cui, Sanae Fukuda, Yosky Kataoka, Kozi Yamaguti, Yasuhito Nakatomi, Yasuhiro Wada, Hirohiko Kuratsune
    Springer Singapore, Oct. 2019, Make Life Visible, 227 - 233
    In book

  • Kazuya Maeda, Akihito Ohnishi, Masahiro Sasaki, Yasuhiko Ikari, Kazuki Aita, Yasuyoshi Watanabe, Hiroyuki Kusuhara, Yuichi Sugiyama, Michio Senda
    The pharmacokinetics of telmisartan are nonlinear within the clinical dose range. To identify the underlying mechanism of this nonlinearity, we conducted a PET study in healthy subjects using [11C]telmisartan. Eight healthy male subjects were enrolled in a 2-way crossover study. PET imaging was performed after intravenous administration of [11C]telmisartan with or without a 1-h oral predose of two 40 mg Micardis® tablets. About 60% of the injected [11C]telmisartan accumulated in the liver within 10 min after injection. With predosing of 80 mg telmisartan, the systemic elimination of [11C]telmisartan was slightly delayed, but the liver exposure started to decrease earlier and biliary excretion was greatly enhanced. Hepatic uptake clearance of the radioactivity was not changed by telmisartan predosing, whereas the biliary clearance of radioactivity from the liver was significantly increased. Thus, the alteration in the pharmacokinetics of the radioactivity could not be explained simply by the saturation of hepatic uptake. Therefore, other mechanisms, such as the saturation of intracellular binding of telmisartan and/or its glucuronide, and the glucuronidation of telmisartan by uridine 5'-diphospho-glucuronosyltransferases, should be considered. This is the first reported human PET study using [11C]telmisartan, the results of which can assist understanding of the hepatobiliary transport of telmisartan in humans.
    Oct. 2019, Drug metabolism and pharmacokinetics, 34(5) (5), 293 - 299, English, International magazine
    Scientific journal

  • 【トランスポーターのすべて】トランスポーターが関連する疾患研究 PET分子イメージング活用創薬 ヒトでの薬物動態を中心に
    渡辺 恭良, 向井 英史
    PETはほとんどすべての薬物分子の動態を追跡できることに加えて、非常に高感度でヒト身体深部に至る定量性が確保できることから、非臨床試験・臨床試験の両者において標準的に創薬に活用される重要なモダリティとなってきた。従来、間接的に類推するしかなかったヒト組織中の薬物濃度推移について直接的な評価ができ、創薬標的、病態診断、治療効果評価に重要な生体分子の発現や機能を可視化するPETプローブを薬効評価のサロゲートエンドポイントとして利用することができる。PETを中心とする分子イメージング技術を、疾患モデル動物とヒトで共通の評価基盤とするイメージング活用創薬により、開発初期から臨床試験・投薬治療まで薬物動態と薬効の関連を強く結びつけた、より実証的でシームレスな創薬研究を実現することができる。(著者抄録)
    医歯薬出版(株), Oct. 2019, 医学のあゆみ, 271(1) (1), 49 - 56, Japanese
    [Refereed]
    Scientific journal

  • Akiko Kuwabara, Naoko Tsugawa, Kei Mizuno, Honami Ogasawara, Yasuyoshi Watanabe, Kiyoshi Tanaka
    Vitamin D deficiency (VDD) is associated with an increased risk of various diseases. Serum 25-hydroxyvitamin D [25(OH)D] concentration is the best marker for vitamin D status and its concentration < 20 ng/mL indicates VDD. However, its measurement is not easily applicable for the evaluation of vitamin D status in the general population because of its cost. Therefore, we aimed to develop a simple questionnaire for easily identifying the risk of VDD. From the total sample (649 healthy subjects aged 19-70 years), 434 and 215 subjects were randomly assigned to the derivation and the validation cohort, respectively. Prediction model for VDD was developed by backward logistic regression analysis. The regression β coefficients of the significant predictors were transformed into integral numbers and used for the individual score. These individual scores were summed to calculate the total risk score (VDD questionnaire for Japanese score: VDDQ-J score). VDD was present in 54.1% of the total subjects. The model for the prediction of VDD consisted of 7 predictors. Areas under the curve were 0.78 and 0.75 in the data set of internal validation and of the external validation, respectively. The cutoff value was determined to be 31 points (range 0-54) with the sensitivity/specificity and positive predictive value/negative predictive value of 61%/79%, and 81%/57%, respectively. Our VDDQ-J score is easy to answer by the wide range of subjects, and well predicts VDD. This risk score would be useful to identify subjects at risk for VDD both in clinical and epidemiological settings.
    Sep. 2019, Journal of bone and mineral metabolism, 37(5) (5), 854 - 863, English, Domestic magazine
    Scientific journal

  • 環状ペプチドによるHGF阻害と高速原子間力顕微鏡による分子動態計測
    酒井 克也, 佐藤 拓輝, 柴田 幹大, 高木 淳一, 加藤 幸成, 向井 英史, 渡辺 恭良, 矢野 聖二, 管 裕明, 松本 邦夫
    (公社)日本生化学会, Sep. 2019, 日本生化学会大会プログラム・講演要旨集, 92回, [2T09a - 03], Japanese

  • 環状ペプチドによるHGF阻害と高速原子間力顕微鏡による分子動態計測
    酒井 克也, 佐藤 拓輝, 柴田 幹大, 高木 淳一, 加藤 幸成, 向井 英史, 渡辺 恭良, 矢野 聖二, 管 裕明, 松本 邦夫
    (公社)日本生化学会, Sep. 2019, 日本生化学会大会プログラム・講演要旨集, 92回, [2T09a - 03], Japanese
    [Refereed]

  • 活性型HGFの選択的検出によるMET活性化状態の診断(Specific Detection of Active HGF for Diagnosis Reflecting Activation Status of HGF-MET Signaling by Macrocyclic Peptide)
    佐藤 拓輝, 酒井 克也, 今村 龍, 向井 英史, 渡辺 恭良, 矢野 聖二, 松本 邦夫
    (一社)日本癌学会, Sep. 2019, 日本癌学会総会記事, 78回, J - 3012, English

  • 活性型HGFの選択的検出によるMET活性化状態の診断(Specific Detection of Active HGF for Diagnosis Reflecting Activation Status of HGF-MET Signaling by Macrocyclic Peptide)
    佐藤 拓輝, 酒井 克也, 今村 龍, 向井 英史, 渡辺 恭良, 矢野 聖二, 松本 邦夫
    日本癌学会, Sep. 2019, 日本癌学会総会記事, 78回, J - 3012, English
    [Refereed]

  • Kyosuke Watanabe, Akihiro T Sasaki, Kanako Tajima, Kenji Mizuseki, Kei Mizuno, Yasuyoshi Watanabe
    Previous studies have revealed that patients with chronic fatigue syndrome and affective disorders (such as depression and anxiety disorders) exhibit a vigilant attentional bias toward negative emotional stimuli. However, it remains unclear whether the change in an attentional bias for negative emotional stimuli can be induced by mental fatigue in healthy individuals. To address this question, we examined healthy participants' (n = 27) performance in a visual probe task and emotional Stroop task before and after the mental-fatigue-inducing task. We demonstrated that acute mental fatigue induced by the long-lasting working memory task led to the alteration of cognitive processing of negative emotional information in the healthy volunteers.
    Jun. 2019, Scientific reports, 9(1) (1), 8797 - 8797, English, International magazine
    Scientific journal

  • Katsuya Sakai, Toby Passioura, Hiroki Sato, Kenichiro Ito, Hiroki Furuhashi, Masataka Umitsu, Junichi Takagi, Yukinari Kato, Hidefumi Mukai, Shota Warashina, Maki Zouda, Yasuyoshi Watanabe, Seiji Yano, Mikihiro Shibata, Hiroaki Suga, Kunio Matsumoto
    Activation of hepatocyte growth factor (HGF) by proteolytic processing is triggered in cancer microenvironments, and subsequent signaling through the MET receptor is involved in cancer progression. However, the structure of HGF remains elusive, and few small/medium-sized molecules can modulate HGF. Here, we identified HiP-8, a macrocyclic peptide consisting of 12 amino acids, which selectively recognizes active HGF. Biochemical analysis and real-time single-molecule imaging by high-speed atomic force microscopy demonstrated that HiP-8 restricted the dynamic domains of HGF into static closed conformations, resulting in allosteric inhibition. Positron emission tomography using HiP-8 as a radiotracer enabled noninvasive visualization and simultaneous inhibition of HGF-MET activation status in tumors in a mouse model. Our results illustrate the conformational change in proteolytic activation of HGF and its detection and inhibition by a macrocyclic peptide, which may be useful for diagnosis and treatment of cancers.
    Jun. 2019, Nature chemical biology, 15(6) (6), 598 - 606, English, International magazine
    Scientific journal

  • 動的PETイメージングとLC/MS/MS解析を組み合わせた核酸医薬リポソーム製剤の動態評価
    向井 英史, 畑中 剣太朗, 八木 信宏, 藁科 翔太, 造田 真希, 高橋 麻衣子, 成島 和哉, 藪内 隼人, 岩野 淳子, 窪山 剛之, 榎園 淳一, 和田 康弘, 渡辺 恭良
    日本DDS学会, Jun. 2019, 日本DDS学会学術集会プログラム予稿集, 35回, 149 - 149, Japanese

  • Kyosuke Watanabe, Satoshi Nozaki, Miki Goto, Ken-Ichi Kaneko, Emi Hayashinaka, Satsuki Irie, Akira Nishiyama, Kazuaki Kasai, Kenji Fujii, Yasuhiro Wada, Kei Mizuno, Kenji Mizuseki, Hisashi Doi, Yasuyoshi Watanabe
    Coenzyme Q10 (CoQ10) plays a key role not only as an essential electron carrier in the mitochondrial electron transport chain, but also as an antioxidant to protect cells from oxidative stress. CoQ10 supplementation is expected to be effective for a variety of diseases. The predominant forms of CoQ10 are the ubiquinol-10 (reduced form) and ubiquinone-10 (oxidized form). Both forms of CoQ10 supplements are commercially available, however, their kinetic difference is still unclear. In order to conduct in vivo analysis of the kinetics of ubiquinol-10 and ubiquinone-10, we succeeded in synthesizing 11C-labeled ubiquinol-10 ([11C]UQL) and ubiquinone-10 ([11C]UQN), respectively. In the present study, we aimed to investigate the kinetics of [11C]UQL and [11C]UQN, both of which were administered via the tail vein of 8-week-old male Sprague-Dawley rats. Whole-body positron emission tomography (PET) imaging was performed to follow the time course of accumulation in the liver, spleen, brain, and other organs. Then, at the two typical time points at 20 or 90 min after injection, we conducted the biodistribution study. Various organs/tissues and blood were collected, weighed and counted with a gamma counter. Percent injected dose per gram of tissue (%ID/g) was calculated as the indicator of the accumulation of each compound. As the results, at both time points, %ID/g of [11C]UQL in the cerebrum, cerebellum, white adipose tissue, muscle, kidney, and testis were higher (P < 0.05) than that of [11C]UQN: at 90-min time point, %ID/g of [11C]UQL in the brown adipose tissue was higher (P < 0.05) than that of [11C]UQN: on the contrary, %ID/g of [11C]UQL in the spleen was lower (P < 0.05) than that of [11C]UQN at 90 min. In a separate study of the metabolite analysis in the plasma, UQL injected into the tail vein of rats was almost unchanged during the PET scanning time, but UQN was gradually converted to the reduced form UQL. Therefore, the uptake values of UQL into the tissues and organs were rather accurate but those of UQN might be the sum of UQN uptake and partly converted UQL uptake. These studies suggested that the accumulation level of administered CoQ10 differs depending on its redox state, and that CoQ10 redox state could be crucial for optimization of the effective supplementation.
    May 2019, Biochemical and biophysical research communications, 512(3) (3), 611 - 615, English, International magazine
    [Refereed]
    Scientific journal

  • Facile radiosyntheses of [C-11]tetrazoles and [C-11]triazines from (hetero)arylborons
    Zhouen Zhang, Takashi Niwa, Yasuyoshi Watanabe, Takamitsu Hosoya
    WILEY, May 2019, JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS, 62, S243 - S244, English

  • Palladium/copper-mediated rapid C-11-cyanation of (hetero)arylstannanes
    Zhouen Zhang, Takashi Niwa, Yasuyoshi Watanabe, Takamitsu Hosoya
    WILEY, May 2019, JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS, 62, S48 - S49, English

  • 非天然型アミノ酸含有抗体発現生産技術と生体直交反応性キレーター修飾の組み合わせによる高均一な64Cu標識トラスツズマブFabの作製
    仁 欽, 藁科 翔太, 毛利 浩太, 高橋 麻衣子, 金山 洋介, 高橋 美穂子, 林 明子, 林中 恵美, 和田 康弘, 渡辺 恭良, 坂本 健作, 向井 英史
    日本分子イメージング学会, May 2019, JSMI Report, 12(2) (2), 98 - 98, Japanese

  • [18F]DPA-714を用いたPETイメージングによるてんかんモデルラットにおける神経炎症の定量的評価
    金子 健一, 馬渡 彩, 神母坂 あみ, 入江 さつき, 林中 恵美, 和田 康弘, 土居 久志, 崔 翼龍, 渡辺 恭良
    日本分子イメージング学会, May 2019, JSMI Report, 12(2) (2), 100 - 100, Japanese

  • 悪性中皮腫特異的マーカーを標的とした抗体PETイメージング
    田原 強, 辻 祥太郎, 仁 欽, 武 玉萍, 井上 美智子, 林中 恵美, 和田 康弘, 渡辺 恭良, 向井 英史, 今井 浩三, 崔 翼龍
    日本分子イメージング学会, May 2019, JSMI Report, 12(2) (2), 138 - 138, Japanese

  • 疲労動物モデルに対する電解水素水の疲労軽減効果研究
    胡 迪, 李 丹溪, 重田 美香, 岡内 隆, 橘 孝士, 樺山 繁, 大崎 雄介, 渡辺 恭良, 崔 翼龍
    日本疲労学会, May 2019, 日本疲労学会誌, 15(1) (1), 64 - 64, Japanese

  • Jun Takeuchi, Takayuki Kikukawa, Haruna Saito, Itsuki Hasegawa, Akitoshi Takeda, Hiroyuki Hatsuta, Joji Kawabe, Yasuhiro Wada, Aya Mawatari, Ami Igesaka, Hisashi Doi, Yasuyoshi Watanabe, Hitoshi Shimada, Soichiro Kitamura, Makoto Higuchi, Tetsuya Suhara, Yoshiaki Itoh
    Background: We previously reported that among cases clinically diagnosed with Alzheimer’s disease, the proportion of amyloid beta (Aβ) -negative case increases in the elderly population. Tauopathy including Argyrophilic Grain Disease (AGD) and Neurofibrillary Tangle-Predominant Dementia (NFTPD), may be the leading causes of such dementia. Objective: To evaluate the involvement of tau, we studied tau accumulation in Amyloid-Negative Dementia Cases in the Elderly (ANDE) with Positron Emission Tomography (PET). Methods: Seven cases with slowly progressive dementia who were older than 80 years and were negative for Aβ were studied. In one case, autopsy obtained 2 years after the PET examination revealed neurofibrillary tangles limited around the parahippocampal gyrus. Four cases showed strong laterality in magnetic resonance imaging atrophy (clinical AGD), while the other three cases had no significant laterality in atrophy (clinical NFTPD). Age-corrected PET data of healthy controls (HC; n = 12) were used as control. Tau accumulation was evaluated with [11C]PBB3-PET. Results: High accumulation was found in the lateral temporal cortex in ANDE. In autopsy case, scattered neurofibrillary tangles were found in the parahippocampal gyrus. In addition, there was a very high accumulation of PBB3 in the large area of bilateral parietal lobes, although no corresponding tau component was found in the autopsied case. Conclusion: Relatively high burden of tau deposition was commonly observed in the lateral temporal cortex and parietal cortex of ANDE, part of which may explain dementia in these subjects. [11C]PBB3 may be useful in detecting tauopathy in ANDE.
    Bentham Science Publishers Ltd., Mar. 2019, The Open Biomedical Engineering Journal, 13(1) (1), 55 - 66, English
    Scientific journal

  • Akira Ishii, Takashi Matsuo, Chika Nakamura, Masato Uji, Takahiro Yoshikawa, Yasuyoshi Watanabe
    Fatigue is a health problem prevalent in modern societies. Fatigue sensation plays an important role as a biological alarm urging rest to maintain homeostasis, and clarifying the neural mechanisms related to fatigue sensations by which we decide to engage in rest is therefore essential. This study enrolled healthy male volunteers and showed that the decrease in alpha-band power as assessed by magnetoencephalography of the left Brodmann's area (BA) 6 before perception of fatigue when a button-press based on the level of fatigue was required was smaller than that before perception of the intention to move when a voluntary button-press was required. In addition, the decrease of alpha-band power in the left BA 6 before the perception of fatigue was not altered compared with that in the right BA 6 when a button-press based on the level of fatigue was required. These results suggest that the button-press based on the perception of fatigue is not prepared before the perception of fatigue. These findings will advance the understanding of the neural mechanisms related to subjective feelings such as fatigue sensation.
    Mar. 2019, Scientific reports, 9(1) (1), 4000 - 4000, English, International magazine
    Scientific journal

  • Qin Ren, Kohta Mohri, Shota Warashina, Yasuhiro Wada, Yasuyoshi Watanabe, Hidefumi Mukai
    Immuno-positron emission tomography (immuno-PET) is expected to improve the specificity of small chemical tracers such as 18F-fluorodeoxyglucose. Whole antibodies significantly accumulate in target molecule-expressing tumors but frequently persist too long in the blood circulation for imaging purposes. We investigated the utility of whole antibodies, 64Cu-labeled via a urokinase-substrate linker, and their exogenous urokinase-responsive cleavage to enhance clearance of immuno-PET probes from the blood and shorten the time required to develop adequate imaging contrast. Specifically, we used 64Cu-labeled trastuzumab in human epidermal growth factor receptor 2 (HER2)-positive tumor-bearing mice. 64Cu-labeled trastuzumab with a urokinase-cleavage site (64Cu-CB-TE1A1P-USL-trastuzumab) was synthesized using a bifunctional chelator incorporating an urokinase substrate peptide. Urokinase cleavage was analyzed in vitro by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and radio-gel permeation-high-performance liquid chromatography. Improvements in radioisotope clearance and HER2-imaging by urokinase injection were evaluated by PET imaging and ex vivo biodistribution studies in A431 tumor-bearing mice. 64Cu-CB-TE1A1P-USL-trastuzumab was cleaved into smaller radioactive fragments by 20 000 IU/mL urokinase treatment in vitro at an efficacy of ∼95%. The probe targeted HER2 in A431 tumors in mice within 24 h post-injection, and approximately two-thirds of the probe in the blood circulation was eliminated via renal clearance of radioactive fragments after three urokinase injections. Therefore, the tumor/blood ratio increased 3.0-fold. Without urokinase injection, the tumor accumulation of 64Cu-CB-TE1A1P-USL-trastuzumab slowly increased, and the blood radioactivity decreased over 72 h. However, the tumor/blood ratios in mice after three urokinase injections were higher at 24 h than those in mice without injections at 72 h. The results indicate that our approach shortened the time required to develop adequate imaging contrast of immuno-PET by >2 days. Therefore, this approach can benefit high-sensitivity imaging under lower radioactive decay conditions and can decrease patient radiation exposure. In addition, it could reduce other adverse effects of radioimmunotherapy.
    Mar. 2019, Molecular pharmaceutics, 16(3) (3), 1065 - 1073, English, International magazine
    Scientific journal

  • Katsumasa Fujiki, Yousuke Kanayama, Shinya Yano, Nozomi Sato, Takuya Yokokita, Peni Ahmadi, Yasuyoshi Watanabe, Hiromitsu Haba, Katsunori Tanaka
    α-Emission radiotherapeutics has potential to be one of most effective cancer therapeutics. Herein, we report a facile synthesis of an 211At-labeled immunoconjugate for use as an α-emission molecular targeting therapy. We synthesized a tetrazine probe modified with closo-decaborate(2-), a prosthetic group that forms a bioavailable stable complex with 211At. Our one-pot three-component double-click labeling method was used to attach decaborate to trastuzumab (anti-HER2 antibody) using decaborate-tetrazine and TCO-aldehyde probes without reducing the antibody binding affinity. Labeling the decaborate-attached trastuzumab with 211At produced in the cyclotron at the RIKEN Nishina Center, at which highly radioactive 211At can be produced, readily furnished the 211At-labeled trastuzumab with a maximum specific activity of 15 MBq μg-1 and retention of the native binding affinity. Intratumor injection of the 211At-labeled trastuzumab in BALB/c nude mice implanted with HER2-expressing epidermoid cancer cells yielded efficient accumulation at the targeted tumor site as well as effective suppression of tumor growth.
    Feb. 2019, Chemical science, 10(7) (7), 1936 - 1944, English, International magazine
    Scientific journal

  • Miki Goto, Akira Nishiyama, Takao Yamaguchi, Kyosuke Watanabe, Kenji Fujii, Yasuyoshi Watanabe, Hisashi Doi
    To enable positron emission tomography (PET) imaging of the in vivo kinetics of ubiquinone and ubiquinol, which is referred to as coenzyme Q10 , their 11 C-radiolabeled counterparts were synthesized herein. 11 C-Labeled ubiquinone [11 C]-1 was realized by Pd-mediated rapid C-[11 C]methylation of [11 C]CH3 I with 39-demethyl-39-(pinacolboryl)ubiquinone, prepared by Ru-catalyzed olefin metathesis of unradiolabeled ubiquinone with 2-(pinacolboryl)propene. Subsequent reduction of [11 C]-1 using Na2 S2 O4 yielded 11 C-labeled ubiquinol [11 C]-2. The synthesis time and [11 C]CH3 I-based radiochemical yield of [11 C]-1 were within 36 minutes and up to 53%, while those of [11 C]-2 were within 38 minutes and up to 39%, respectively. After radiopharmaceutical formulation, the qualities of [11 C]-1 and [11 C]-2 were confirmed to be applicable for animal PET studies. The analytical values of [11 C]-1 and [11 C]-2 are as follows: radioactivity of up to 3.5 and 1.4 GBq, molar activity of 21 to 78 and 48 to 76 GBq/μmol, radiochemical purity of greater than 99% and greater than 95%, and chemical purity of greater than 99% and 77%, respectively. The concept behind this radiolabeling procedure is that unradiolabeled natural ubiquinone can be converted to 11 C-radiolabeled ubiquinone and ubiquinol via a pinacolborane-substituted ubiquinone derivative. Each PET probe was used for molecular imaging using rats to investigate the in vivo kinetics and biodistribution of the coenzyme Q10 .
    Feb. 2019, Journal of labelled compounds & radiopharmaceuticals, 62(2) (2), 86 - 94, English, International magazine
    Scientific journal

  • Hidefumi Mukai, Kentaro Hatanaka, Nobuhiro Yagi, Shota Warashina, Maki Zouda, Maiko Takahashi, Kazuya Narushima, Hayato Yabuuchi, Junko Iwano, Takeshi Kuboyama, Junichi Enokizono, Yasuhiro Wada, Yasuyoshi Watanabe
    In vivo biodistribution analyses, especially in tumors, of nucleic acids delivered with nanoparticles are important to develop drug delivery technologies for medical use. We previously developed wrapsome® (WS), an ~100 nm liposomal nanoparticle that can encapsulate siRNA, and reported that WS accumulates in tumors in vivo and inhibits their growth by an enhanced permeability and retention effect. In the present study, we evaluated the pharmacokinetics of nucleic acid-containing nanoparticles by combining dynamic positron emission tomography (PET) imaging and liquid chromatography-tandem mass spectrometry (LC/MS/MS) analysis. An 18-mer phosphorothioate oligodeoxynucleotide (ODN), trabedersen, was used as a model drug and was encapsulated in WS. Dynamic PET imaging and time-activity curve analysis of WS-encapsulated 64Cu-labeled ODNs administered to mice with MIA PaCa-2 subcutaneous xenograft tumors showed tumor accumulation (~3% injected dose per gram (%ID/g)) and liver accumulation (~30 %ID/g) at 24 h. Under these conditions, LC/MS/MS analysis showed that the level of intact ODNs was 1.62 %ID/g in the tumor and 1.70 %ID/g in the liver. From these pharmacokinetic data, the intact/accumulated ODN ratios were calculated using the following equation: intact/accumulated ODN ratio (%) = %ID/g LC/MS/MS, tissue, mean/%ID/g PET, tissue, mean × 100. Interestingly, the ratios for the tumor and kidney were maintained at 20-50% over 48 h after administration of the WS-encapsulated form. In contrast, the ratio for the liver rapidly decreased at 24 h, showing the same pattern as that for naked ODN. These different patterns indicate that WS effectively protected the ODN in the tumor and kidney, but protected it less efficiently in the liver. A combined approach of dynamic PET imaging and LC/MS/MS analysis will assist the development of nanoparticle-encapsulated nucleic acid drugs, such as those using WSs, to determine their detailed pharmacokinetics.
    Jan. 2019, Journal of controlled release : official journal of the Controlled Release Society, 294, 185 - 194, English, International magazine
    Scientific journal

  • [11C]PBB3-PETを用いた神経原線維変化優位型認知症の脳内タウ蓄積分布に関する検討
    竹内 潤, 齊藤 明奈, 武田 景敏, 河邉 讓治, 和田 康弘, 馬渡 彩, 土居 久志, 渡辺 恭良, 北村 聡一郎, 島田 斉, 樋口 真人, 須原 哲也, 伊藤 義彰
    (一社)日本神経学会, Dec. 2018, 臨床神経学, 58(Suppl.) (Suppl.), S312 - S312, Japanese

  • Satoshi Nozaki, Aya Mawatari, Yuka Nakatani, Emi Hayashinaka, Yasuhiro Wada, Yukihiro Nomura, Takahito Kitayoshi, Kouji Akimoto, Shinji Ninomiya, Hisashi Doi, Yasuyoshi Watanabe
    PURPOSE: Thiamine is an essential component of glucose metabolism and energy production. The disulfide derivative, thiamine tetrahydrofurfuryl disulfide (TTFD), is better absorbed than readily-available water-soluble thiamine salts because it does not require the rate-limiting transport system required for thiamine absorption. However, the detailed pharmacokinetics of thiamine and TTFD under normal and pathological conditions have not yet been clarified. C-11-labeled thiamine and TTFD were recently synthesized by our group. In this study, to clarify the differences in pharmacokinetics and metabolism of these probes, a quantitative PET imaging study and radiometabolite analysis of C-11-labeled thiamine and TTFD were performed in the rat heart. PROCEDURES: Positron emission tomography (PET) imaging with [11C]thiamine and [11C]TTFD was performed in normal rats to determine the pharmacokinetics of these probes, and the radiometabolites of both probes from the blood and heart tissue were analyzed by thin-layer chromatography. RESULTS: Accumulation of [11C]TTFD was significantly higher than that of [11C]thiamine in the rat heart. Moreover, as a result of the radiometabolite analysis of heart tissue at 15 min after the injection of [11C]TTFD, thiamine pyrophosphate, which serves as a cofactor for the enzymes involved in glucose metabolism, was found as the major radiometabolite and at a significantly higher level than in the [11C]thiamine-injected group. CONCLUSIONS: PET imaging techniques for visualizing the kinetics and metabolism of thiamine using [11C]thiamine and [11C]TTFD were developed in this study. Consequently, noninvasive PET imaging for the pathophysiology of thiamine-related cardiac function may provide novel information about heart failure and related disorders.
    Dec. 2018, Molecular imaging and biology, 20(6) (6), 1001 - 1007, English, International magazine
    Scientific journal

  • Kayo Takahashi, Takamitsu Hosoya, Kayo Onoe, Tadayuki Takashima, Masaaki Tanaka, Akira Ishii, Yasuhito Nakatomi, Shusaku Tazawa, Kazuhiro Takahashi, Hisashi Doi, Yasuhiro Wada, Yasuyoshi Watanabe
    Aromatase, an enzyme that converts androgens to estrogens, has been reported to be involved in several brain functions, including synaptic plasticity, neurogenesis, neuroprotection, and regulation of sexual and emotional behaviours in rodents, pathophysiology of Alzheimer's disease and autism spectrum disorders in humans. Aromatase has been reported to be involved in aggressive behaviours in genetically modified mice and in personality traits by genotyping studies on humans. However, no study has investigated the relationship between aromatase in living brains and personality traits including aggression. We performed a positron emission tomography (PET) study in 21 healthy subjects using 11C-cetrozole, which has high selectivity and affinity for aromatase. Before performing PET scans, subjects answered the Buss-Perry Aggression Questionnaire and Temperament and Character Inventory to measure their aggression and personality traits, respectively. A strong accumulation of 11C-cetrozole was detected in the thalamus, hypothalamus, amygdala, and medulla. Females showed associations between aromatase levels in subcortical regions, such as the amygdala and supraoptic nucleus of the hypothalamus, and personality traits such as aggression, novelty seeking, and self-transcendence. In contrast, males exhibited associations between aromatase levels in the cortices and harm avoidance, persistence, and self-transcendence. The association of aromatase levels in the thalamus with cooperativeness was common to both sexes. The present study suggests that there might exist associations between aromatase in the brain and personality traits. Some of these associations may differ between sexes, while others are likely common to both.
    Nov. 2018, Scientific reports, 8(1) (1), 16841 - 16841, English, International magazine
    Scientific journal

  • Zhouen Zhang, Takashi Niwa, Yasuyoshi Watanabe, Takamitsu Hosoya
    A palladium(ii)-mediated rapid 11C-cyanation of (hetero)arylborons with [11C]NH4CN/NH3 has been developed using bench-stable and readily available reagents. The method showed excellent functional-group tolerance, and allowed the highly efficient synthesis of a wide range of [11C]cyanoarenes, including PET tracers for aromatase imaging. A mechanistic study of the 11C-cyanation suggests the instantaneous formation of a mono[11C]cyanopalladium(ii) complex that reacts smoothly with arylborons.
    ROYAL SOC CHEMISTRY, Nov. 2018, Organic & biomolecular chemistry, 16(41) (41), 7711 - 7716, English, International magazine
    Scientific journal

  • Takao Hoshina, Satoshi Nozaki, Takashi Hamazaki, Satoshi Kudo, Yuka Nakatani, Hiroko Kodama, Haruo Shintaku, Yasuyoshi Watanabe
    INTRODUCTION: Menkes disease (MD) is an X-linked recessive disorder caused by dysfunction of a copper-transporting protein, leading to severe neurodegeneration in early childhood. We investigated whether a lipophilic copper chelator, disulfiram, could enhance copper absorption from the intestine and transport copper across the blood-brain barrier in MD model mice. METHODS: Wild type and MD model mice were pretreated with disulfiram for 30 min before oral administration of 64CuCl2. Each organ was sequentially analyzed for radioactivity with γ counting. Copper uptake into the brain parenchyma was assessed by ex vivo autoradiography. RESULTS: In wild type mice, orally administered copper was initially detected in the intestine within 2 h, reaching a maximum level in the liver (19.6 ± 3.8 percentage injected dose per gram [%ID/g]) at 6 h. In MD model mice, the copper reached the maximum level in the liver (5.3 ± 1.5 %ID/g) at 4 h, which was lower than that of wild type mice (19.0 ± 7.4 %ID/g) (P < 0.05). Pretreatment of disulfiram in MD model mice increased the copper level in the brain (0.59 ± 0.28 %ID/g) at 24 h compared with MD model mice without disulfiram (0.07 ± 0.05 %ID/g) (P < 0.05). Ex vivo autoradiography revealed that high levels of copper uptake was observed in the cerebral cortex upon disulfiram pretreatment. CONCLUSION: Our data demonstrated that disulfiram enhanced the delivery of orally administered copper into the central nervous system in MD model mice. The administration of disulfiram will enable patients to avoid unpleasant subcutaneous copper injection in the future.
    Nov. 2018, Journal of inherited metabolic disease, 41(6) (6), 1285 - 1291, English, International magazine
    Scientific journal

  • Yasuyoshi Watanabe
    Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease characterized by chronic, profound, disabling, and unexplained fatigue. A variety of studies have been performed to establish objective biomarkers of the disease, including positron emission tomography (PET) molecular imaging and neuro-functional imaging using magnetic resonance imaging (MRI) and magnetoencephalogram (MEG). In this chapter, we summarize the results from PET, MRI, and MEG imaging. Regional cerebral blood flow and glucose utilization rates are decreased in patients with ME/CFS as compared with age- and sex-matched healthy subjects. Acetyl-L-carnitine uptake into the releasable pool of glutamate and serotonin transporters densities are decreased in a few specific brain regions, mostly in the anterior cingulate in the patients. Although it is hypothesized that brain inflammation is involved in the pathophysiology of ME/CFS, there was no direct evidence of neuroinflammation in patients. Our recent PET study successfully demonstrated that neuroinflammation is present in widespread brain areas in ME/CFS patients, and is associated with the severity of neuropsychological symptoms. Evaluation of neuroinflammation in patients with ME/CFS may be essential for understanding the core pathophysiology, as well as for developing objective diagnostic criteria and effective medical treatments for ME/CFS. By using specific neurological features of these patients such as prefrontal cortical atrophies and the over-guarding phenomenon were found using MRI and functional MRI, respectively. We here describe related pathophysiological findings and topics in order to aid in the development of future therapies for ME/CFS patients.
    Nov. 2018, Brain and nerve = Shinkei kenkyu no shinpo, 70(11) (11), 1193 - 1201, Japanese, Domestic magazine
    Scientific journal

  • Yuka Nakamoto, Ambara R Pradipta, Hidefumi Mukai, Maki Zouda, Yasuyoshi Watanabe, Almira Kurbangalieva, Peni Ahmadi, Yoshiyuki Manabe, Koichi Fukase, Katsunori Tanaka
    Radiolabeled biomolecules with short half-life times are of increasing importance for positron emission tomography (PET) imaging studies. Herein, we demonstrate an improved and generalized method for synthesizing a [radiometal]-unsaturated aldehyde as a lysine-labeling probe that can be easily conjugated into various biomolecules through the RIKEN click reaction. As a case study, 68 Ga-PET imaging of U87MG xenografted mice is demonstrated by using the 68 Ga-DOTA-RGDyK peptide, which is selective to αV β3 integrins.
    Oct. 2018, Chembiochem : a European journal of chemical biology, 19(19) (19), 2055 - 2060, English, International magazine
    Scientific journal

  • Logopenic型進行性失語症患者における臨床症状とアミロイド・タウPETとの関連
    武田 景敏, 竹内 潤, 齊藤 明奈, 河邉 譲治, 和田 康弘, 馬渡 彩, 神母坂 あみ, 土居 久志, 渡辺 恭良, 北村 聡一郎, 島田 斉, 樋口 真人, 須原 哲也, 伊藤 義彰
    (一社)日本認知症学会, Sep. 2018, Dementia Japan, 32(3) (3), 419 - 419, Japanese

  • Takayuki Kikukawa, Takato Abe, Suzuka Ataka, Haruna Saito, Itsuki Hasegawa, Toshikazu Mino, Jun Takeuchi, Joji Kawabe, Yasuhiro Wada, Yasuyoshi Watanabe, Yoshiaki Itoh
    Mild cognitive impairment (MCI) can include the transition from a normal state to dementia. To explore biomarkers for the development of dementia, we performed an 18-month follow-up study in 28 patients with amnestic MCI. Amyloid deposition was examined using PiB PET, and cerebral blood flow (CBF) was examined using SPECT. Cognitive function was periodically assessed. The rate of conversion to dementia was higher in the PiB-positive/equivocal group (74%) than in the PiB-negative group (33%) (p = 0.041). Perfusion SPECT was performed in 16 patients. MCI patients with an AD-characteristic pattern of reduced CBF had a higher PiB-positive/equivocal rate (82%) than those with a non-AD pattern (20%) (p = 0.018), and patients with an AD pattern had a higher conversion rate (82%) than those with a non-AD pattern (40%) (p = 0.094). Clinically, all PiB-positive converters were diagnosed as having Alzheimer's disease (AD), whereas PiB-negative converters were thought to have some form of dementia other than AD. Amyloid PET is useful for predicting conversion to AD in MCI patients. A pattern analysis of perfusion SPECT findings might also be helpful for predicting conversion to AD, but with a lower specificity.
    Sep. 2018, Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 39(9) (9), 1597 - 1602, English, International magazine
    Scientific journal

  • Ying Zeng, Di Hu, Wei Yang, Emi Hayashinaka, Yasuhiro Wada, Yasuyoshi Watanabe, Qunli Zeng, Yilong Cui
    Placebo analgesia is the beneficial effect that follows despite a pharmacologically inert treatment. Modern neuroimaging studies in humans have delineated the hierarchical brain regions involved in placebo analgesia. However, because of the lack of proper approaches to perform molecular and cellular manipulations, the detailed molecular processes behind it have not been clarified. To address this issue, we developed an animal model of placebo analgesia in rats and analyzed the placebo analgesia related brain activity using small-animal neuroimaging method. We show here that gabapentin-based Pavlovian conditioning successfully induced placebo analgesia in neuropathic pain model rats and hierarchical brain regions are involved in placebo analgesia in rats, including the prelimbic cortex (PrL) of the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), ventrolateral periaqueductal gray matter (vlPAG), etc. The functional couplings in placebo responders between the mPFC and vlPAG was interrupted by naloxone, an antagonist of μ opioid receptor. Moreover, both local chemical lesion and microinfusion of naloxone in the mPFC suppressed the placebo analgesia. These results suggest that the intrinsic μ opioid system in the mPFC causally contribute to placebo analgesia in rats, and the small-animal neuroimaging approach could provide important insights toward understanding the placebo effect in great detail.
    Academic Press Inc., Sep. 2018, NeuroImage, 178, 602 - 612, English, International magazine
    [Refereed]
    Scientific journal

  • Akihiro Ogura, Sayaka Urano, Tsuyoshi Tahara, Satoshi Nozaki, Regina Sibgatullina, Kenward Vong, Takehiro Suzuki, Naoshi Dohmae, Almira Kurbangalieva, Yasuyoshi Watanabe, Katsunori Tanaka
    This work represents the first broad study of testing diverse heterogenous glycoconjugates (7 different glycoalbumins) for their differential in vivo binding (11 different cancer cell types) in both cell- and animal-based studies. As a result, various changes in biodistribution, excretion, and even tumor adhesion were observed.
    Aug. 2018, Chemical communications (Cambridge, England), 54(63) (63), 8693 - 8696, English, International magazine
    Scientific journal

  • Kazushi Matsumura, Maki Zouda, Yasuhiro Wada, Fumiyoshi Yamashita, Mitsuru Hashida, Yasuyoshi Watanabe, Hidefumi Mukai
    Radiolabeled antibodies, polyethylene glycol-conjugated (PEGylated) peptides, liposomes, and other materials were investigated as positron-emission tomography (PET) probes. These substances accumulate in tumors but often remain too long in circulation. We investigated the combination of intravenous urokinase injection and its substrate linker as a triggered radioisotope clearance enhancement system to improve imaging contrast. To this end, we synthesized a four-arm PEGylated 64Cu-bombesin analog tetramer with a urokinase substrate linker. In mouse blood, it was almost perfectly cleaved and degraded into smaller radioactive fragments in vitro with urokinase (≥20,000 IU/mL). In mouse blood circulation, ∼50-65% of the probe was rapidly degraded after the urokinase injection and the radioactive fragments were eliminated mainly from the kidney. In contrast, tumor radioactivity levels did not change, and therefore, the tumors were clearly visualized. The tumor/blood ratio, an indicator of imaging contrast, increased 2.5 times, while elimination of the radioisotope from the blood was enhanced. This approach has the potential to improve imaging contrast using various PET probes. It could also shorten the time required to obtain sufficient contrast and decrease patient radiation exposure.
    Jul. 2018, International journal of pharmaceutics, 545(1-2) (1-2), 206 - 214, English, International magazine
    Scientific journal

  • 【in vivoイメージングとセラノスティクスの新展開】PETを用いた薬物動態解析とDDS研究開発
    向井 英史, 渡辺 恭良
    ポジトロンエミッショントモグラフィー(PET)は、その高い感度や定量性から、非臨床試験・臨床試験の両者において標準的に活用されるモダリティとなりつつある。従来間接的に類推するしかなかったヒト組織中の薬物濃度推移について直接的な評価ができ、創薬標的分子や、病態診断や治療評価に重要な生体分子の発現や機能を可視化するPETプローブを薬効評価のサロゲートエンドポイントとして利用することも可能である。PETを中心とする分子イメージング技術を動物モデルとヒトで共通の評価基盤とするイメージング活用創薬により、開発初期から臨床試験・投薬治療まで薬物動態と薬効の関連を強く結びつけた、より実証的でシームレスな創薬研究が実現する。(著者抄録)
    日本DDS学会, Jul. 2018, Drug Delivery System, 33(3) (3), 204 - 213, Japanese
    [Refereed]
    Scientific journal

  • Akira Ishii, Takuya Ishizuka, Yuki Muta, Masaaki Tanaka, Emi Yamano, Yasuyoshi Watanabe
    Fatigue sensation is an essential biological alarm that urges us to take rest to avoid disrupting homeostasis and thus plays an important role in maintaining well-being. However, there are situations in which the anticipation of unpleasant fatigue sensation undesirably reduces motivation for activity. The aim of this study was to examine whether thinking positively about the fatigue sensation would increase motivation to accomplish the workload. Fourteen healthy male volunteers participated in this study and performed a two-back test for 30 min to induce mental fatigue sensation. After their subjective level of fatigue had recovered to the baseline level, they re-experienced the fatigue sensation experienced in the two-back test positively, negatively, and without any modification (i.e., re-experienced the fatigue sensation as it was). The level of motivation to perform another two-back test they felt during the re-experiencing was assessed. The neural activity related to the re-experiencing was recorded using magnetoencephalography. The level of the motivation to perform another two-back test was increased by positively re-experiencing the fatigue sensation. The increase in delta band power in Brodmann area 7 was positively associated with the increase in motivation. These results show that positive thinking about fatigue sensation can enhance motivation and suggest that this enhanced motivation may have some effects on visual attention system.
    Jun. 2018, Experimental brain research, 236(6) (6), 1735 - 1747, English, International magazine
    Scientific journal

  • Satoshi Tamada, Kyoko Ebisu, Sayaka Yasuda, Minoru Kato, Noriko Ninomiya, Takeshi Yamasaki, Taro Iguchi, Tatsuya Nakatani, Yasuyoshi Watanabe
    BACKGROUND: Cancer-related fatigue is one of the most prevalent symptoms that patients with cancer experience, but the mechanisms underlying it are unknown. We aimed to quantify and mechanistically evaluate the improvement in fatigue related to administration of the Kampo medicine, Kamikihito. MATERIALS AND METHODS: Initially, we recruited outpatients with urological diseases and compared fatigue levels of 37 patients with cancer with a control group of 23 volunteers who had recovered completely from cancer or who were being treated for dysuria. Fatigue level was estimated using an autonomic function analyzer. Then, Kamikihito was administered to another 35 patients treated with hormone or antitumor therapy for prostate cancer and metastatic renal cell cancer. Subjective fatigue and other problems of the patients were assessed using the Chalder fatigue scale, the Center for Epidemiologic Studies Depression scale, and the Epworth sleepiness scale. Serum levels of derivatives of reactive oxygen species and biological antioxidant potential were also measured. RESULTS: Patients in the cancer treatment group experienced more fatigue compared with the control patients when evaluated using an autonomic function analyzer. The group of 35 patients who were administered Kamikihito showed improved scores for fatigue, depression, and sleepiness. Autonomic nervous system balance was also improved with Kamikihito administration. The Kamikihito group also had significantly lower reactive oxygen species metabolite levels and significantly higher antioxidant potential. CONCLUSIONS: Fatigue was more serious in patients with cancer than in control patients. Kamikihito rescued this fatigue and improved anxiety and sleepiness. It restored autonomic nervous system balance and antioxidant function.
    Jun. 2018, Prostate international, 6(2) (2), 55 - 60, English, International magazine
    Scientific journal

  • Isao Kii, Shino Hirahara-Owada, Masataka Yamaguchi, Takashi Niwa, Yuka Koike, Rie Sonamoto, Harumi Ito, Kayo Takahashi, Chihiro Yokoyama, Takuya Hayashi, Takamitsu Hosoya, Yasuyoshi Watanabe
    Oxytocin (OXT) and arginine vasopressin (AVP) are structurally similar neuropeptide hormones that function as neurotransmitters in the brain, and have opposite key roles in social behaviors. These peptides bind to their G protein-coupled receptors (OXTR and AVPRs), inducing calcium ion-dependent signaling pathways and endocytosis of these receptors. Because selective agonists and antagonists for these receptors have been developed as therapeutic and diagnostic agents for diseases such as psychiatric disorders, facile methods are in demand for the evaluation of selectivity between these receptors. In this study, we developed a quantitative assay for OXT- and AVP-induced endocytosis of their receptors. The mutated Oplophorus luciferase, nanoKAZ, was fused to OXTR and AVPRs to enable rapid quantification of agonist-induced endocytosis by bioluminescence reduction. Agonist stimulation significantly decreases bioluminescence of nanoKAZ-fused receptors in living cells. Using this system, we evaluated clinically used OXTR antagonist atosiban and a reported pyrazinyltriazole derivative, hereby designated as PF13. Atosiban acted as an antagonist of AVPR1a, as well as an agonist for AVPR1b, whereas PF13 antagonized OXTR more selectively than atosiban, as reported previously. This paper shows a strategy for quantification of agonist-induced endocytosis of OXTR and AVPRs, and confirms its potent utility in the evaluation of agonists and antagonists.
    May 2018, Analytical biochemistry, 549, 174 - 183, English, International magazine
    Scientific journal

  • Hidefumi Mukai, Maiko Takahashi, Yasuyoshi Watanabe
    Bacterial cancer therapy, wherein bacteria are used as a gene expression system for the exogenous protein of interest in the body, has started becoming a focus area of research; therefore, studying potential bacterial species for use is extremely important. Here, we investigated the use of Brevibacillus choshinensis as an effective and safe provider of anticancer proteins in the body, using a transformant expressing murine tumor necrosis factor-α (mTNF-α). The transformant sustainably provided mTNF-α in tumors in mice for a few hours post-injection. The growth of TNF-α-sensitive tumors was inhibited even by the control transformant, which did not provide mTNF-α; intratumoral mTNF-α provision by Brevibacillus choshinensis had additive effects on tumor growth inhibition. In contrast, intratumorally injected recombinant mTNF-α did not inhibit tumor growth because of rapid elimination from the tumor. Blood biochemical and histochemical analyses showed that intravenous injection of the transformant that did not provide mTNF-α did not lead to tissue injury and dysfunction or infiltration of inflammatory cells over 1 week. Considering the findings, this approach is expected to have a high degree of usability as a delivery system for protein pharmaceuticals, especially from the viewpoints of loading capacity and cost effectiveness.
    May 2018, Cancer gene therapy, 25(3-4) (3-4), 47 - 57, English, International magazine
    Scientific journal

  • Ken-Ichi Kaneko, Masaaki Tanaka, Akira Ishii, Yumiko Katayama, Takayoshi Nakaoka, Satsuki Irie, Hideki Kawahata, Takashi Yamanaga, Yasuhiro Wada, Takeshi Miyake, Kota Toshimoto, Kazuya Maeda, Yilong Cui, Masaru Enomoto, Etsushi Kawamura, Norifumi Kawada, Joji Kawabe, Susumu Shiomi, Hiroyuki Kusuhara, Yuichi Sugiyama, Yasuyoshi Watanabe
    Various positron emission tomography (PET) probes have been developed to assess in vivo activities in humans of drug transporters, which aid in the prediction of pharmacokinetic properties of drugs and the impact of drug-drug interactions. We developed a new PET probe, sodium (3R, 5R)-3, 5-dihydroxy-7-((1S, 2S, 6S, 8S)-6-hydroxy-2-methyl-8- ((1-[11C]-(E)-2-methyl-but-2-enoyl) oxy) -1, 2, 6, 7, 8, 8a-hexahydronaphthalen-1-yl) heptanoate ([11C]DPV), and demonstrated its usefulness for the quantitative investigation of Oatps (gene symbol SLCO) and Mrp2 (gene symbol ABCC2) in rats. To further analyze the species differences and verify the pharmacokinetic parameters in humans, serial PET scanning of the abdominal region with [11C]DPV was performed in six healthy volunteers with and without an OATP1Bs and MRP2 inhibitor, rifampicin (600 mg, oral), in a crossover fashion. After intravenous injection, [11C]DPV rapidly distributed to the liver and kidney followed by secretion into the bile and urine. Rifampicin significantly reduced the liver distribution of [11C]DPV 3-fold, resulting in a 7.5-fold reduced amount of excretion into the bile and the delayed elimination of [11C]DPV from the blood circulation. The hepatic uptake clearance (CLuptake, liver) and canalicular efflux clearance (CLint, bile) of [11C]DPV (544 ± 204 and 10.2 ± 3.5 µl/min per gram liver, respectively) in humans were lower than the previously reported corresponding parameters in rats (1800 and 298 µl/min per gram liver, respectively) (Shingaki et al., 2013). Furthermore, rifampicin treatment significantly reduced CLuptake, liver and CLint, bile by 58% and 44%, respectively. These results suggest that PET imaging with [11C]DPV is an effective tool for quantitatively characterizing the OATP1Bs and MRP2 functions in the human hepatobiliary transport system.
    May 2018, Drug metabolism and disposition: the biological fate of chemicals, 46(5) (5), 719 - 728, English, International magazine
    Scientific journal

  • がん組織イメージングコントラストの改善を目的としたウロキナーゼ薬剤に対する基質ペプチドを有する免疫PETプローブの有用性評価
    毛利 浩太, 仁 欽, 藁科 翔太, 林中 恵美, 和田 康弘, 渡辺 恭良, 向井 英史
    日本分子イメージング学会, May 2018, JSMI Report, 11(2) (2), 66 - 66, Japanese

  • 静脈内投与後腫瘍組織に生着した大腸菌のプラスミド維持の評価
    野村 祥子, Erike Sukowati, 高橋 麻衣子, 渡辺 恭良, 向井 英史
    日本DDS学会, May 2018, 日本DDS学会学術集会プログラム予稿集, 34回, 184 - 184, Japanese

  • [18F]Fluorine-incorporated(S)-ketoprofen methyl ester PETイメージングによる神経炎症の定量的評価
    金子 健一, 馬渡 彩, 入江 さつき, 林中 恵美, 和田 康弘, 土居 久志, 崔 翼龍, 渡辺 恭良
    日本分子イメージング学会, May 2018, JSMI Report, 11(2) (2), 124 - 124, Japanese

  • 慢性疲労動物を用いた疲労の慢性化機序の解析
    胡 迪, 李 丹渓, 重田 美香, 岡内 隆, 渡辺 恭良, 崔 翼龍
    日本疲労学会, May 2018, 日本疲労学会誌, 14(1) (1), 41 - 41, Japanese

  • 慢性疲労に誘発されたラットの体温調節系の機能的変化(Chronic fatigue induced functional change of the thermoregulatory system in rats)
    李 丹渓, 胡 迪, 重田 美香, 岡内 隆, 渡辺 恭良, 崔 翼龍
    日本疲労学会, May 2018, 日本疲労学会誌, 14(1) (1), 64 - 64, English

  • ウロキナーゼ静脈内投与により腎クリアランスが促進されコントラストが向上する免疫PETプローブの開発
    仁 欽, 毛利 浩太, 藁科 翔太, 林中 恵美, 和田 康弘, 渡辺 恭良, 向井 英史
    (公社)日本薬学会, Mar. 2018, 日本薬学会年会要旨集, 138年会(2) (2), 244 - 244, Japanese

  • Yasuyoshi Watanabe, Hirohiko Kuratsune
    Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease characterized by chronic, profound, disabling, and unexplained fatigue. The first patient with ME/CFS in Japan was identified and described in 1990 by Prof. Teruo Kitani and Dr. Hirohiko Kuratsune of the Research Institute for Microbial Diseases, Osaka University. Since then, a variety of studies have been performed to determine the objective biomarkers of the disease. Although it is hypothesized that brain inflammation is involved in the pathophysiology of ME/CFS, there is to date no direct evidence of neuroinflammation in patients with ME/CFS. Our recent positron emission tomography study successfully demonstrated that microglial activation, which is linked to neuroinflammation, occurs in widespread brain areas in patients with ME/CFS, and is associated with the severity of the neuropsychological symptoms. Thus, evaluation of neuroinflammation in patients with ME/CFS may be essential for understanding the core pathophysiology of the disease, and for developing objective diagnostic criteria and effective medical treatments for ME/CFS. Here, we describe disease-related pathophysiological findings and topics, and discuss the history of the diagnostic and therapeutic attempts based on previous findings in Japan.
    Jan. 2018, Brain and nerve = Shinkei kenkyu no shinpo, 70(1) (1), 5 - 9, Japanese, Domestic magazine
    Scientific journal

  • Yasuhito Nakatomi, Hirohiko Kuratsune, Yasuyoshi Watanabe
    Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by chronic, profound, disabling, and unexplained fatigue; cognitive impairment; and chronic widespread pain. By using positron emission tomography, our study demonstrated neuroinflammation in the brain of patients with ME/CFS. Neuroinflammation was found to be widespread in the brain areas of the patients with ME/CFS and was associated with the severity of their neuropsychological symptoms. The ongoing research would lead to the establishment of objective diagnostic criteria and development of an appropriate therapy.
    Jan. 2018, Brain and nerve = Shinkei kenkyu no shinpo, 70(1) (1), 19 - 25, Japanese, Domestic magazine
    Scientific journal

  • Naoko Saito, Emi Yamano, Akira Ishii, Masaaki Tanaka, Junji Nakamura, Yasuyoshi Watanabe
    Some components of the neural circuits underlying innate odor-evoked responses have recently been elucidated. Odor information detected by the olfactory receptors is transmitted from the olfactory bulb to the cortical amygdala, where physiological and emotional states such as attraction or avoidance are controlled. Thus, activation of specific olfactory receptors can elicit changes in physiological and/or psychological state. Here, we examined on the odorant Hex-Hex Mix, which has been reported to induce anti-fatigue effects. Fatigue is a prevalent condition that is often related to overwork and psychological stress. Various anti-fatigue treatments have been developed, including supplements and odorants. However, the mechanisms underlying the anti-fatigue effects of these substances are currently unclear. In the present study, we analyzed the involvement of the olfactory system in the mechanisms underlying this effect. We identified the human olfactory receptors activated by Hex-Hex Mix, and evaluated whether activation of these olfactory receptors by a newly developed odorant elicited a similar anti-fatigue effect to Hex-Hex Mix. We assessed anti-fatigue effects with behavioral tests, and 17 healthy males performed the 2-back test as a fatigue-inducing task with or without exposure to the new odorant. Immediately before and after the task, participants performed a cognitive task to evaluate their level of mental fatigue. We found that the difference value of the correct response rate on the cognitive task in the evaluation session was significantly different between in the odorant condition and in the without-odorant condition during the fatigue-inducing session suggesting that the new odorant may improve performance in the fatigue-inducing condition. The results indicated that the new odorant activates the same olfactory receptors as Hex-Hex Mix, which has been reported to induce anti-fatigue effects. Our findings suggest that the olfactory receptors in the olfactory system may be involved in the attenuation of fatigue.
    2018, PloS one, 13(3) (3), e0195263, English, International magazine
    Scientific journal

  • Keisuke Kokubun, Kiyotaka Nemoto, Hiroki Oka, Hiroki Fukuda, Yoshinori Yamakawa, Yasuyoshi Watanabe
    Stress is associated with a greater risk for various health problems including reduced gray matter volume (GMV) and density in a number of brain regions. Previous studies show that neuroimaging could be a means to objectively evaluate stress. However, to date, no definite neuroimaging-derived measures are available to detect stress. In this research we used the gray-matter brain healthcare quotient (GM-BHQ), an MRI-based quotient for monitoring brain health based on GMV, as an objective scale to measure the association of stress with the whole brain. We recruited 63 healthy adults to acquire structural T1-weighted images and stress levels evaluated using three representative stress scales: the Profile of Mood States (POMS), Perceived Stress Scale (PSS) and Chalder Fatigue Scale (CFS). We found that the GM-BHQ was sensitive to fatigue and the interaction between fatigue and stress.
    2018, Frontiers in behavioral neuroscience, 12, 154 - 154, English, International magazine
    Scientific journal

  • Mizuno K, Sasaki AT, Ebisu K, Tajima K, Kajimoto O, Nojima J, Kuratsune H, Hori H, Watanabe Y
    Health and a vibrant life are sought by everyone. To improve quality of life (QOL), maintain a healthy state, and prevent various diseases, evaluations of the effects of potentially QOL-increasing factors are important. Chronic oxidative stress and inflammation cause deteriorations in central nervous system function, leading to low QOL. In healthy individuals, aging, job stress, and cognitive load over several hours also induce increases in oxidative stress, suggesting that preventing the accumulation of oxidative stress caused by daily stress and daily work contributes to maintaining QOL and ameliorating the effects of aging. Hydrogen has anti-oxidant activity and can prevent inflammation, and may thus contribute to improve QOL. The present study aimed to investigate the effects of drinking hydrogen-rich water (HRW) on the QOL of adult volunteers using psychophysiological tests, including questionnaires and tests of autonomic nerve function and cognitive function. In this double-blinded, placebo-controlled study with a two-way crossover design, 26 volunteers (13 females, 13 males; mean age, 34.4 ± 9.9 years) were randomized to either a group administered oral HRW (600 mL/d) or placebo water (PLW, 600 mL/d) for 4 weeks. Change ratios (post-treatment/pre-treatment) for K6 score and sympathetic nerve activity during the resting state were significantly lower after HRW administration than after PLW administration. These results suggest that HRW may reinforce QOL through effects that increase central nervous system functions involving mood, anxiety, and autonomic nerve function.
    2018, Med Gas Res., 7(4) (4), 247 - 255, English, International magazine
    [Refereed]
    Scientific journal

  • Hiroyuki Kusuhara, Tadayuki Takashima, Hisako Fujii, Tsutomu Takashima, Masaaki Tanaka, Akira Ishii, Shusaku Tazawa, Kazuhiro Takahashi, Kayo Takahashi, Hidekichi Tokai, Tsuneo Yano, Makoto Kataoka, Akihiro Inano, Suguru Yoshida, Takamitsu Hosoya, Yuichi Sugiyama, Shinji Yamashita, Taisuke Hojo, Yasuyoshi Watanabe
    The aim of the present study is to investigate the pharmacokinetics of our newly developed aromatase inhibitors (cetrozole and TMD-322) in healthy subjects by a cassette microdose strategy. A cocktail of cetrozole and TMD-322 was administered intravenously or orally (1.98 μg for each drug) to six healthy volunteers in a crossover fashion. Anastrozole (1.98 μg) was also included in the oral cocktail. Total body clearance and bioavailability were 12.1 ± 7.1 mL/min/kg and 34.9 ± 32.3% for cetrozole, and 16.8 ± 3.5 mL/min/kg and 18.4 ± 12.2% for TMD-322, respectively. The area under the plasma concentration-time curves of cetrozole and TMD-322 after oral administration was markedly lower than that of anastrozole because of their high hepatic clearance. Two subjects out of six exhibited 4- and 17-fold larger exposure of cetrozole than the others following intravenous and oral administration, respectively. Such variation was not observed for TMD-322 and anastrozole. Extensive metabolism of cetrozole and TMD-322 was observed in the CYP2C19 expression system among the test CYP isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4). We report the first clinical investigation of our aromatase inhibitors by a cassette microdose strategy in healthy Japanese subjects. This strategy offers an optional approach for candidate selection as a phase zero study in drug development.
    Dec. 2017, Drug metabolism and pharmacokinetics, 32(6) (6), 293 - 300, English, International magazine
    Scientific journal

  • Akira Ishii, Masaaki Tanaka, Takahiro Yoshikawa, Yasuyoshi Watanabe
    Since fatigue is prevalent in modern societies, it is necessary to clarify the neural mechanisms of fatigue. The regulation of performance through fatigue sensation is one of the mechanisms that decreases performance in fatigue. However, it is unknown whether subjective feeling of fatigue is necessary for the regulation of performance. Here, we examined whether decreased performance occurs without increased fatigue sensation through the experiment which was designed to test if fatigue can be learned unconsciously. Healthy male volunteers performed a fatigue-inducing hand-grip task for 10 min while viewing a target image presented without awareness. On the next day, they viewed a control and the target images presented with awareness and the neural activity caused by viewing the images was measured using magnetoencephalography. Results showed the level of fatigue sensation was not altered but grip-strength was decreased by viewing the target image on the second day. The level of beta band power in Brodmann's area 31 was increased by viewing the target image and this increase was negatively associated with the decrease of grip-strength caused in the hand-grip task. These findings demonstrated that fatigue can be learned unconsciously and that there is a mechanism to decrease performance without fatigue sensation.
    Nov. 2017, Scientific reports, 7(1) (1), 16103 - 16103, English, International magazine
    Scientific journal

  • Shinsuke Sasada, Hiroaki Kurihara, Takayuki Kinoshita, Masayuki Yoshida, Natsuki Honda, Tatsunori Shimoi, Akihiko Shimomura, Kan Yonemori, Chikako Shimizu, Akinobu Hamada, Yousuke Kanayama, Yasuyoshi Watanabe, Yasuhiro Fujiwara, Kenji Tamura
    Nov. 2017, European journal of nuclear medicine and molecular imaging, 44(12) (12), 2146 - 2147, English, International magazine
    Scientific journal

  • Satoshi Nozaki, Naoko Ozaki, Shinobu Suzuki, Miki Goto, Aya Mawatari, Yuka Nakatani, Emi Hayashinaka, Yasuhiro Wada, Hisashi Doi, Yasuyoshi Watanabe
    PURPOSE: In vivo detection of pathological insults during the early stages of rheumatoid synovitis is essential to allow early anti-inflammatory treatment for prevention of joint destruction. Whether rheumatoid synovitis pathology and the efficacy of therapies can be visualized by positron emission tomography (PET) tracers specific to the inflammatory process was investigated. PROCEDURES: Using a collagen-induced experimental rat model of rheumatoid arthritis, in vivo imaging using the PET tracers [11C]PK11195, which binds to the translocator protein mainly expressed on myeloid cells, and [11C]ketoprofen, for cyclooxygenase imaging, was performed. To evaluate therapeutic efficacy, model animals were administered the tumour necrosis factor alpha blocker etanercept subcutaneously. RESULTS: [11C]PK11195 and [11C]ketoprofen uptakes were significantly higher in inflamed paws of collagen-induced arthritis rats than in normal rats. The data showed a correlation between tracer uptake values and paw swelling. After treatment with etanercept, [11C]ketoprofen uptake was significantly lower in treated animals than in untreated ones, whereas [11C]PK11195 uptake in the inflamed regions was comparable to that in the untreated group. CONCLUSIONS: With [11C]PK11195 and [11C]ketoprofen tracers, non-invasive in vivo PET imaging for rheumatoid synovitis can provide diagnostic evidence of early synovitis and allow monitoring inflammatory cell activity during treatment.
    Oct. 2017, Molecular imaging and biology, 19(5) (5), 746 - 753, English, International magazine
    Scientific journal

  • Tomonori Fukuchi, Takashi Okauchi, Mika Shigeta, Seiichi Yamamoto, Yasuyoshi Watanabe, Shuichi Enomoto
    PURPOSE: Positron emission tomography (PET) is a useful imaging modality that quantifies the physiological distributions of radiolabeled tracers in vivo in humans and animals. However, this technique is unsuitable for multiple-tracer imaging because the annihilation photons used for PET imaging have a fixed energy regardless of the selection of the radionuclide tracer. This study developed a multi-isotope PET (MI-PET) system and evaluated its imaging performance. METHODS: Our MI-PET system is composed of a PET system and additional γ-ray detectors. The PET system consists of pixelized gadolinium orthosilicate (GSO) scintillation detectors and has a ring geometry that is 95 mm in diameter with an axial field of view of 37.5 mm. The additional detectors are eight bismuth germanium oxide (BGO) scintillation detectors, each of which is 50 × 50 × 30 mm3 , arranged into two rings mounted on each side of the PET ring with a 92-mm-inner diameter. This system can distinguish between different tracers using the additional γ-ray detectors to observe prompt γ-rays, which are emitted after positron emission and have an energy intrinsic to each radionuclide. Our system can simultaneously acquire double- (two annihilation photons) and triple- (two annihilation photons and a prompt γ-ray) coincidence events. The system's efficiency for detecting prompt de-excitation γ-rays was measured using a positron-γ emitter, 22 Na. Dual-radionuclide (18 F and 22 Na) imaging of a rod phantom and a mouse was performed to demonstrate the performance of the developed system. Our system's basic performance was evaluated by reconstructing two images, one containing both tracers and the other containing just the second tracer, from list-mode data sets that were categorized by the presence or absence of the prompt γ-ray. RESULTS: The maximum detection efficiency for 1275 keV γ-rays emitted from 22 Na was approximately 7% at the scanner's center, and the minimum detection efficiency was 5.1% at the edge of the field of view. Dual-radionuclide imaging of the point sources and rod phantom revealed that our system maintained PET's intrinsic spatial resolution and quantitative nature for the second tracer. We also successfully acquired simultaneous double- and triple-coincidence events from a mouse containing 18 F-fluoro-deoxyglucose and 22 Na dissolved in water. The dual-tracer distributions in the mouse obtained by our MI-PET were reasonable from the viewpoints of physiology and pharmacokinetics. CONCLUSIONS: This study demonstrates the feasibility of multiple-tracer imaging using PET with additional γ-ray detectors. This method holds promise for enabling the reconstruction of quantitative multiple-tracer images and could be very useful for analyzing multiple-molecular dynamics.
    Jun. 2017, Medical physics, 44(6) (6), 2257 - 2266, English, International magazine
    Scientific journal

  • Nobuhiro Nakai, Masatoshi Nagano, Fumihito Saitow, Yasuhito Watanabe, Yoshinobu Kawamura, Akiko Kawamoto, Kota Tamada, Hiroshi Mizuma, Hirotaka Onoe, Yasuyoshi Watanabe, Hiromu Monai, Hajime Hirase, Jin Nakatani, Hirofumi Inagaki, Tomoyuki Kawada, Taisuke Miyazaki, Masahiko Watanabe, Yuka Sato, Shigeo Okabe, Kazuo Kitamura, Masanobu Kano, Kouichi Hashimoto, Hidenori Suzuki, Toru Takumi
    Serotonin is a critical modulator of cortical function, and its metabolism is defective in autism spectrum disorder (ASD) brain. How serotonin metabolism regulates cortical physiology and contributes to the pathological and behavioral symptoms of ASD remains unknown. We show that normal serotonin levels are essential for the maintenance of neocortical excitation/inhibition balance, correct sensory stimulus tuning, and social behavior. Conversely, low serotonin levels in 15q dup mice (a model for ASD with the human 15q11-13 duplication) result in impairment of the same phenotypes. Restoration of normal serotonin levels in 15q dup mice revealed the reversibility of a subset of ASD-related symptoms in the adult. These findings suggest that serotonin may have therapeutic potential for discrete ASD symptoms.
    Jun. 2017, Science advances, 3(6) (6), e1603001, English, International magazine
    Scientific journal

  • PETイメージングによる64Cu標識エクソソームの動態評価
    藁科 翔太, 造田 真希, 和田 康弘, 渡辺 恭良, 向井 英史
    日本DDS学会, Jun. 2017, 日本DDS学会学術集会プログラム予稿集, 33回, 198 - 198, Japanese

  • Palladium(II)-Mediated Rapid C-11-Cyanation of Aryl Borons: a General Method for the Synthesis of PET Tracers with a [cyano-C-11]Cyanoarene Structure
    Zhouen Zhang, Takashi Niwa, Yasuyoshi Watanabe, Takamitsu Hosoya
    WILEY, May 2017, JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS, 60, S45 - S45, English

  • 標的性を付与した先駆的医薬品の開発と評価 創薬・DDS評価におけるPETイメージングの活用
    向井 英史, 渡辺 恭良
    (公社)日本薬剤学会, May 2017, 日本薬剤学会年会講演要旨集, 32年会, 31 - 31, Japanese

  • [18F]DPA-714 PETイメージングによる神経炎症の定量的評価
    金子 健一, 馬渡 彩, 入江 さつき, 胡 迪, 中岡 貴義, 林中 恵美, 和田 康弘, 土居 久志, 崔 翼龍, 渡辺 恭良
    日本分子イメージング学会, May 2017, JSMI Report, 10(2) (2), 159 - 159, Japanese

  • 内側前脳束の脳内自己刺激後における脳内糖代謝変容部位の検索
    岡内 隆, 武 玉萍, 重田 美香, 林中 恵美, 和田 康弘, 渡辺 恭良, 崔 翼龍
    日本分子イメージング学会, May 2017, JSMI Report, 10(2) (2), 163 - 163, Japanese

  • 動物モデル 新しい慢性疲労モデルの確立および慢性化形成に関わる血中ホルモンの動態変化の解析
    胡 迪, 李 丹渓, 重田 美香, 岡内 隆, 渡邊 恭良, 崔 翼龍
    日本疲労学会, May 2017, 日本疲労学会誌, 13(1) (1), 54 - 54, Japanese

  • ラットの慢性中枢性疲労発生期における体温調節システムの機能的変化(Functional change of the thermoregulatory system during chronic fatigue formation in rats)
    李 丹渓, 胡 迪, 重田 美香, 岡内 隆, 李 峰, 渡邊 恭良, 崔 翼龍
    日本疲労学会, May 2017, 日本疲労学会誌, 13(1) (1), 101 - 101, English

  • Kazuki Tsubokura, Kenward K H Vong, Ambara R Pradipta, Akihiro Ogura, Sayaka Urano, Tsuyoshi Tahara, Satoshi Nozaki, Hirotaka Onoe, Yoichi Nakao, Regina Sibgatullina, Almira Kurbangalieva, Yasuyoshi Watanabe, Katsunori Tanaka
    Metal complex catalysis within biological systems is largely limited to cell and bacterial systems. In this work, a glycoalbumin-AuIII complex was designed and developed that enables organ-specific, localized propargyl ester amidation with nearby proteins within live mice. The targeted reactivity can be imaged through the use of Cy7.5- and TAMRA-linked propargyl ester based fluorescent probes. This targeting system could enable the exploitation of other metal catalysis strategies for biomedical and clinical applications.
    Mar. 2017, Angewandte Chemie (International ed. in English), 56(13) (13), 3579 - 3584, English, International magazine
    Scientific journal

  • PETによる体内動態解析を指向したエクソソーム表面への64Cu標識
    藁科 翔太, 造田 真希, 仁 欽, 渡辺 恭良, 向井 英史
    (公社)日本薬学会, Mar. 2017, 日本薬学会年会要旨集, 137年会(4) (4), 91 - 91, Japanese

  • がん治療用細菌マシンを目的としたRGDペプチド提示大腸菌の作製とがん細胞に対する相互作用の評価
    高橋 麻衣子, 渡辺 恭良, 向井 英史
    (公社)日本薬学会, Mar. 2017, 日本薬学会年会要旨集, 137年会(4) (4), 98 - 98, Japanese

  • Masayuki Nakano, Yasuhisa Tamura, Masanori Yamato, Satoshi Kume, Asami Eguchi, Kumi Takata, Yasuyoshi Watanabe, Yosky Kataoka
    NG2-expressing neural progenitor cells (i.e., NG2 glial cells) maintain their proliferative and migratory activities even in the adult mammalian central nervous system (CNS) and produce myelinating oligodendrocytes and astrocytes. Although NG2 glial cells have been observed in close proximity to neuronal cell bodies in order to receive synaptic inputs, substantive non-proliferative roles of NG2 glial cells in the adult CNS remain unclear. In the present study, we generated NG2-HSVtk transgenic rats and selectively ablated NG2 glial cells in the adult CNS. Ablation of NG2 glial cells produced defects in hippocampal neurons due to excessive neuroinflammation via activation of the interleukin-1 beta (IL-1β) pro-inflammatory pathway, resulting in hippocampal atrophy. Furthermore, we revealed that the loss of NG2 glial cell-derived hepatocyte growth factor (HGF) exacerbated these abnormalities. Our findings suggest that NG2 glial cells maintain neuronal function and survival via the control of neuroimmunological function.
    Feb. 2017, Scientific reports, 7, 42041 - 42041, English, International magazine
    Scientific journal

  • Liliya Latypova, Regina Sibgatullina, Akihiro Ogura, Katsumasa Fujiki, Alsu Khabibrakhmanova, Tsuyoshi Tahara, Satoshi Nozaki, Sayaka Urano, Kazuki Tsubokura, Hirotaka Onoe, Yasuyoshi Watanabe, Almira Kurbangalieva, Katsunori Tanaka
    Structurally well-defined heterogeneous N-glycoclusters are prepared on albumin via a double click procedure. The number of glycan molecules present, in addition to the spatial arrangement of glycans in the heterogeneous glycoclusters, plays an important role in the in vivo kinetics and organ-selective accumulation through glycan pattern recognition mechanisms.
    Feb. 2017, Advanced science (Weinheim, Baden-Wurttemberg, Germany), 4(2) (2), 1600394 - 1600394, English, International magazine
    Scientific journal

  • Takayuki Kikukawa, Haruna Saito, Itsuki Hasegawa, Jun Takeuchi, Akitoshi Takeda, Joji Kawabe, Yasuhiro Wada, Aya Mawatari, Yasuyoshi Watanabe, Soichiro Kitamura, Hitoshi Shimada, Makoto Higuchi, Tetsuya Suhara, Yoshiaki Itoh
    OMICS Publishing Group, 2017, Journal of Alzheimer’s Disease & Parkinsonism, 07(06) (06)
    Scientific journal

  • Satoshi Kume, Yukako Nishimura, Kei Mizuno, Nae Sakimoto, Hiroshi Hori, Yasuhisa Tamura, Masanori Yamato, Rika Mitsuhashi, Keigo Akiba, Jun-Ichi Koizumi, Yasuyoshi Watanabe, Yosky Kataoka
    It is widely accepted that listening to music improves subjective feelings and reduces fatigue sensations, and different kinds of music lead to different activations of these feelings. Recently, cardiac autonomic nervous modulation has been proposed as a useful objective indicator of fatigue. However, scientific considerations of the relation between feelings of fatigue and cardiac autonomic nervous modulation while listening to music are still lacking. In this study, we examined which subjective feelings of fatigue are related to participants' cardiac autonomic nervous function while they listen to music. We used an album of comfortable and relaxing environmental music, with blended sounds from a piano and violin as well as natural sound sources. We performed a crossover trial of environmental music and silent sessions for 20 healthy subjects, 12 females, and 8 males, after their daily work shift. We measured changes in eight types of subjective feelings, including healing, fatigue, sleepiness, relaxation, and refreshment, using the KOKORO scale, a subjective mood measurement system for self-reported feelings. Further, we obtained measures of cardiac autonomic nervous function on the basis of heart rate variability before and after the sessions. During the music session, subjective feelings significantly shifted toward healing and a secure/relaxed feeling and these changes were greater than those in the silent session. Heart rates (ΔHR) in the music session significantly decreased compared with those in the silent session. Other cardiac autonomic parameters such as high-frequency (HF) component and the ratio of low-frequency (LF) and HF components (LF/HF) were similar in the two sessions. In the linear regression analysis of the feelings with ΔHR and changes in LF/HF (ΔLF/HF), increases and decreases in ΔHR were correlated to the feeling axes of Fatigue-Healing and Anxiety/Tension-Security/Relaxation, whereas those in ΔLF/HF were related to the feeling axes of Sleepiness-Wakefulness and Gloomy-Refreshed. This indicated that listening to music improved the participants' feelings of fatigue and decreased their heart rates. However, it did not reduce the cardiac LF/HF, suggesting that cardiac LF/HF might show a delayed response to fatigue. Thus, we demonstrated changes in cardiac autonomic nervous functions based on feelings of fatigue.
    2017, Frontiers in neuroscience, 11, 108 - 108, English, International magazine
    Scientific journal

  • Neural basis of individual differences in the response to mental stress: a magnetoencephalography study.
    Emi Yamano, Akira Ishii, Masaaki Tanaka, Shusaku Nomura, Yasuyoshi Watanabe
    Stress is a risk factor for the onset of mental disorders. Although stress response varies across individuals, the mechanism of individual differences remains unclear. Here, we investigated the neural basis of individual differences in response to mental stress using magnetoencephalography (MEG). Twenty healthy male volunteers completed the Temperament and Character Inventory (TCI). The experiment included two types of tasks: a non-stress-inducing task and a stress-inducing task. During these tasks, participants passively viewed non-stress-inducing images and stress-inducing images, respectively, and MEG was recorded. Before and after each task, MEG and electrocardiography were recorded and subjective ratings were obtained. We grouped participants according to Novelty seeking (NS) - tendency to be exploratory, and Harm avoidance (HA) - tendency to be cautious. Participants with high NS and low HA (n = 10) assessed by TCI had a different neural response to stress than those with low NS and high HA (n = 10). Event-related desynchronization (ERD) in the beta frequency band was observed only in participants with high NS and low HA in the brain region extending from Brodmann's area 31 (including the posterior cingulate cortex and precuneus) from 200 to 350 ms after the onset of picture presentation in the stress-inducing task. Individual variation in personality traits (NS and HA) was associated with the neural response to mental stress. These findings increase our understanding of the psychological and neural basis of individual differences in the stress response, and will contribute to development of the psychotherapeutic approaches to stress-related disorders.
    Dec. 2016, Brain imaging and behavior, 10(4) (4), 1160 - 1171, English, International magazine
    Scientific journal

  • Hisashi Doi, Kengo Sato, Hideo Shindou, Kengo Sumi, Hiroko Koyama, Takamitsu Hosoya, Yasuyoshi Watanabe, Satoshi Ishii, Hideo Tsukada, Koji Nakanishi, Masaaki Suzuki
    The blood-brain barrier permeability of ginkgolide B was examined using positron emission tomography (PET) probes of a 18F-incorporated ginkgolide B ([18F]-2) and a 11C-incorporated methylbenzyl-substituted ginkgolide B ([11C]-3). PET studies in monkeys showed low uptake of [18F]-2 into the brain, but small amounts of [11C]-3 were accumulated in the parenchyma. Furthermore, when cyclosporine A was preadministered to rats, the accumulation of [18F]-2 in the rat brain did not significantly change, however, the accumulation of [11C]-3 was five times higher than that in the control rat. These results provide effective approaches for investigating the drug potential of ginkgolides.
    Nov. 2016, Bioorganic & medicinal chemistry, 24(21) (21), 5148 - 5157, English, International magazine
    Scientific journal

  • Emi Yamano, Masahiro Sugimoto, Akiyoshi Hirayama, Satoshi Kume, Masanori Yamato, Guanghua Jin, Seiki Tajima, Nobuhito Goda, Kazuhiro Iwai, Sanae Fukuda, Kouzi Yamaguti, Hirohiko Kuratsune, Tomoyoshi Soga, Yasuyoshi Watanabe, Yosky Kataoka
    Chronic fatigue syndrome (CFS) is a persistent and unexplained pathological state characterized by exertional and severely debilitating fatigue, with/without infectious or neuropsychiatric symptoms, lasting at least 6 consecutive months. Its pathogenesis remains incompletely understood. Here, we performed comprehensive metabolomic analyses of 133 plasma samples obtained from CFS patients and healthy controls to establish an objective diagnosis of CFS. CFS patients exhibited significant differences in intermediate metabolite concentrations in the tricarboxylic acid (TCA) and urea cycles. The combination of ornithine/citrulline and pyruvate/isocitrate ratios discriminated CFS patients from healthy controls, yielding area under the receiver operating characteristic curve values of 0.801 (95% confidential interval [CI]: 0.711-0.890, P < 0.0001) and 0.750 (95% CI: 0.584-0.916, P = 0.0069) for training (n = 93) and validation (n = 40) datasets, respectively. These findings provide compelling evidence that a clinical diagnostic tool could be developed for CFS based on the ratios of metabolites in plasma.
    Oct. 2016, Scientific reports, 6, 34990 - 34990, English, International magazine
    Scientific journal

  • Takahiro Yoshikawa, Masaaki Tanaka, Akira Ishii, Yoko Yamano, Yasuyoshi Watanabe
    BACKGROUND: Changes of resting brain activities after visual food stimulation might affect the feeling of pleasure in eating food in daily life and spontaneous appetitive motives. We used magnetoencephalography (MEG) to identify brain areas related to the activity changes. METHODS: Fifteen healthy, right-handed males [age, 25.4 ± 5.5 years; body mass index, 22.5 ± 2.7 kg/m2 (mean ± SD)] were enrolled. They were asked to watch food or mosaic pictures for 5 min and to close their eyes for 3 min before and after the picture presentation without thinking of anything. Resting brain activities were recorded during two eye-closed sessions. The feeling of pleasure in eating food in daily life and appetitive motives in the study setting were assessed by visual analogue scale (VAS) scores. RESULTS: The γ-band power of resting oscillatory brain activities was decreased after the food picture presentation in the right insula [Brodmann's area (BA) 13], the left orbitofrontal cortex (OFC) (BA11), and the left frontal pole (BA10). Significant reductions of the α-band power were observed in the dorsolateral prefrontal cortex (DLPFC) (BA46). Particularly, the feeling of pleasure in eating food was positively correlated with the power decrease in the insula and negatively with that in the DLPFC. The changes in appetitive motives were associated with the power decrease in the frontal pole. CONCLUSIONS: These findings suggest automatic brain mechanics whereby changes of the resting brain activity might be associated with positive feeling in dietary life and have an impact on the irresistible appetitive motives through emotional and cognitive brain functions.
    BMC, Sep. 2016, Behavioral and brain functions : BBF, 12(1) (1), 26 - 26, English, International magazine
    Scientific journal

  • Akira Ishii, Masaaki Tanaka, Yasuyoshi Watanabe
    It has been hypothesized that fatigue sensation impairs the ability and efficiency to perform activities and can be a cause of fatigue itself. As such, it is important to clarify the neural mechanisms of fatigue sensation. The re-experiencing of mental fatigue sensation involves brain regions including Brodmann's area (BA) 40, BA 39, and the pulvinar nucleus. In the present study, we examined neural activity caused by re-experiencing a physical fatigue sensation that had been experienced. Fifteen healthy male volunteers participated in fatigue and control experiments in a crossover fashion. In the fatigue experiment, participants performed a handgrip task for 10 min to induce a physical fatigue sensation and then re-experienced the physical fatigue sensation during magnetoencephalography (MEG) session. In the control experiment, they did not perform the handgrip task but re-experienced the sensation without physical fatigue in an MEG session. Neural activity related to re-experiencing physical fatigue sensations of the right hand (right condition), left hand (left condition), and related to listening to the auditory cues (sound condition) was assessed using spatial filtering analyses of the MEG data. Changes in oscillatory band power in some brain regions, including BA 40, were common between the right and left conditions. A part of the neural activity related to the re-experiencing physical fatigue sensation, such as the decrease in alpha (8-13 Hz) band power in the BA 40, was also observed in the sound condition. These findings may help to understand the neural mechanisms related to intentionally and unintentionally re-experiencing physical fatigue sensation.
    Sep. 2016, Experimental brain research, 234(9) (9), 2433 - 46, English, International magazine
    Scientific journal

  • Yasuhisa Tamura, Kayo Takahashi, Kumi Takata, Asami Eguchi, Masanori Yamato, Satoshi Kume, Masayuki Nakano, Yasuyoshi Watanabe, Yosky Kataoka
    UNLABELLED: Neural stem cells in two neurogenic regions, the subventricular zone and the subgranular zone (SGZ) of the hippocampal dentate gyrus, can divide and produce new neurons throughout life. Hippocampal neurogenesis is related to emotions, including depression/anxiety, and the therapeutic effects of antidepressants, as well as learning and memory. The establishment of in vivo imaging for proliferative activity of neural stem cells in the SGZ might be used to diagnose depression and to monitor the therapeutic efficacy of antidepressants. Positron emission tomography (PET) imaging with 3'-deoxy-3'-[(18)F]fluoro-l-thymidine ([(18)F]FLT) has been studied to allow visualization of proliferative activity in two neurogenic regions of adult mammals; however, the PET imaging has not been widely used because of lower accumulation of [(18)F]FLT, which does not allow quantitative assessment of the decline in cellular proliferative activity in the SGZ under the condition of depression. We report the establishment of an enhanced PET imaging method with [(18)F]FLT combined with probenecid, an inhibitor of drug transporters at the blood-brain barrier, which can allow the quantitative visualization of neurogenic activity in rats. Enhanced PET imaging allowed us to evaluate reduced cell proliferation in the SGZ of rats with corticosterone-induced depression, and further the recovery of proliferative activity in rats under treatment with antidepressants. This enhanced [(18)F]FLT-PET imaging technique with probenecid can be used to assess the dynamic alteration of neurogenic activity in the adult mammalian brain and may also provide a means for objective diagnosis of depression and monitoring of the therapeutic effect of antidepressant treatment. SIGNIFICANCE STATEMENT: Adult hippocampal neurogenesis may play a role in major depression and antidepressant therapy. Establishment of in vivo imaging for hippocampal neurogenic activity may be useful to diagnose depression and monitor the therapeutic efficacy of antidepressants. Positron emission tomography (PET) imaging has been studied to allow visualization of neurogenic activity; however, PET imaging has not been widely used due to the lower accumulation of the PET tracer in the neurogenic regions. Here, we succeeded in establishing highly quantitative PET imaging for neurogenic activity in adult brain with an inhibitor for drug transporter. This enhanced PET imaging allowed evaluation of the decline of neurogenic activity in the hippocampus of rats with depression and the recovery of neurogenic activity by antidepressant treatment.
    Aug. 2016, The Journal of neuroscience : the official journal of the Society for Neuroscience, 36(31) (31), 8123 - 31, English, International magazine
    Scientific journal

  • Sanae Fukuda, Junzo Nojima, Osami Kajimoto, Kouzi Yamaguti, Yasuhito Nakatomi, Hirohiko Kuratsune, Yasuyoshi Watanabe
    The aim of this study was to evaluate the benefit of oral ubiquinol-10 supplementation in CFS patients using an open-label study and a randomized, double-blinded, placebo-controlled (RCT) study. Twenty patients with CFS were randomly enrolled in an 8-week open-label oral ubiquinol-10 (150 mg ubiquinol-10/day) study. The patients and the attending physicians were not blinded to the supplementation. Forty-three patients with CFS were randomly assigned to receive either ubiquinol-10 (150 mg/day) or placebo every day for 12 weeks. The patients and the attending physicians were blinded to the supplementation, and a total of 31 patients (N = 17 in the ubiquinol group and 14 in the placebo group) completed the study. The beneficial effects of ubiquinol-10 were observed in the open-label study we conducted prior to the RCT. The RCT results suggest that supplementation with ubiquinol-10 for 12 weeks is effective for improving several CFS symptoms. © 2016 BioFactors, 42(4):431-440, 2016.
    Jul. 2016, BioFactors (Oxford, England), 42(4) (4), 431 - 40, English, International magazine
    Scientific journal

  • Atsushi Narita, Susumu Shiomi, Yutaka Katayama, Takashi Yamanaga, Hiromitsu Daisaki, Kazuo Hamada, Yasuyoshi Watanabe
    Our aim in this study was to verify the usefulness of the standardized uptake value (SUV) normalized by individual CT-based lean body mass (LBMCT) in application of PET response criteria in solid tumors (PERCIST).We retrospectively investigated 14 patients (4 male and 10 female) with malignant lymphoma who were undergoing chemotherapy. (18)F-FDG PET/CT examinations were performed before and after chemotherapy. The LBMCT was calculated by estimation of fat weight from CT data (from skull base to pelvis). The mean ± standard deviation (SD) and the Bland-Altman plot were used for comparison among body weight, LBMCT, and LBM derived from a predictive equation (LBMPE). Indices for FDG uptake in the liver were: SUV, SUV based on LBMPE (SULPE), and SUV based on LBMCT (SULCT). Overall differences between the uptake values were analyzed by one-way ANOVA. If the ANOVA showed significance, differences between uptake values were investigated further by use of the Tukey-Kramer test. The mean values of body weight, LBMPE, and LBMCT were: 55.4 ± 14.9 (39.0-112.0), 43.0 ± 10.5 (31.3-75.2), and 35.3 ± 9.8 (23.4-75.8) kg, respectively. There was a wide dispersion between LBMPE and LBMCT (differences, 7.6 ± 3.6 kg; 95 % CI, 6.42-8.85). LBMPE was higher than LBMCT in all the cases except in Case 11. The mean uptake values significantly differed among SUV, SULPE, and SULCT (F = 68.3, p < 0.05). Whereas SULPE deviated from PERCIST criteria in seven patients, SULCT satisfied the criteria except in one case. These results suggest that liver SULCT is useful for application of PERCIST.
    Jul. 2016, Radiological physics and technology, 9(2) (2), 170 - 7, English, Domestic magazine
    Scientific journal

  • Akihito Ohnishi, Michio Senda, Tomohiko Yamane, Tomoko Mikami, Hiroyuki Nishida, Tomoyuki Nishio, Go Akamatsu, Yasuhiko Ikari, Shogo Kimoto, Kazuki Aita, Masahiro Sasaki, Hiroko Shinkawa, Yasuji Yamamoto, Miho Shukuri, Aya Mawatari, Hisashi Doi, Yasuyoshi Watanabe, Hirotaka Onoe
    INTRODUCTION: Neuroinflammatory processes play an important role in the pathogenesis of Alzheimer's disease (AD). As a biomarker of neuroinflammatory processes, we designed (11)C-labeled ketoprofen methyl ester ([(11)C]KTP-Me) to increase the blood-brain barrier permeability of ketoprofen (KTP), a selective cyclooxygenase-1 (COX-1) inhibitor. Animal studies indicated that [(11)C]KTP-Me enters the brain and accumulates in activated microglia of inflammatory lesions. In a first-in-human study, we reported that [(11)C]KTP-Me is a safe positron emission tomography (PET) tracer and enters the brain; the radioactivity is washed out from normal cerebral tissue. Here we explored the efficacy of [(11)C]KTP-Me as a diagnostic biomarker of neuroinflammatory processes in AD. METHODS: [(11)C]KTP-Me was synthesized by rapid C-[(11)C]methylation of [(11)C]CH3I and the corresponding arylacetate precursor. Nine subjects (four healthy subjects, two Pittsburgh compound-B (PiB)-positive patients with mild cognitive impairment (MCI), and three PiB-positive AD patients) underwent a dynamic brain PET scan for 70min after injection. We evaluated differences in cortical retention and washout rate in the brain between healthy subjects and MCI/AD patients. RESULTS: A brain distribution pattern reflecting blood flow in the early-phase image was seen in both healthy subjects and MCI/AD patients. Cortical activity gradually cleared in all groups. However, we observed no obvious difference in the washout rate between healthy subjects and MCI/AD patients or between MCI and AD patients. CONCLUSIONS: [(11)C]KTP-Me cannot be useful as a potential diagnostic biomarker for MCI/AD. Further improvements in binding affinity and specificity, etc., are needed to be a diagnostic biomarker of neuroinflammation in AD. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: [(11)C]KTP-Me is a new tracer that targets COX-1. [(11)C]KTP-Me is expected to be a diagnostic biomarker of neuroinflammation in AD in the future. The effectiveness was limited in a small number of AD patients. Therefore, further studies are needed to clarify the usefulness of [(11)C]KTP-Me.
    Jul. 2016, Nuclear medicine and biology, 43(7) (7), 438 - 44, English, International magazine
    Scientific journal

  • Sanae Fukuda, Junzo Nojima, Yukari Motoki, Kouzi Yamaguti, Yasuhito Nakatomi, Naoko Okawa, Kazumi Fujiwara, Yasuyoshi Watanabe, Hirohiko Kuratsune
    We sought to determine whether oxidative stress and anti-oxidative activity could act as biomarkers that discriminate patients with chronic fatigue syndrome (CFS) from healthy volunteers at acute and sub-acute fatigue and resting conditions. We calculated the oxidative stress index (OSI) from reactive oxygen metabolites-derived compounds (d-ROMs) and the biological antioxidant potential (BAP). We determined changes in d-ROMs, BAP, and OSI in acute and sub-acute fatigue in two healthy groups, and compared their values at rest between patients with CFS (diagnosed by Fukuda 1994 criteria) and another group of healthy controls. Following acute fatigue in healthy controls, d-ROMs and OSI increased, and BAP decreased. Although d-ROMs and OSI were significantly higher after sub-acute fatigue, BAP did not decrease. Resting condition yielded higher d-ROMs, higher OSI, and lower BAP in patients with CFS than in healthy volunteers, but lower d-ROMs and OSI when compared with sub-acute controls. BAP values did not significantly differ between patients with CFS and controls in the sub-acute condition. However, values were significantly higher than in the resting condition for controls. Thus, measured of oxidative stress (d-ROMS) and anti-oxidative activity (BAP) might be useful for discriminating acute, sub-acute, and resting fatigue in healthy people from patients with CFS, or for evaluating fatigue levels in healthy people.
    Jul. 2016, Biological psychology, 118, 88 - 93, English, International magazine
    Scientific journal

  • Ayumi Tsutsui, Akihiro Ogura, Tsuyoshi Tahara, Satoshi Nozaki, Sayaka Urano, Mitsuko Hara, Soichi Kojima, Almira Kurbangalieva, Hirotaka Onoe, Yasuyoshi Watanabe, Naoyuki Taniguchi, Katsunori Tanaka
    Advanced glycation end products (AGEs) are associated with various diseases, especially during aging and the development of diabetes and uremia. To better understand these biological processes, investigation of the in vivo kinetics of AGEs, i.e., analysis of trafficking and clearance properties, was carried out by molecular imaging. Following the preparation of Cy7.5-labeled AGE-albumin and intravenous injection in BALB/cA-nu/nu mice, noninvasive fluorescence kinetics analysis was performed. In vivo imaging and fluorescence microscopy analysis revealed that non-enzymatic AGEs were smoothly captured by scavenger cells in the liver, i.e., Kupffer and other sinusoidal cells, but were unable to be properly cleared from the body. Overall, these results highlight an important link between AGEs and various disorders associated with them, which may serve as a platform for future research to better understand the processes and mechanisms of these disorders.
    Jun. 2016, Organic & biomolecular chemistry, 14(24) (24), 5755 - 60, English, International magazine
    Scientific journal

  • Akihiro Ogura, Tsuyoshi Tahara, Satoshi Nozaki, Hirotaka Onoe, Almira Kurbangalieva, Yasuyoshi Watanabe, Katsunori Tanaka
    Multivalent interactions play an essential role in molecular recognition in living systems. These effects were employed to target tumor cells using albumin clusters bearing ∼10 molecules of asparagine-linked glycans (N-glycans). Noninvasive near-infrared fluorescence imaging clearly revealed A431 tumors implanted in BALB/cA-nu/nu mice after 1h in an N-glycan structure-dependent manner, thereby demonstrating the efficient use of glycan multivalency effects for tumor targeting in vivo.
    May 2016, Bioorganic & medicinal chemistry letters, 26(9) (9), 2251 - 4, English, International magazine
    Scientific journal

  • Tomotaka Shingaki, Yumiko Katayama, Takayoshi Nakaoka, Tadayuki Takashima, Kayo Onoe, Takashi Okauchi, Emi Hayashinaka, Yasuhiro Wada, Yilong Cui, Yasuyoshi Watanabe
    To select appropriate antiemetics relieving teriparatide-induced nausea and vomiting during osteoporosis treatment using PET molecular imaging and pharmacokinetic analysis.Rats were pretreated with subcutaneous teriparatide, followed by oral administration of antiemetics with different pharmacological effects. The pharmacokinetics of antiemetics were assessed by oral administration of 2-deoxy-2-[F-18]fluoro-d-glucose ([F-18]FDG) under free moving conditions in vivo. The effect of teriparatide on the permeability of Caco-2 cell membranes to [F-18]FDG was assessed in vitro. The effects of antiemetics on teriparatide-induced suppression of gastrointestinal motility in vivo was assayed by positron emission tomography (PET) using orally administered [F-18]FDG.Teriparatide delayed the time-radioactivity profile of [F-18]FDG in blood and significantly reduced its absorption rate constant (k (a) ), determined from non-compartmental analysis, to 60% of control. In contrast, co-administration of granisetron or mosapride restored the time-radioactivity profile and k (a) of [F-18]FDG to control levels. Teriparatide had no effect on Caco-2 membrane permeability to [F-18]FDG. Pharmacokinetic PET imaging data analysis quantitatively showed the pharmacological effects of teriparatide-induced suppression of upper gastrointestinal motility and its restoration by granisetron and mosapride.Teriparatide-induced abdominal discomfort might be attributed to GI motility, and PET imaging analysis is a useful tool to for the selection of appropriate antiemetics.
    SPRINGER/PLENUM PUBLISHERS, May 2016, PHARMACEUTICAL RESEARCH, 33(5) (5), 1235 - 1248, English, International magazine
    [Refereed]
    Scientific journal

  • Akinori Kanzaki, Takashi Okauchi, Di Hu, Tomotaka Shingaki, Yumiko Katayama, Hidenori Koyama, Yasuyoshi Watanabe, Yilong Cui
    Homeostasis is known to be involved in maintaining the optimal internal environment, helping to achieve the best performance of biological functions. At the same time, a deviation from optimal conditions often attenuates the performance of biological functions, and such restricted performance could be considered as individual fatigue, including physical and mental fatigue. The present study seeks to develop an animal model of chronic or subacute fatigue in which the recovery time is extended through the gradual disruption of homeostasis. We show that repeated short-term rest periods with certain lengths of sleep during continuous fatigue loading extend recovery from spontaneous nighttime activity but not physical performance in comparison with a continuous fatigue-loading procedure. Furthermore, the immobility time in a forced swimming test was extended by repeated short-term rests. These results suggest that repeated short-term rest with certain lengths of sleep during continuous fatigue loading is able to extend the recovery from mental fatigue but not from physical fatigue and that this effect might occur via the disruption of a homeostatic mechanism that is involved in restoring the optimal internal environment. (c) 2016 Wiley Periodicals, Inc.
    WILEY-BLACKWELL, May 2016, JOURNAL OF NEUROSCIENCE RESEARCH, 94(5) (5), 424 - 429, English, International magazine
    [Refereed]
    Scientific journal

  • Akira Ishii, Masaaki Tanaka, Yasuyoshi Watanabe
    Fatigue is a major contributor to workplace accidents, morbidity, and mortality. To prevent the disruption of homeostasis and to concurrently accomplish an assigned workload, it is essential to control the level of workload based on the subjective estimation of the level of fatigue that will be experienced in the near future. In this study, we aimed to clarify the neural mechanisms related to predicting subjective levels of fatigue that would be experienced 60 min later, using magnetoencephalography. Sixteen healthy male volunteers participated in this study. In relation to the prediction, a decrease of alpha band power in the right Brodmann's area (BA) 40 and BA 9 at 1200 to 1350 ms and that in the right BA 9 at 1350 to 1500 ms, and a decrease of gamma band power in the right BA 10 at 1500 to 1650 ms were observed. In addition, the decreased level of alpha band power in BA 9 at 1200 to 1350 ms was positively associated with the daily level of fatigue. These findings may help increase our understanding of the neural mechanisms activated to indicate the need to take a rest based on the prediction of the subjective fatigue in the future.
    Apr. 2016, Scientific reports, 6, 25097 - 25097, English, International magazine
    Scientific journal

  • ウロキナーゼ静脈内投与による樹状PEG修飾64Cuボンベシンアナログテトラマーのスイッチング型腎クリアランスを意図したPETプローブ
    向井 英史, 松村 一史, 造田 真希, 林中 恵美, 山下 富義, 橋田 充, 和田 康弘, 渡辺 恭良
    日本分子イメージング学会, Apr. 2016, JSMI Report, 9(2) (2), 130 - 130, Japanese
    [Refereed]

  • 慢性疼痛モデルラットにおける線条体ドーパミンD2受容体の変容
    岡内 隆, 曾 瑩, 神母坂 あみ, 胡 迪, 林中 恵美, 和田 康弘, 土居 久志, 渡辺 恭良, 崔 翼龍
    日本分子イメージング学会, Apr. 2016, JSMI Report, 9(2) (2), 183 - 183, Japanese

  • Noriyasu Kamei, Tomotaka Shingaki, Yousuke Kanayama, Misa Tanaka, Riyo Zochi, Koki Hasegawa, Yasuyoshi Watanabe, Mariko Takeda-Morishita
    Our recent work suggested that intranasal coadministration with the cell-penetrating peptide (CPP) penetratin increased the brain distribution of the peptide drug insulin. The present study aimed to distinctly certify the ability of penetratin to facilitate the nose-to-brain delivery of insulin by quantitatively evaluating the distribution characteristics in brain using radioactive (64)Cu-NODAGA-insulin. Autoradiography and analysis using a gamma counter of brain areas demonstrated that the accumulation of radioactivity was greatest in the olfactory bulb, the anterior part of the brain closest to the administration site, at 15 min after intranasal administration of (64)Cu-NODAGA-insulin with l- or d-penetratin. The brain accumulation of (64)Cu-NODAGA-insulin with penetratin was confirmed by ELISA using unlabeled insulin in which intact insulin was delivered to the brain after intranasal coadministration with l- or d-penetratin. By contrast, quantification of cerebrospinal fluid (CSF) samples showed increased insulin concentration in only the anterior portion of the CSF at 15 min after intranasal coadministration with l-penetratin. This study gives the first concrete proof that penetratin can accelerate the direct transport of insulin from the nasal cavity to the brain parenchyma. Further optimization of intranasal administration with CPP may increase the efficacy of delivery of biopharmaceuticals to the brain while reducing the risk of systemic drug exposure.
    Mar. 2016, Molecular pharmaceutics, 13(3) (3), 1004 - 11, English, International magazine
    Scientific journal

  • イメージング技術が切り拓く遺伝子・核酸デリバリーの最前線 核酸創薬におけるポジトロンエミッショントモグラフィーの活用
    向井 英史, 渡辺 恭良
    (公社)日本薬学会, Mar. 2016, 日本薬学会年会要旨集, 136年会(1) (1), 286 - 286, Japanese

  • Akihiro Ogura, Tsuyoshi Tahara, Satoshi Nozaki, Koji Morimoto, Yasuhiko Kizuka, Shinobu Kitazume, Mitsuko Hara, Soichi Kojima, Hirotaka Onoe, Almira Kurbangalieva, Naoyuki Taniguchi, Yasuyoshi Watanabe, Katsunori Tanaka
    A series of N-glycans, each sequentially trimmed from biantennary sialoglycans, were homo- or heterogeneously clustered efficiently on fluorescent albumin using a method that combined strain-promoted alkyne-azide cyclization and 6π-azaelectrocyclization. Noninvasive in vivo kinetics and dissection analysis revealed, for the first time, a glycan-dependent shift from urinary to gall bladder excretion mediated by sequential trimming of non-reducing end sialic acids. N-glycoalbumins that were trimmed further, in particular, GlcNAc- and hybrid biantennary-terminated congeners, were selectively taken up by sinusoidal endothelial and stellate cells in the liver, which are critical for diagnosis and treatment of liver fibrillation. Our glycocluster strategy can not only reveal the previously unexplored extracellular functions of N-glycan trimming, but will be classified as the newly emerging glycoprobes for diagnostic and therapeutic applications.
    Feb. 2016, Scientific reports, 6, 21797 - 21797, English, International magazine
    Scientific journal

  • Miho Shukuri, Aya Mawatari, Masahiro Ohno, Masaaki Suzuki, Hisashi Doi, Yasuyoshi Watanabe, Hirotaka Onoe
    UNLABELLED: Cyclooxygenase (COX), a prostanoid-synthesizing enzyme, is considered to be involved in the neuroinflammatory process of neurodegenerative diseases. However, the role of COX in the progression of neurodegeneration is not well understood. We hypothesized that in vivo imaging of COX by PET will contribute to elucidation of the function of COX during the neurodegenerative process in Alzheimer's disease (AD). (11)C-labeled ketoprofen methyl ester (racemic (RS)-(11)C-KTP-Me) developed recently by our group is a useful PET probe for in vivo imaging of COX-1 during neuroinflammation. The (S)-enantiomer of ketoprofen is known to be pharmacologically more active than the (R)-enantiomer. We thus synthesized (11)C-labeled (S)-ketoprofen methyl ester ((S)-(11)C-KTP-Me) as an improved PET probe specific for COX-1 and applied it for investigation of the changes in COX-1 during the progression of AD in a mouse model. METHODS: The specificity of (S)-(11)C-KTP-Me for COXs was examined in PET studies with rats that had intrastriatal injection of lipopolysaccharide. To determine the details of changes in COX-1 during progression of amyloid-β (Aβ) plaque formation in amyloid precursor protein transgenic (APP-Tg) mice, we performed immunohistochemical studies and ex vivo autoradiography with (S)-(11)C-KTP-Me. RESULTS: PET studies using hemispheric lipopolysaccharide injection into rats revealed that the sensitivity of (S)-(11)C-KTP-Me in neuroinflammation was much higher than that of (RS)-(11)C-KTP-Me and (R)-(11)C-KTP-Me; these results closely corresponded to the inhibitory activities of each enantiomer against COX-1 estimated by an in vitro assay. In APP-Tg mice, (S)-(11)C-KTP-Me administration resulted in progressive and significant increases in accumulation of radioactivity in the brain from 16 to 24 mo old in accordance with the histopathologic appearance of abundant Aβ plaques and activated microglia, whereas few changes in radioactivity accumulation and few Aβ plaques were seen in age-matched wild-type control mice. High-radioactivity accumulation by (S)-(11)C-KTP-Me was markedly observed in the frontal cortex and hippocampus in which COX-1-expressing activated microglia tightly surrounded and enclosed large and more intensely stained Aβ plaques, indicating neuroinflammation that originated with Aβ. CONCLUSION: (S)-(11)C-KTP-Me is a potent PET probe that is highly selective for COX-1. Studies using APP-Tg mice demonstrated that (S)-(11)C-KTP-Me could detect activated microglia that are associated with amyloid plaque progression, suggesting the involvement of COX-1 in the neuroinflammatory process in AD.
    Feb. 2016, Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 57(2) (2), 291 - 6, English, International magazine
    Scientific journal

  • Tomotaka Shingaki, Yumiko Katayama, Takayoshi Nakaoka, Satsuki Irie, Kayo Onoe, Takashi Okauchi, Emi Hayashinaka, Masataka Yamaguchi, Nobuyoshi Tanki, Takayuki Ose, Takuya Hayashi, Yasuhiro Wada, Tomoyuki Furubayashi, Yilong Cui, Toshiyasu Sakane, Yasuyoshi Watanabe
    We performed positron emission tomography (PET) using 2-deoxy-2[F-18]fluoro-u-glucose ([F-18]FDG) to evaluate the pharmacokinetics of nasal drug absorption in the rat. The dosing solution of [F-18]FDG was varied in volume (ranging from 5 to 25 mu l) and viscosity (using 0% to 3% concentrations of hydroxypropy-Icellulose). We modeled the pharmacokinetic parameters regarding the nasal cavity and pharynx using mass balance equations, and evaluated the values that were obtained by fitting concentration-time profiles using WinNonlin((R)) software. The regional nasal permeability was also estimated using the active surface area derived from the PET images. The translocation of [18F]FDG from the nasal cavity was visualized using PET. Analysis of the PET imaging data revealed that the pharmacokinetic parameters were independent of the dosing solution volume; however, the viscosity increased the absorption rate constant and decreased the mucociliary clearance rate constant. Nasal permeability was initially higher but subsequently decreased until the end of the study, indicating regional differences in permeability in the nasal cavity. We concluded that the visualization of drug translocation in the nasal cavity in the rat using PET enables quantitative analysis of nasal drug absorption, thereby facilitating the development of nasal formulations for human use. (C) 2015 Elsevier B.V. All rights reserved.
    ELSEVIER SCIENCE BV, Feb. 2016, EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, 99, 45 - 53, English, International magazine
    [Refereed]
    Scientific journal

  • Hiroaki Kurihara, Chikako Shimizu, Yasuji Miyakita, Masayuki Yoshida, Akinobu Hamada, Yousuke Kanayama, Kan Yonemori, Jun Hashimoto, Hitomi Tani, Makoto Kodaira, Mayu Yunokawa, Harukaze Yamamoto, Yasuyoshi Watanabe, Yasuhiro Fujiwara, Kenji Tamura
    Molecular imaging can visualize the biological processes at the molecular and cellular levels in vivo using certain tracers for specific molecular targets. Molecular imaging of breast cancer can be performed with various imaging modalities, however, positron emission tomography (PET) is a sensitive and non-invasive molecular imaging technology and this review will focus on PET molecular imaging of breast cancer, such as FDG-PET, FLT-PET, hormone receptor PET, and anti-HER2 PET.
    Jan. 2016, Breast cancer (Tokyo, Japan), 23(1) (1), 24 - 32, English, Domestic magazine
    Scientific journal

  • Low putamen activity associated with poor reward sensitivity in childhood chronic fatigue syndrome.
    Kei Mizuno, Junko Kawatani, Kanako Tajima, Akihiro T Sasaki, Tetsuya Yoneda, Masanori Komi, Toshinori Hirai, Akemi Tomoda, Takako Joudoi, Yasuyoshi Watanabe
    Motivational signals influence a wide variety of cognitive processes and components of behavioral performance. Cognitive dysfunction in patients with childhood chronic fatigue syndrome (CCFS) may be closely associated with a low motivation to learn induced by impaired neural reward processing. However, the extent to which reward processing is impaired in CCFS patients is unclear. The aim of the present functional magnetic resonance imaging (fMRI) study was to determine whether brain activity in regions related to reward sensitivity is impaired in CCFS patients. fMRI data were collected from 13 CCFS patients (mean age, 13.6 ± 1.0 years) and 13 healthy children and adolescents (HCA) (mean age, 13.7 ± 1.3 years) performing a monetary reward task. Neural activity in high- and low-monetary-reward conditions was compared between CCFS and HCA groups. Severity of fatigue and the reward obtained from learning in daily life were evaluated by questionnaires. Activity of the putamen was lower in the CCFS group than in the HCA group in the low-reward condition, but not in the high-reward condition. Activity of the putamen in the low-reward condition in CCFS patients was negatively and positively correlated with severity of fatigue and the reward from learning in daily life, respectively. We previously revealed that motivation to learn was correlated with striatal activity, particularly the neural activity in the putamen. This suggests that in CCFS patients low putamen activity, associated with altered dopaminergic function, decreases reward sensitivity and lowers motivation to learn.
    2016, NeuroImage. Clinical, 12, 600 - 606, English, International magazine
    Scientific journal

  • Takashi Niwa, Hidenori Ochiai, Yasuyoshi Watanabe, Takamitsu Hosoya
    Ni/Cu-catalyzed transformation of fluoroarenes to arylboronic acid pinacol esters via C-F bond cleavage has been achieved. Further versatile derivatization of an arylboronic ester has allowed for the facile two-step conversion of a fluoroarene to diverse functionalized arenes, demonstrating the synthetic utility of the method.
    Nov. 2015, Journal of the American Chemical Society, 137(45) (45), 14313 - 8, English, International magazine
    Scientific journal

  • Masaaki Tanaka, Akira Ishii, Yasuyoshi Watanabe
    BACKGROUND: Fatigue, defined as difficulty initiating or sustaining voluntary activities, can be classified as physical or mental. In this study, we use magnetoencephalography (MEG) to quantify the effect of physical fatigue on neural activity under the condition of simulated physical load. METHODS: Thirteen healthy right-handed male volunteers participated in this study. The experiment consisted of one fatigue-inducing physical task session performed between two MEG sessions. During the 10-min physical task session, participants performed maximum-effort handgrips with the left hand lasting 1 s every 4 s; during MEG sessions, 3-min recordings were made during the eyes-closed state. MEG data were analyzed using narrow-band adaptive spatial filtering methods. RESULTS: Alpha-frequency band (8-13 Hz) power in the left postcentral gyrus, precentral gyrus, and middle frontal gyrus (Brodmann's areas 1, 2, 3, 4, 6, and 46) were decreased after performing the physical fatigue-inducing task. CONCLUSIONS: These results show that performing the physical fatigue-inducing task caused activation of the left sensorimotor and prefrontal areas, manifested as decreased alpha-frequency band power in these brain areas. Our results increase understanding of the neural mechanisms of physical fatigue.
    Nov. 2015, Behavioral and brain functions : BBF, 11(1) (1), 35 - 35, English, International magazine
    Scientific journal

  • Masaaki Tanaka, Seiki Tajima, Kei Mizuno, Akira Ishii, Yukuo Konishi, Teruhisa Miike, Yasuyoshi Watanabe
    Fatigue is defined as a condition or phenomenon of decreased ability and efficiency of mental and/or physical activities, caused by excessive mental or physical activities, diseases, or syndromes. It is often accompanied by a peculiar sense of discomfort, a desire to rest, and reduced motivation, referred to as fatigue sensation. Acute fatigue is a normal condition or phenomenon that disappears after a period of rest; in contrast, chronic fatigue, lasting at least 6 months, does not disappear after ordinary rest. Chronic fatigue impairs activities and contributes to various medical conditions, such as cardiovascular disease, epileptic seizures, and death. In addition, many people complain of chronic fatigue. For example, in Japan, more than one third of the general adult population complains of chronic fatigue. It would thus be of great value to clarify the mechanisms underlying chronic fatigue and to develop efficient treatment methods to overcome it. Here, we review data primarily from behavioral, electrophysiological, and neuroimaging experiments related to neural dysfunction as well as autonomic nervous system, sleep, and circadian rhythm disorders in fatigue. These data provide new perspectives on the mechanisms underlying chronic fatigue and on overcoming it.
    Nov. 2015, The journal of physiological sciences : JPS, 65(6) (6), 483 - 98, English, Domestic magazine
    Scientific journal

  • Kei Mizuno, Shinichiro Takiguchi, Mika Yamazaki, Mizuki Asano, Shiho Kato, Kikuko Kuriyama, Yasuyoshi Watanabe, Norihiro Sadato, Akemi Tomoda
    Reactive attachment disorder (RAD) is characterized by markedly disturbed and developmentally inappropriate social relatedness due to parental maltreatment. RAD patients often display a high number of comorbid attention deficit/hyperactivity disorder (ADHD) symptoms, and certain RAD symptoms are difficult to discriminate from ADHD. One of the core characteristics of ADHD is a decrease in neural reward processing due to dopamine dysfunction. The aim of the present study was to determine whether the brain activity involved in reward processing in RAD patients is impaired in comparison with ADHD patients and typically developed controls. Five RAD patients, 17 typically developed (TD) controls and 17 ADHD patients aged 10-16 years performed tasks with high and low monetary reward while undergoing functional magnetic resonance imaging. ADHD patients were tested before and after 3 months treatment with osmotic release oral system-methylphenidate. Before treatment, ADHD patients showed that striatal and thalamus activities only in the tasks with low monetary reward were lower than TD controls. RAD patients showed decrease in activity of the caudate, putamen and thalamus during both the high and low monetary reward conditions in comparison with all the other groups. In RAD patients, the activity of the putamen was associated with the severity of posttraumatic stress and overt dissociation. Reward sensitivity was markedly decreased in children and adolescents with RAD, as evidenced by a diminished neural response during reward perception. This suggests that dopaminergic dysfunction exists in these patients, and may inform future dopaminergic treatment strategies for RAD.
    Oct. 2015, Asian journal of psychiatry, 17, 89 - 93, English, International magazine
    Scientific journal

  • Kazunari Tominaga, Chikako Tsumoto, Suzuka Ataka, Kei Mizuno, Kayo Takahashi, Hirokazu Yamagami, Tetsuya Tanigawa, Joji Kawabe, Toshio Watanabe, Yasuhiro Fujiwara, Susumu Shiomi, Yasuyoshi Watanabe, Tetsuo Arakawa
    AIMS: To elucidate the role of cerebral serotonin neurotransmission in visceral perception in functional dyspepsia (FD), we observationally examined the regional expression level of the serotonin transporter (SERT) and its correlation with clinical symptoms. MAIN METHODS: FD patients (Rome III criteria; N=9, age range: 36-76years) and healthy controls (N=8, age range: 25-61years) participated in this study. Positron emission tomography scanning with [(11)C]N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine ([(11)C]DASB), which binds specifically to SERT, was used to quantify the binding potential (BPND) of [(11)C]DASB in the midbrain, thalamus, caudate, putamen, amygdala, and hippocampus with reference to co-registered magnetic resonance images. Clinical symptoms were assessed using the Gastrointestinal Symptoms Rating Scale (GSRS). Self-Rating Depression Scale (SDS), and State-Trait Anxiety Inventory (STAI). KEY FINDINGS: BPND of the midbrain (P=0.041) and thalamus (P=0.031) was higher in FD patients than in controls. The BPND values in the midbrain correlated with total GSRS (r=0.663, P=0.004) and abdominal pain (r=0.419, P=0.047) scores. Its values in the thalamus correlated with total GSRS (r=0.423, P=0.044), abdominal pain (r=0.502, P=0.022), and indigestion (r=0.476, P=0.028) scores. Its value in the hippocampus correlated with abdominal pain and state-STAI scores (r=0.528, P=0.017; r=0.428, P=0.043). SIGNIFICANCE: Up-regulation of the SERT level in the midbrain and thalamus may underlie the pathogenesis of FD such as abdominal and psychological symptoms via a brain-gut interaction.
    Sep. 2015, Life sciences, 137, 150 - 7, English, International magazine
    Scientific journal

  • 高齢者タウオパチーを疑う認知症患者のPBB3-PETタウイメージング
    竹内 潤, 安宅 鈴香, 島田 斉, 樋口 真人, 和田 康弘, 塩見 進, 渡辺 恭良, 須原 哲也, 嶋田 裕之, 伊藤 義彰
    (一社)日本認知症学会, Sep. 2015, Dementia Japan, 29(3) (3), 387 - 387, Japanese

  • Tomotaka Shingaki, W. Ewan Hume, Tadayuki Takashima, Yumiko Katayama, Takashi Okauchi, Emi Hayashinaka, Yasuhiro Wada, Yilong Cui, Hiroyuki Kusuhara, Yuichi Sugiyama, Yasuyoshi Watanabe
    Purpose To evaluate the function of multidrug and toxin extrusion proteins (MATEs) using C-11-labeled metformin ([C-11] metformin) by positron emission tomography (PET). Methods PET was performed by intravenous bolus injection of [C-11] metformin. Pyrimethamine at 0.5 and 5 mg/kg was intravenously administered to mice 30 min prior to the scan. Integration plot analysis was conducted for calculating liver (CLuptake, liver), kidney (CLuptake, kidney) tissue uptake, intrinsic biliary (CLint, bile) and urinary (CLint, urine) excretion clearances of [C-11] metformin. Results Visualization by PET showed that pyrimethamine increased concentrations of [C-11] metformin in the liver and kidneys, and decreased the concentrations in the urinary bladder without changing the blood profiles. Pyrimethamine had no effect on the CLuptake, liver and CLuptake, kidney, which were similar to the blood-flow rate. CLint, bile with regard to the liver concentration was unable to be determined, but administration of 0.5 and 5 mg/kg of pyrimethamine increased the liver-to-blood ratio to 1.6 and 2.3-fold, respectively, indicating that pyrimethamine inhibited the efflux of [C-11] metformin from the liver. CLint, urine with regard to the corticomedullary region concentrations was decreased 37 and 68% of the control by administration of 0.5 and 5 mg/kg of pyrimethamine, respectively (P<0.05). Conclusions Tissue concentration based investigations using [C-11] metformin by PET enables the functional analysis of MATEs in the liver and kidneys.
    SPRINGER/PLENUM PUBLISHERS, Aug. 2015, PHARMACEUTICAL RESEARCH, 32(8) (8), 2538 - 2547, English, International magazine
    [Refereed]
    Scientific journal

  • 病態解明のための生体機能イメージング法の新展開 PETを中心とした分子イメージングによる個体レベルでの病態解明と診断・創薬への展開
    向井 英史, 渡辺 恭良
    (公社)日本分析化学会, Aug. 2015, 日本分析化学会講演要旨集, 64年会, 5 - 5, Japanese

  • Hisashi Doi, Aya Mawatari, Masakatsu Kanazawa, Satoshi Nozaki, Yukihiro Nomura, Takahito Kitayoshi, Kouji Akimoto, Masaaki Suzuki, Shinji Ninomiya, Yasuyoshi Watanabe
    To enable in vivo analysis of the kinetics of vitamin B1 (thiamine) and its derivatives by positron emission tomography (PET), (11)C-labeled thiamine ([(11)C]-1) has been synthesized. This was carried out via a rapid, multistep synthesis consisting of Pd(0)-mediated C-[(11)C]methylation of a thiazole ring for 3 min and benzylation with 5-(bromomethyl)pyrimidine for 7 min. The [(11)C]-1 was also converted to (11)C-labeled fursultiamine ([(11)C]-2), a prodrug of vitamin B1, by disulfide formation with S-tetrahydrofurfurylthiosulfuric acid sodium salt. Characterization of [(11)C]-1 and [(11)C]-2 showed them to be suitable for use as PET probes for in vivo pharmacokinetic and medical studies. The total durations of the preparations of [(11)C]-1 and [(11)C]-2 were shorter than 60 and 70 min, respectively. The [(11)C]CH3I-based decay-corrected radiochemical yields of [(11)C]-1 and [(11)C]-2 were 9-16% and 4-10%, respectively. The radioactivities of the final injectable solutions of [(11)C]-1 and [(11)C]-2 were 400-700 and 100-250 MBq, respectively. The radiochemical purity of both [(11)C]-1 and [(11)C]-2 was 99%, and the chemical purities of [(11)C]-1 and [(11)C]-2 were 99% and 97-99%, respectively. In vivo PET imaging of normal rats was illustrated by the distribution of [(11)C]-1 and [(11)C]-2 following intravenous injection.
    Jun. 2015, The Journal of organic chemistry, 80(12) (12), 6250 - 8, English, International magazine
    Scientific journal

  • 生理条件下代謝開裂部位導入による64Cu標識ボンベシンアナログテトラマーを用いた癌PETイメージングの画像コントラスト改善
    松村 一史, 向井 英史, 造田 真希, 高橋 麻衣子, 林中 恵美, 山下 富義, 橋田 充, 和田 康弘, 渡辺 恭良
    日本DDS学会, Jun. 2015, 日本DDS学会学術集会プログラム予稿集, 31回, 140 - 140, Japanese
    [Refereed]

  • 神経・内分泌・免疫機能の破綻を伴う新たな慢性疲労モデルの確立
    神崎 暁慶, 崔 翼龍, 片山 由美子, 岡内 隆, 胡 迪, 新垣 友隆, 小山 英則, 渡辺 恭良
    日本疲労学会, May 2015, 日本疲労学会誌, 11(1) (1), 66 - 66, Japanese

  • Hisako Fujii, Sanae Fukuda, Daisuke Narumi, Tomohiko Ihara, Yasuyoshi Watanabe
    BACKGROUND: It has been recognized that an increase in outdoor ambient temperatures has a negative impact on health, particularly fatigue and sleep quality; however, the relationship among fatigue, sleep quality, and air temperature has yet to be sufficiently elucidated. OBJECTIVES: To examine whether fatigue and sleep quality in a healthy Japanese population were affected by rising air temperature at three time points in summer and to investigate the confounding factors for fatigue. METHODS: A total of 602 healthy volunteers in Osaka, Japan, participated in a survey that was conducted at the end of July, August, and September in 2010. The questionnaire consisted of four sections; demographic variables, accommodation status, fatigue, and sleep quality. We used the Chalder fatigue scale for assessment of fatigue, and the Japanese version of the Pittsburgh Sleep Quality Index (PSQI) for assessment of sleep quality. RESULTS: The fatigue score was positively correlated with the sleep quality score in the total cohort. All the questionnaires at the three time points were completed by 162 participants. There were significant differences in fatigue scores among the surveys. We stratified the subjects into two groups of good and poor sleepers using a cutoff value of the PSQI. The good sleepers did not show differences in fatigue score regardless of the change in air temperature. However, the fatigue score of poor sleepers was greater at higher air temperatures. The use of air conditioners, accommodation type, and subject's age were confounding factors for fatigue. CONCLUSIONS: High air temperatures in summer increased fatigue in healthy volunteers, especially those with poor sleep patterns, depending on the use of air conditioners, accommodation status, and subject's age.
    Apr. 2015, Environmental research, 138, 17 - 21, English, International magazine
    Scientific journal

  • 創薬と臨床開発の新時代を見据えたPETによる医薬品候補化合物の薬物動態評価
    新垣 友隆, 崔 翼龍, 渡辺 恭良
    日本医学会, Apr. 2015, 日本医学会総会会誌, 29回(学術講演要旨) (学術講演要旨), 68 - 68, Japanese

  • Yilong Cui, Hiroshi Toyoda, Takeo Sako, Kayo Onoe, Emi Hayashinaka, Yasuhiro Wada, Chihiro Yokoyama, Hirotaka Onoe, Yosky Kataoka, Yasuyoshi Watanabe
    Cortical spreading depression (SD) is a self-propagating wave of depolarization that is thought to be an underling mechanism of migraine aura. Growing evidence demonstrates that cortical SD triggers neurogenic meningeal inflammation and contributes to migraine headaches via subsequent activation of trigeminal afferents. Although direct and indirect evidence shows that cortical SD activates the trigeminal ganglion (peripheral pathway) and the trigeminal nucleus caudalis (TNC, the first central site of the trigeminal nociceptive pathway), it is not yet known whether cortical SD activates the high-order trigeminal nociceptive pathway in the brain. To address this, we induced unilateral cortical SD in rats, and then examined brain activity using voxel-based statistical parametric mapping analysis of FDG-PET imaging. The results show that approximately 40 h after the induction of unilateral cortical SD, regional brain activity significantly increased in several regions, including ipsilateral TNC, contralateral ventral posteromedial (VPM) and posterior thalamic nuclei (Po), the trigeminal barrel-field region of the primary somatosensory cortex (S1BF), and secondary somatosensory cortex (S-2). These results suggest that cortical SD is a noxious stimulus that can activate the high-order trigeminal nociceptive pathway even after cortical SD has subsided, probably due to prolonged meningeal inflammation. (C) 2014 Elsevier Inc. All rights reserved.
    ACADEMIC PRESS INC ELSEVIER SCIENCE, Mar. 2015, NEUROIMAGE, 108, 17 - 22, English, International magazine
    [Refereed]
    Scientific journal

  • Satoshi Kume, Masanori Yamato, Yasuhisa Tamura, Guanghua Jin, Masayuki Nakano, Yukiharu Miyashige, Asami Eguchi, Yoshiyuki Ogata, Nobuhito Goda, Kazuhiro Iwai, Emi Yamano, Yasuyoshi Watanabe, Tomoyoshi Soga, Yosky Kataoka
    In the present study, prior to the establishment of a method for the clinical diagnosis of chronic fatigue in humans, we validated the utility of plasma metabolomic analysis in a rat model of fatigue using capillary electrophoresis-mass spectrometry (CE-MS). In order to obtain a fatigued animal group, rats were placed in a cage filled with water to a height of 2.2 cm for 5 days. A food-restricted group, in which rats were limited to 10 g/d of food (around 50% of the control group), was also assessed. The food-restricted group exhibited weight reduction similar to that of the fatigued group. CE-MS measurements were performed to evaluate the profile of food intake-dependent metabolic changes, as well as the profile in fatigue loading, resulting in the identification of 48 metabolites in plasma. Multivariate analyses using hierarchical clustering and principal component analysis revealed that the plasma metabolome in the fatigued group showed clear differences from those in the control and food-restricted groups. In the fatigued group, we found distinctive changes in metabolites related to branched-chain amino acid metabolism, urea cycle, and proline metabolism. Specifically, the fatigued group exhibited significant increases in valine, leucine, isoleucine, and 2-oxoisopentanoate, and significant decreases in citrulline and hydroxyproline compared with the control and food-restricted groups. Plasma levels of total nitric oxide were increased in the fatigued group, indicating systemic oxidative stress. Further, plasma metabolites involved in the citrate cycle, such as cis-aconitate and isocitrate, were reduced in the fatigued group. The levels of ATP were significantly decreased in the liver and skeletal muscle, indicative of a deterioration in energy metabolism in these organs. Thus, this comprehensive metabolic analysis furthered our understanding of the pathophysiology of fatigue, and identified potential diagnostic biomarkers based on fatigue pathophysiology.
    PUBLIC LIBRARY SCIENCE, Mar. 2015, PLOS ONE, 10(3) (3), e0120106, English, International magazine
    [Refereed]
    Scientific journal

  • 脳標的化薬物デリバリー研究の最前線 PETを用いた鼻腔内投与後の薬物動態と直接的脳移行の可視化
    新垣 友隆, 古林 呂之, 坂根 稔康, 崔 翼龍, 渡辺 恭良
    (公社)日本薬学会, Mar. 2015, 日本薬学会年会要旨集, 135年会(1) (1), 198 - 198, Japanese

  • Yasuhiro Wada, Seiichi Yamamoto, Yasuyoshi Watanabe
    For small animal positron emission tomography (PET) research using high radioactivity, such as dynamic studies, the resulting high random coincidence rate of the system degrades image quality. The random coincidence rate is increased not only by the gamma photons from inside the axial-field-of-view (axial-FOV) of the PET system but also by those from outside the axial-FOV. For brain imaging in small animal studies, significant interference is observed from gamma photons emitted from the body. Single gamma photons from the body enter the axial-FOV and increase the random and scatter coincidences. Shielding against the gamma photons from outside the axial-FOV would improve the image quality. For this purpose, we developed a body shield for a small animal PET system, the microPET Primate 4-ring system, and evaluated its performance. The body shield is made of 9-mm-thick lead and it surrounds most of a rat's body. We evaluated the effectiveness of the body shield using a head phantom and a body phantom with a radioactivity concentration ratio of 1: 2 and a maximum total activity of approximately 250 MBq. The random coincidence rate was dramatically decreased to 1/10, and the noise equivalent count rate (NECR) was increased 6 times with an activity of 7 MBq in the head phantom. The true count rate was increased to 35% due to the decrease in system deadtime. The average scatter fraction was decreased to 1/2.5 with the body shield. Count rate measurements of rat were also conducted with an injection activity of approximately 25 MBq of [ C-11] N, N-dimethyl-2-(2-amino-4cyanophenylthio) benzylamine ([C-11] DASB) and approximately 70 and 310 MBq of 2-deoxy-2-(F-18) fluoro-D-glucose ([F-18] FDG). Using the body shield, [F-18] FDG images of rats were improved by increasing the amount of radioactivity injected. The body shield designed for small animal PET systems is a promising tool for improving image quality and quantitation accuracy in small animal molecular imaging research.
    IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC, Feb. 2015, IEEE TRANSACTIONS ON NUCLEAR SCIENCE, 62(1) (1), 95 - 100, English
    [Refereed]
    Scientific journal

  • Akira Ishii, Takuma Karasuyama, Taiki Kikuchi, Masaaki Tanaka, Emi Yamano, Yasuyoshi Watanabe
    There have been several studies which have tried to clarify the neural mechanisms of fatigue sensation; however fatigue sensation has multiple aspects. We hypothesized that past experience related to fatigue sensation is an important factor which contributes to future formation of fatigue sensation through the transfer to memories that are located within specific brain structures. Therefore, we aimed to investigate the neural mechanisms of fatigue sensation related to memory. In the present study, we investigated the neural activity caused by re-experiencing the fatigue sensation that had been experienced during a fatigue-inducing session. Thirteen healthy volunteers participated in fatigue and non-fatigue experiments in a crossover fashion. In the fatigue experiment, they performed a 2-back test session for 40 min to induce fatigue sensation, a rest session for 15 min to recover from fatigue, and a magnetoencephalography (MEG) session in which they were asked to re-experience the state of their body with fatigue that they had experienced in the 2-back test session. In the non-fatigue experiment, the participants performed a free session for 15 min, a rest session for 15 min, and an MEG session in which they were asked to re-experience the state of their body without fatigue that they had experienced in the free session. Spatial filtering analyses of oscillatory brain activity showed that the delta band power in the left Brodmann's area (BA) 39, alpha band power in the right pulvinar nucleus and the left BA 40, and beta band power in the left BA 40 were lower when they re-experienced the fatigue sensation than when they re-experienced the fatigue-free sensation, indicating that these brain regions are related to re-experiencing the fatigue sensation. Our findings may help clarify the neural mechanisms underlying fatigue sensation.
    2015, PloS one, 10(3) (3), e0122455, English, International magazine
    Scientific journal

  • Hiroaki Kurihara, Akinobu Hamada, Masayuki Yoshida, Schuichi Shimma, Jun Hashimoto, Kan Yonemori, Hitomi Tani, Yasuji Miyakita, Yousuke Kanayama, Yasuhiro Wada, Makoto Kodaira, Mayu Yunokawa, Harukaze Yamamoto, Chikako Shimizu, Kazuhiro Takahashi, Yasuyoshi Watanabe, Yasuhiro Fujiwara, Kenji Tamura
    BACKGROUND: The purpose of this study was to determine whether brain metastases from HER2-positive breast cancer could be detected noninvasively using positron emission tomography (PET) with (64)Cu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-trastuzumab. METHODS: PET was performed on five patients with brain metastases from HER2-positive breast cancer, at 24 or 48 h after the injection of approximately 130 MBq of the probe (64)Cu-DOTA-trastuzumab. Radioactivity in metastatic brain tumors was evaluated based on PET images in five patients. Autoradiography, immunohistochemistry (IHC), and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis were performed in one surgical case to confirm HER2 specificity of (64)Cu-DOTA-trastuzumab. RESULTS: Metastatic brain lesions could be visualized by (64)Cu-DOTA-trastuzumab PET in all of five cases, which might indicated that trastuzumab passes through the blood-brain barrier (BBB). The HER2 specificity of (64)Cu-DOTA-trastuzumab was demonstrated in one patient by autoradiography, immunohistochemistry, and LC-MS/MS. CONCLUSIONS: Cu-DOTA-trastuzumab PET could be a potential noninvasive procedure for serial identification of metastatic brain lesions in patients with HER2-positive breast cancer. TRIAL REGISTRATION: UMIN000004170.
    2015, EJNMMI research, 5, 8 - 8, English, International magazine
    Scientific journal

  • Kayo Takahashi, Kei Mizuno, Akihiro T Sasaki, Yasuhiro Wada, Masaaki Tanaka, Akira Ishii, Kanako Tajima, Naohiro Tsuyuguchi, Kyosuke Watanabe, Semir Zeki, Yasuyoshi Watanabe
    Using [(11)C]raclopride, a dopamine D2/D3 receptor antagonist, we undertook a positron emission tomography (PET) study to investigate the involvement of the dopaminergic neurotransmitter system when subjects viewed the pictures of partners to whom they were romantically attached. Ten subjects viewed pictures of their romantic partners and, as a control, of friends of the same sex for whom they had neutral feelings during the PET study. We administered [(11)C]raclopride to subjects using a timing for injecting the antagonist which had been determined in previous studies to be optimal for detecting increases in the amount of dopamine released by stimulation. The results demonstrated statistically significant activation of the dopaminergic system in two regions, the medial orbitofrontal cortex (mOFC) and medial prefrontal cortex, the former of which has been strongly implicated in a variety of rewarding experiences, including that of beauty and love. A positive correlation was obtained in mOFC between excitement levels and dopaminergic activation only in the love but not in the control condition.
    2015, Frontiers in human neuroscience, 9, 191 - 191, English, International magazine
    Scientific journal

  • Kei Mizuno, Masaaki Tanaka, Hiroki C Tanabe, Takako Joudoi, Junko Kawatani, Yoshihito Shigihara, Akemi Tomoda, Teruhisa Miike, Kyoko Imai-Matsumura, Norihiro Sadato, Yasuyoshi Watanabe
    The ability to divide one's attention deteriorates in patients with childhood chronic fatigue syndrome (CCFS). We conducted a study using a dual verbal task to assess allocation of attentional resources to two simultaneous activities (picking out vowels and reading for story comprehension) and functional magnetic resonance imaging. Patients exhibited a much larger area of activation, recruiting additional frontal areas. The right middle frontal gyrus (MFG), which is included in the dorsolateral prefrontal cortex, of CCFS patients was specifically activated in both the single and dual tasks; this activation level was positively correlated with motivation scores for the tasks and accuracy of story comprehension. In addition, in patients, the dorsal anterior cingulate gyrus (dACC) and left MFG were activated only in the dual task, and activation levels of the dACC and left MFG were positively associated with the motivation and fatigue scores, respectively. Patients with CCFS exhibited a wider area of activated frontal regions related to attentional resources in order to increase their poorer task performance with massive mental effort. This is likely to be less efficient and costly in terms of energy requirements. It seems to be related to the pathophysiology of patients with CCFS and to cause a vicious cycle of further increases in fatigue.
    2015, NeuroImage. Clinical, 9, 355 - 68, English, International magazine
    Scientific journal

  • 【DDS研究30年:温故知新】(第7章)バイオイメージング技術 PET分子イメージング活用創薬
    渡辺 恭良, 向井 英史, 新垣 友隆
    (株)じほう, Jan. 2015, PHARM TECH JAPAN, 31(2) (2), 442 - 447, Japanese
    [Refereed]
    Scientific journal

  • Fukuda S, Koyama H, Kondo K, Fujii H, Hirayama Y, Tabata T, Okamura M, Yamakawa T, Okada S, Hirata S, Kiyama H, Kajimoto O, Watanabe Y, Inaba M, Nishizawa Y
    BACKGROUND: Fatigue is a predictor of cardiovascular events in patients with end-stage renal disease (ESRD) undergoing hemodialysis treatment. We hypothesized that multinutritional support would improve quality of life, fatigue symptoms, and potential quantitative measures including endocrine, immune and autonomic functions in patients with ESRD undergoing hemodialysis. METHODS: Two hundred and two hemodialysis patients were randomly assigned to receive active treatment (containing vitamin B1, vitamin B2, niacin, vitamin B6, vitamin B12, folic acid, vitamin C, carnitine, coenzyme Q10, naïve galacto-oligosaccharide, and zinc) or placebo after each dialysis session for 12 weeks. The patients and attending physicians were blinded to the treatment, and 172 patients (86 in each group) completed the study. Fatigue was evaluated via fatigue questionnaire at 0, 4, and 12 weeks. To assess human herpes virus (HHV) 6 and 7 reactivation, numbers of viral DNA copies were determined in saliva by polymerase chain reaction at weeks 0 and 12. Autonomic function was determined via measurement of beat-to-beat variation by using acceleration plethysmography. RESULTS: Clinical characteristics, changes in fatigue, quality of life score, endocrine functions, and laboratory data did not differ significantly between the two groups. Several parameters of heart rate variability significantly increased after nutritional treatment compared to placebo. Nutritional drink for 12 weeks significantly suppressed HHV7 DNA copy numbers. Similarly, HHV6 DNA copy numbers tended to be decreased by treatment but without reaching statistical significance. CONCLUSIONS: Nutritional supplementation may modulate immune and autonomic dysfunction in ESRD patients undergoing hemodialysis.
    2015, PloS one, 10(3) (3), e0119578, English, International magazine
    [Refereed]
    Scientific journal

  • Yilong Cui, Yosky Kataoka, Yasuyoshi Watanabe
    A migraine is a recurring neurological disorder characterized by unilateral, intense, and pulsatile headaches. In one-third of migraine patients, the attacks are preceded by a visual aura, such as a slowly-propagating scintillating scotoma. Migraine aura is thought to be a result of the neurovascular phenomenon of cortical spreading depression (SD), a self-propagating wave of depolarization that spreads across the cerebral cortex. Several animal experiments have demonstrated that cortical SD causes intracranial neurogenic inflammation around the meningeal blood vessels, such as plasma protein extravasation and pro-inflammatory peptide release. Cortical SD has also been reported to activate both peripheral and central trigeminal nociceptive pathways. Although several issues remain to be resolved, recent evidence suggests that cortical SD could be the initial trigger of intracranial neurogenic inflammation, which then contributes to migraine headaches via subsequent activation of trigeminal afferents.
    Oct. 2014, Neuroscience bulletin, 30(5) (5), 812 - 22, English, International magazine
    Scientific journal

  • Akihito Ohnishi, Michio Senda, Tomohiko Yamane, Masahiro Sasaki, Tomoko Mikami, Tomoyuki Nishio, Yasuhiko Ikari, Hiroyuki Nishida, Miho Shukuri, Tadayuki Takashima, Aya Mawatari, Hisashi Doi, Yasuyoshi Watanabe, Hirotaka Onoe
    INTRODUCTION: Neuroinflammatory processes play an important role in the pathogenesis of Alzheimer's disease and other brain disorders, and nonsteroidal anti-inflammatory drugs (NSAIDs) are considered therapeutic candidates. As a biomarker of neuroinflammatory processes, (11)C-labeled ketoprofen methyl ester ([(11)C]KTP-Me) was designed to allow cerebral penetration of ketoprofen (KTP), an active form of a selective cyclooxygenase-1 inhibitor that acts as an NSAID. Rat neuroinflammation models indicate that [(11)C]KTP-Me enters the brain and is retained in inflammatory lesions, accumulating in activated microglia. [(11)C]KTP-Me is washed out from normal tissues, leading to the present first-in-human exploratory study. METHODS: [(11)C]KTP-Me was synthesized by rapid C-[(11)C]methylation of [(11)C]CH3I and the corresponding arylacetate precursor, purified with high-performance liquid chromatography, and prepared as an injectable solution including PEG400, providing radiochemical purity of >99% and specific activity of >25GBq/μmol at injection. Six young healthy male humans were injected with [(11)C]KTP-Me and scanned with PET camera to determine the early-phase brain time course followed by three whole-body scans starting 8, 20, and 40 min post-injection, together with sequential blood sampling and labeled metabolite analysis. RESULTS: No adverse effects were observed during PET scanning after [(11)C]KTP-Me injection. [(11)C]KTP-Me was rapidly metabolized to (11)C-labeled ketoprofen ([(11)C]KTP) within 2-3 min and was gradually cleared from blood. The radioactivity entered the brain with an average peak cortical SUV of 1.5 at 2 min. The cortical activity was gradually washed out. Whole-body images indicated that the urinary bladder was the major excretory pathway. The organ with the highest radiation dose was the urinary bladder (average dose of 41μGy/MBq, respectively). The mean effective dose was 4.7μSv/MBq, which was comparable to other (11)C-labeled radiopharmaceuticals. CONCLUSION: [(11)C]KTP-Me demonstrated a favorable dosimetry, biodistribution, and safety profile. [(11)C]KTP-Me entered the human brain, and the radioactivity was washed out from cerebral tissue. These data warrant further exploratory studies on patients with neuroinflammation.
    Aug. 2014, Nuclear medicine and biology, 41(7) (7), 594 - 9, English, International magazine
    Scientific journal

  • Kei Mizuno, Kanako Tajima, Yasuyoshi Watanabe, Hirohiko Kuratsune
    BACKGROUND: It is known that enhancement of sympathetic nerve activity based on a decrease in parasympathetic nerve activity is associated with fatigue induced by mental tasks lasting more than 30 min. However, to measure autonomic nerve function and assess fatigue levels in both clinical and industrial settings, shorter experimental durations and more sensitive measurement methods are needed. The aim of the present study was to establish an improved method for inducing fatigue and evaluating the association between it and autonomic nerve activity. METHODS: Twenty-eight healthy female college students participated in the study. We used a kana pick-out test (KPT) as a brief verbal cognitive task and recorded electrocardiography (ECG) to measure autonomic nerve activity. The experimental design consisted of a 16-min period of ECG: A pre-task resting state with eyes open for 3 min and eyes closed for 3 min, the 4-min KPT, and a post-task resting state with eyes open for 3 min and eyes closed for 3 min. RESULTS: Baseline fatigue sensation, measured by a visual analogue scale before the experiment, was associated with the decrease in parasympathetic sinus modulation, as indicated the by ratio of low-frequency component power (LF) to high-frequency component power (HF), during the KPT. The LF/HF ratio during the post-KPT rest with eyes open tended to be greater than the ratio during the KPT and correlated with fatigue sensation. Fatigue sensation was correlated negatively with log-transformed HF, which is an index of parasympathetic sinus modulation, during the post-KPT rest with eyes open. CONCLUSIONS: The methods described here are useful for assessing the association between fatigue sensation and autonomic nerve activity using a brief cognitive test in healthy females.
    Jul. 2014, Behavioral and brain functions : BBF, 10, 25 - 25, English, International magazine
    Scientific journal

  • Atsushi Narita, Susumu Shiomi, Joji Kawabe, Hiroyuki Tsushima, Takashi Yamanaga, Yasuyoshi Watanabe
    A database is an important factor in the statistical analysis of myocardial scintigraphy. Our aim in this study was to verify the validity of the threshold method using phantoms and to create a clinical database using this method. Since this method involves artificially excluding a low count area on a polar map, we created a myocardial phantom with defects. Then, we applied this method to the construction of a control database (CDB) for which we used stress-rest scans of 152 male and 52 female Japanese patients. The clinical relevance of this database was investigated by comparison of the values between the CDB and a Japanese normal database. In the study evaluation, we mainly used the summed extent score (SES) and a severity map (severity). Data from the phantom with defects demonstrated that the threshold method could compensate for defective areas, enabling the use of data for the creation of the CDB. Comparison of the CDB with the Japanese normal database showed a good relationship with respect to the SES and severity (Initial post-stress: SES: r = 0.978; severity: r = 0.997, Redistribution: SES: r = 0.944; severity: r = 0.993). The threshold method facilitates the effective creation of a database by use of clinical data. This enables individual institutions to build their own databases, taking into account differences in collection and processing conditions between institutions as well as the characteristics of individual equipment.
    Jul. 2014, Radiological physics and technology, 7(2) (2), 340 - 51, English, Domestic magazine
    Scientific journal

  • Zhouen Zhang, Hisashi Doi, Hiroko Koyama, Yasuyoshi Watanabe, Masaaki Suzuki
    The nucleosides zidovudine (AZT), stavudine (d4T), and telbivudine (LdT) are approved for use in the treatment of human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infections. To promote positron emission tomography (PET) imaging studies on their pharmacokinetics, pharmacodynamics, and applications in cancer diagnosis, a convenient one-pot method for Pd(0)-Cu(I) co-mediated rapid C-C coupling of [(11)C]methyl iodide with stannyl precursor was successfully established and applied to synthesize the PET tracers [(11)C]zidovudine, [(11)C]stavudine, and [(11)C]telbivudine. After HPLC purification and radiopharmaceutical formulation, the desired PET tracers were obtained with high radioactivity (6.4-7.0 GBq) and specific radioactivity (74-147 GBq/µmol) and with high chemical (>99%) and radiochemical (>99.5%) purities. This one-pot Pd(0)-Cu(I) co-mediated rapid C-[(11)C]methylation also worked well for syntheses of [methyl-(11)C]thymidine and [methyl-(11)C]4'-thiothymidine, resulting twice the radioactivity of those prepared by a previous two-pot method. The mechanism of one-pot Pd(0)-Cu(I) co-mediated rapid C-[(11)C]methylation was also discussed.
    WILEY-BLACKWELL, Jun. 2014, Journal of labelled compounds & radiopharmaceuticals, 57(8) (8), 540 - 9, English, International magazine
    Scientific journal

  • Takahiro Yoshikawa, Masaaki Tanaka, Akira Ishii, Yasuyoshi Watanabe
    'Hara-Hachibu' in Japanese means a subjective sense by which we stop eating just before the motivation to eat is completely lost, a similar concept to caloric restriction (CR). Insular cortex is a critical platform which integrates sensory information into decision-making processes in eating behavior. We compared the responses of insular cortex, as assessed by magnetoencephalography (MEG), immediately after presentation of food images in the Fasting condition with those in the 'Hara-Hachibu' condition. Eleven healthy, right-handed males [age, 27.2±9.6 years; body mass index, 22.6±2.1kg/m(2) (mean±SD)] were enrolled in a randomized, two-crossover experiment (Fasting and 'Hara-Hachibu' conditions). Before the MEG recordings in the 'Hara-Hachibu' condition, the participants consumed rice balls as much as they judged themselves to have consumed shortly before reaching satiety. During the MEG recordings, they viewed food pictures projected on a screen. The intensities of MEG responses to viewing food pictures were significantly lower in the 'Hara-Hachibu' condition than those in the Fasting condition (P<0.05). The intensities of the MEG responses to the visual food stimuli in the 'Hara-Hachibu' condition was positively associated with the factor-3 (food tasted) (r=0.693, P=0.018) and aggregated scores (r=0.659, P=0.027) of the Power of Food Scale, a self-report measure of hedonic hunger. These findings may help to elucidate the neural basis of variability of appetite phenotypes under the condition of CR among individuals, and to develop possible strategies for the maintenance of adequate CR in daily life.
    ELSEVIER, Jun. 2014, Brain research, 1568, 31 - 41, English, International magazine
    Scientific journal

  • Yasuhito Nakatomi, Kei Mizuno, Akira Ishii, Yasuhiro Wada, Masaaki Tanaka, Shusaku Tazawa, Kayo Onoe, Sanae Fukuda, Joji Kawabe, Kazuhiro Takahashi, Yosky Kataoka, Susumu Shiomi, Kouzi Yamaguti, Masaaki Inaba, Hirohiko Kuratsune, Yasuyoshi Watanabe
    UNLABELLED: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disease characterized by chronic, profound, disabling, and unexplained fatigue. Although it is hypothesized that brain inflammation is involved in the pathophysiology of CFS/ME, there is no direct evidence of neuroinflammation in patients with CFS/ME. Activation of microglia or astrocytes is related to neuroinflammation. (11)C-(R)-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carboxamide ((11)C-(R)-PK11195) is a ligand of PET for a translocator protein that is expressed by activated microglia or astrocytes. We used (11)C-(R)-PK11195 and PET to investigate the existence of neuroinflammation in CFS/ME patients. METHODS: Nine CFS/ME patients and 10 healthy controls underwent (11)C-(R)-PK11195 PET and completed questionnaires about fatigue, fatigue sensation, cognitive impairments, pain, and depression. To measure the density of translocator protein, nondisplaceable binding potential (BP(ND)) values were determined using linear graphical analysis with the cerebellum as a reference region. RESULTS: The BP(ND) values of (11)C-(R)-PK11195 in the cingulate cortex, hippocampus, amygdala, thalamus, midbrain, and pons were 45%-199% higher in CFS/ME patients than in healthy controls. In CFS/ME patients, the BP(ND) values of (11)C-(R)-PK11195 in the amygdala, thalamus, and midbrain positively correlated with cognitive impairment score, the BP(ND) values in the cingulate cortex and thalamus positively correlated with pain score, and the BP(ND) value in the hippocampus positively correlated with depression score. CONCLUSION: Neuroinflammation is present in widespread brain areas in CFS/ME patients and was associated with the severity of neuropsychologic symptoms. Evaluation of neuroinflammation in CFS/ME patients may be essential for understanding the core pathophysiology and for developing objective diagnostic criteria and effective medical treatments.
    Jun. 2014, Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 55(6) (6), 945 - 50, English, International magazine
    Scientific journal

  • Masaaki Suzuki, Hisashi Doi, Hiroko Koyama, Zhouen Zhang, Takamitsu Hosoya, Hirotaka Onoe, Yasuyoshi Watanabe
    Positron emission tomography is a noninvasive method for monitoring drug (or diagnostic) behavior and its localization on the target molecules in the living systems, including the human body, using a short-lived positron-emitting radionuclide. New methodologies for introducing representative short-lived radionuclides, (11)C and (18)F, into the carbon frameworks of biologically active organic compounds have been established by developing rapid C-[(11)C]methylations and C-[(18)F]fluoromethylations using rapid Pd(0)-mediated cross-coupling reactions between [(11)C]methyl iodide (sp(3)-hybridized carbon) and an excess amount of organotributylstannane or organoboronic acid ester having sp(2) (phenyl, heteroaromatic, or alkenyl), sp(alkynyl), or sp(3) (benzyl and cinnamyl)-hybridized carbons; and [(18)F]fluoromethyl halide (iodide or bromide) and an organoboronic acid ester, respectively. These rapid reactions provide a firm foundation for an efficient and general synthesis of short-lived (11)C- or (18)F-labeled PET molecular probes to promote in vivo molecular imaging studies.
    Jun. 2014, Chemical record (New York, N.Y.), 14(3) (3), 516 - 41, English, International magazine
    Scientific journal

  • Masaaki Tanaka, Akira Ishii, Yasuyoshi Watanabe
    Mental fatigue can be defined as a psychobiological state caused by prolonged periods of demanding cognitive activity and manifests as a reduced efficiency in cognitive performance. Mental fatigue is one of the most significant causes of accidents in modern society. Therefore, understanding the neural mechanisms of mental fatigue is important. However, the neural mechanisms of mental fatigue are not fully understood. In this study, we investigated the neural activity that results from mental fatigue caused by a continuous attention load. We used magnetoencephalography (MEG) to evaluate the neural activities during the attention task. Ten healthy male volunteers participated in this study. They performed a continuous attention task lasting 10 min. Subjective ratings of mental fatigue, mental stress, boredom, and sleepiness were performed just after the task trial. MEG data were analyzed using narrow-band adaptive spatial filtering methods. An increase in the beta-frequency band (13-25 Hz) power in the right inferior and middle frontal gyri (Brodmann׳s areas 44 and 9 respectively) was caused by the mental fatigue. The increase in the beta-frequency band power in the right middle frontal gyrus was negatively associated with the self-reported level of mental stress and was positively associated with those of boredom and sleepiness. These results demonstrate that performing a continuous mental fatigue-inducing task causes changes in the activation of the prefrontal cortex, and manifests as an increased beta-frequency power in this brain area as well as sleepiness. Our results contribute to greater understanding of the neural mechanisms of mental fatigue.
    May 2014, Brain research, 1561, 60 - 6, English, International magazine
    Scientific journal

  • タウイメージング用放射性薬剤[11C]PBB3の大阪市立大学での臨床研究に向けた合成検討
    徳田 安則, 山岡 高章, 小畑 久子, 張 明栄, 島田 斉, 樋口 真人, 須原 哲也, 渡辺 恭良, 高橋 和弘
    日本分子イメージング学会, May 2014, JSMI Report, 7(2) (2), 127 - 127, Japanese

  • Masaaki Tanaka, Akira Ishii, Yasuyoshi Watanabe
    Chronic cognitive fatigue is characterized by a sensation of long-lasting fatigue that impairs cognitive functions. Facilitation and inhibition systems in the central nervous system play primary roles in determining the output to the peripheral system, that is, performance. Sensory input from the peripheral system to the central nervous system activates the inhibition system to limit performance, whereas motivational input activates the facilitation system to enhance performance. The dysfunction of the facilitation system and central sensitization and classical conditioning of the inhibition system play important roles in the pathophysiology of chronic cognitive fatigue. Because the dorsolateral prefrontal cortex receives input from both the facilitation and inhibition systems to determine performance, metabolic, functional, and structural impairments of the dorsolateral prefrontal cortex induced by repetitive and prolonged overwork, stress, and stress responses contribute to the impaired functioning and cognitive performance that occur in people with chronic cognitive fatigue. This hypothesis of the regulatory mechanism of performance provides a new perspective on the neural mechanisms underlying chronic cognitive fatigue.
    May 2014, Medical hypotheses, 82(5) (5), 567 - 71, English, International magazine
    Scientific journal

  • Shiho Nomura, Satoshi Nozaki, Takashi Hamazaki, Taisuke Takeda, Eiichi Ninomiya, Satoshi Kudo, Emi Hayashinaka, Yasuhiro Wada, Tomoko Hiroki, Chie Fujisawa, Hiroko Kodama, Haruo Shintaku, Yasuyoshi Watanabe
    UNLABELLED: Menkes disease (MD), an X-linked recessive disorder of copper metabolism caused by mutations in the copper-transporting ATP7A gene, results in growth failure and severe neurodegeneration in early childhood. Subcutaneous copper-histidine injection is the standard treatment for MD, but it has limited clinical efficacy. Furthermore, long-term copper injection causes excess copper accumulation in the kidneys, resulting in renal dysfunction. To attempt to resolve this issue, we used PET imaging with (64)Cu to investigate the effects of disulfiram on copper biodistribution in living mice serving as an animal model for MD (MD model mice). METHODS: Macular mice were used as MD model mice, and C3H/He mice were used as wild-type mice. Mice were pretreated with 2 types of chelators (disulfiram, a lipophilic chelator, and d-penicillamine, a hydrophilic chelator) 30 min before (64)CuCl2 injection. After (64)CuCl2 injection, emission scans covering the whole body were performed for 4 h. After the PET scans, the brain and kidneys were analyzed for radioactivity with γ counting and autoradiography. RESULTS: After copper injection alone, marked accumulation of radioactivity ((64)Cu) in the liver was demonstrated in wild-type mice, whereas in MD model mice, copper was preferentially accumulated in the kidneys (25.56 ± 3.01 percentage injected dose per gram [%ID/g]) and was detected to a lesser extent in the liver (13.83 ± 0.26 %ID/g) and brain (0.96 ± 0.08 %ID/g). Copper injection with disulfiram reduced excess copper accumulation in the kidneys (14.54 ± 2.68 %ID/g) and increased copper transport into the liver (29.42 ± 0.98 %ID/g) and brain (5.12 ± 0.95 %ID/g) of MD model mice. Copper injection with d-penicillamine enhanced urinary copper excretion and reduced copper accumulation in most organs in both mouse groups. Autoradiography demonstrated that disulfiram pretreatment induced copper transport into the brain parenchyma and reduced copper accumulation in the renal medulla. CONCLUSION: PET studies with (64)Cu revealed that disulfiram had significant effects on the copper biodistribution of MD. Disulfiram increased copper transport into the brain and reduced copper uptake in the kidneys of MD model mice. The application of (64)Cu PET for the treatment of MD and other copper-related disorders may be useful in clinical settings.
    May 2014, Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 55(5) (5), 845 - 51, English, International magazine
    Scientific journal

  • Kayo Takahashi, Takamitsu Hosoya, Kayo Onoe, Hisashi Doi, Hiroko Nagata, Toshiyuki Hiramatsu, Xiao-Le Li, Yumiko Watanabe, Yasuhiro Wada, Tadayuki Takashima, Masaaki Suzuki, Hirotaka Onoe, Yasuyoshi Watanabe
    UNLABELLED: Aromatase (an enzyme that converts androgens to estrogens) in the brain is involved in neuroprotection, synaptic plasticity, and regulation of sexual and emotional behaviors. To investigate the physiologic and pathologic importance of aromatase in the brain, including in humans, we here report the development of a novel PET probe for aromatase, (11)C-cetrozole, which allows noninvasive quantification of aromatase expression. METHODS: (11)C-cetrozole was synthesized by the C-(11)C-methylation method developed by our group. In vitro autoradiography of frozen sections and a binding study with rat brain homogenates were conducted to demonstrate the specific binding and the dissociation constant. PET studies with anesthetized rhesus monkeys were performed to analyze the dynamics in the brain. RESULTS: In vitro and in vivo studies using (11)C-cetrozole showed its superiority in brain aromatase imaging in terms of specificity and selectivity, compared with previously developed (11)C-vorozole. PET studies showed that (11)C-cetrozole had a higher signal-to-noise ratio, providing a sharper image than (11)C-vorozole, because the radioactive metabolite of (11)C-vorozole was taken up into the brain. High specific binding of (11)C-cetrozole was observed in the amygdala and hypothalamus, and we also noted binding in the nucleus accumbens of rhesus monkeys for the first time. CONCLUSION: These results suggest that PET imaging with newly developed (11)C-cetrozole is suitable for quantifying the expression of brain aromatase in vivo, possibly providing critical information regarding the functional roles of aromatase in human neurologic and emotional disorders.
    May 2014, Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 55(5) (5), 852 - 7, English, International magazine
    Scientific journal

  • 樹状型ポリエチレングリコール修飾によるボンベシンアナログ誘導体PETプローブの腫瘍内貯留性向上
    向井 英史, 松村 一史, 造田 真希, 高橋 麻衣子, 林中 恵美, 山下 富義, 橋田 充, 和田 康弘, 渡辺 恭良
    日本分子イメージング学会, May 2014, JSMI Report, 7(2) (2), 111 - 111, Japanese
    [Refereed]

  • 64Cu標識前立腺癌標的ペプチドDUP-1の化学修飾がもたらす代謝安定性と腫瘍集積性の向上
    松村 一史, 向井 英史, 造田 真希, 高橋 麻衣子, 林中 恵美, 山下 富義, 橋田 充, 和田 康弘, 渡辺 恭良
    日本分子イメージング学会, May 2014, JSMI Report, 7(2) (2), 118 - 118, Japanese
    [Refereed]

  • 11C標識TelbivudineによるB型肝炎モデルマウスのPETイメージング
    金山 洋介, 佐古 健生, 張 周恩, 蔵地 理代, Hume William Ewan, 林中 恵美, 和田 康弘, 崔 翼龍, 小嶋 聡一, 渡辺 恭良
    日本分子イメージング学会, May 2014, JSMI Report, 7(2) (2), 120 - 120, Japanese

  • Positron Emission Tomography(PET)を用いた経鼻吸収評価系の構築と脳への直接移行性に関する研究
    新垣 友隆, 片山 由美子, 和田 康弘, 崔 翼龍, 古林 呂之, 坂根 稔康, 渡辺 恭良
    (公社)日本薬剤学会, May 2014, 日本薬剤学会年会講演要旨集, 29年会, 159 - 159, Japanese

  • Hidefumi Mukai, Daiki Ozaki, Yilong Cui, Takeshi Kuboyama, Hiroko Yamato-Nagata, Kayo Onoe, Maiko Takahashi, Yasuhiro Wada, Takeshi Imanishi, Tetsuya Kodama, Satoshi Obika, Masaaki Suzuki, Hisashi Doi, Yasuyoshi Watanabe
    Recently, we demonstrated the utility of positron emission tomography (PET) imaging-based pharmacokinetic evaluation studies for preclinical experiments and microdose clinical trials, mainly focused on low molecular weight compounds. In order to investigate the pharmacokinetics of nucleic acid drugs and their drug delivery systems (DDSs) in vivo by using PET imaging, we developed a novel and efficient method for radiolabeling oligodeoxynucleotides with the positron-emitting radionuclide F-18 (stoichiometry-focused Huisgen-type F-18 labeling). By using this method, we succeeded in synthesizing a variety of F-18-labeled oligodeoxynucleotides with not only phosphodiesters (PO) in natural forms, but also phosphorothioate (PS) and bridged nucleic acid (BNA) in artificial forms, and then performed PET studies and radioactive metabolite analyses of these F-18-labeled oligodeoxynucleotides. The tissue-distribution and dynamic changes in radioactivity showed significantly different profiles between these antisense oligodeoxynucleotides. The radioactivity of F-18-labeled PO-DNA and PO-BNA rapidly accumulated in the kidneys and liver and then moved to the renal medulla, ureter, bladder, and intestine. However, the radioactivity of F-18-labeled PS-DNA and PS-BNA, possessing PS backbone structures, was retained in the blood for relatively long periods and then gradually accumulated in the liver and kidneys. The metabolite analysis showed that F-18-labeled PO-DNA rapidly degraded by 5 min and F-18-labeled PO-BNA gradually degraded over time by 60 min. Conversely, F-18-labeled PS-DNA and PS-BNA were shown to be much more stable. To demonstrate the usefulness of the PET imaging technique for evaluating the improved targeting potential of the DDS, we designed and synthesized a cholesterol-modified oligodeoxynucleotide, that we developed as an antisense nucleic acid drug against proprotein convertase subtilisin/kexin type 9 (PCSK9) for hypercholesterolemia therapy, and evaluated its pharmacokinetics using PET imaging. As expected, the F-18-labeled cholesterolmodified PS-BNA-type oligodeoxynucleotide showed much higher and more rapid accumulation in the delivery target organ, that is, the liver, which encourages us to develop this drug. These results suggest that dynamic PET studies using F-18-incorporated oligodeoxynucleotide synthesized by stoichiometry-focused Huisgen-type labeling is useful for quantitative pharmacokinetic evaluation of nucleic acid drugs and their delivery systems. (C) 2014 Elsevier B.V. All rights reserved.
    ELSEVIER SCIENCE BV, Apr. 2014, JOURNAL OF CONTROLLED RELEASE, 180, 92 - 99, English, International magazine
    [Refereed]
    Scientific journal

  • 適度な血中循環の延長と多点認識を目指した化学修飾による癌PETイメージング用ペプチドプローブの改良
    松村 一史, 向井 英史, 造田 真希, 高橋 麻衣子, 林中 恵美, 川上 茂, 山下 富義, 橋田 充, 和田 康弘, 渡辺 恭良
    (公社)日本薬学会, Mar. 2014, 日本薬学会年会要旨集, 134年会(2) (2), 254 - 254, Japanese
    [Refereed]

  • Takahiro Yoshikawa, Masaaki Tanaka, Akira Ishii, Shigeo Fujimoto, Yasuyoshi Watanabe
    Currently, little is known about the brain function that allows individuals to suppress eating behavior. The present study used magnetoencephalography (MEG) to examine changes in neural activity over time that were related to suppression of motivation to eat in 11 healthy males. The MEG experiment consisted of four motivation sessions and four suppression sessions in an alternating and counterbalanced order. During MEG recordings, participants viewed a set of food pictures and mosaic pictures projected onto a screen, and were then asked to rate their motivation to eat and the suppression of the motivation to eat during the recordings. The present study demonstrated a higher β-band (13-25 Hz) event-related synchronization (ERS) level during the suppression sessions relative to the motivation sessions in the left supplementary motor area (SMA) 200-300 ms after the start of food picture presentation. Similar differences were also observed in θ-band (4-8 Hz) event-related desynchronization (ERD) in the left dorsolateral prefrontal cortex (DLPFC) after 500-600 ms. Negative relationships were observed between these levels of MEG responses and the number of food items for which the participants reported the motivation to eat during the MEG recordings. These findings indicate that the left DLPFC and SMA, particularly the DLPFC, play prominent roles in the suppression of motivation to eat. This may help to clarify the temporal aspects of the neural basis of self-control of appetitive motivation as well as aid development of self-control strategies such as cognitive behavioral therapy for patients with disordered appetite.
    ELSEVIER, Jan. 2014, Brain research, 1543, 120 - 7, English, International magazine
    Scientific journal

  • Masaaki Tanaka, Akira Ishii, Yasuyoshi Watanabe
    We sought to clarify the neural effect of mental fatigue on physical fatigue using magnetoencephalography (MEG) and classical conditioning techniques. Eleven right-handed volunteers participated in this study. On the first day, participants performed fatigue-inducing maximum handgrip trials for 10 min; metronome sounds were started 5 min after the beginning of the trials. We used metronome sounds as conditioned stimuli and maximum handgrip trials as unconditioned stimuli to cause physical fatigue. On the next day, MEG recordings during the imagery of maximum grips of the right hand guided by the metronome sounds were performed for 10 min just before (control session) and after (mental fatigue session) a 30-min fatigue-inducing mental task session. In the right anterior cingulate cortex (Brodmann's area 23), the alpha-band event-related synchronization of the mental fatigue session relative to the control session within the time window of 500–600 ms after the onset of handgrip cue sounds was identified. We demonstrated that mental fatigue suppresses activities in the right anterior cingulate cortex during physical fatigue.
    Jan. 2014, Brain research, 1542, 49 - 55, English, International magazine
    Scientific journal

  • 渡辺 恭良, 土居 久志, 馬渡 彩, 金澤 奨勝, 野崎 聡, 中谷 友香, 野村 之博, 秋元 浩二, 二宮 伸二
    公益社団法人 日本ビタミン学会, 2014, ビタミン, 88(5) (5), 309 - 310, Japanese

  • Masanori Yamato, Yasuhisa Tamura, Asami Eguchi, Satoshi Kume, Yukiharu Miyashige, Masayuki Nakano, Yasuyoshi Watanabe, Yosky Kataoka
    During acute viral infections such as influenza, humans often experience not only transient fever, but also prolonged fatigue or depressive feelings with a decrease in social activity for days or weeks. These feelings are thought to be due to neuroinflammation in the brain. Recent studies have suggested that chronic neuroinflammation is a precipitating event of various neurological disorders, but the mechanism determining the duration of neuroinflammation has not been elucidated. In this study, neuroinflammation was induced by intraperitoneal injection of polyriboinosinic:polyribocytidylic acid (poly I:C), a Toll-like receptor-3 agonist that mimics viral infection in male Sprague-Dawley rats, and then investigated how the neuroinflammation shift from acute to the chronic state. The rats showed transient fever and prolonged suppression of spontaneous activity for several days following poly I:C injection. NS-398, a cyclooxygenase-2 inhibitor, completely prevented fever, but did not improve spontaneous activity, indicating that suppression of spontaneous activity was not induced by the arachidonate cascade that generated the fever. The animals overexpressed interleukin (IL)-1β and IL-1 receptor antagonist (IL-1ra) in the brain including the cerebral cortex. Blocking the IL-1 receptor in the brain by intracerebroventricular (i.c.v.) infusion of recombinant IL-1ra completely blocked the poly I:C-induced suppression of spontaneous activity and attenuated amplification of brain interferon (IFN)-α expression, which has been reported to produce fatigue-like behavior by suppressing the serotonergic system. Furthermore, i.c.v. infusion of neutralizing antibody for IL-1ra prolonged recovery from suppression of spontaneous activity. Our findings indicated that IL-1β is the key trigger of neuroinflammation and that IL-1ra prevents the neuroinflammation entering the chronic state.
    2014, PloS one, 9(3) (3), e90950, English, International magazine
    Scientific journal

  • Akira Ishii, Masaaki Tanaka, Yasuyoshi Watanabe
    There have been several studies of the neural mechanisms underlying sensation of fatigue. However, little is known about the neural mechanisms underlying self-evaluation of the level of fatigue. The aim of this study was to identify the neural substrates involved in self-evaluation of the level of mental fatigue. We used magnetoencephalography (MEG) with high temporal resolution on 14 healthy participants. During MEG recordings, participants were asked to evaluate their level of mental fatigue in time with execution cues (evaluation trials) or to do nothing in time with execution cues (control trials). The MEG data were analyzed with equivalent current dipole (ECD) and spatial filtering methods to localize the neural activity related to the evaluation of mental fatigue. The daily level of fatigue sensation was assessed using the Checklist Individual Strength questionnaire. In evaluation trials, ECDs were observed in the posterior cingulate cortex (PCC) in seven of 14 participants, with a mean latency of 366.0 ms. The proportion of the participants with ECDs in the PCC was higher in evaluation trials than in control trials (P<0.05, McNemar test). The extent of the decreased delta band power in the PCC (Brodmann's area 31) 600-700 ms after the onset of the execution cue and that in the dorsolateral prefrontal cortex (DLPFC; Brodmann's area 9) 800-900 ms after the onset of the execution cue were greater in the evaluation trials than in the control trials. The decrease in delta band power in the DLPFC was positively related to that in the PCC and to the daily level of fatigue sensation. These data suggest that the PCC and DLPFC are involved in the self-evaluation of mental fatigue.
    2014, PloS one, 9(4) (4), e95763, English, International magazine
    Scientific journal

  • Akira Ishii, Masaaki Tanaka, Yasuyoshi Watanabe
    Fatigue is defined as a decline in the ability and efficiency of mental and/or physical activities that is caused by excessive mental and/or physical activities. Fatigue can be classified as physical or mental. Mental fatigue manifests as potentially impaired cognitive function and is one of the most significant causes of accidents in modern society. Recently, it has been shown that the neural mechanisms of mental fatigue related to cognitive task performance are more complex than previously thought and that mental fatigue is not caused only by impaired activity in task-related brain regions. There is accumulating evidence supporting the existence of mental facilitation and inhibition systems. These systems are involved in the neural mechanisms of mental fatigue, modulating the activity of task-related brain regions to regulate cognitive task performance. In this review, we propose a new conceptual model: the dual regulation system of mental fatigue. This model contributes to our understanding of the neural mechanisms of mental fatigue and the regulatory mechanisms of cognitive task performance in the presence of mental fatigue.
    2014, Reviews in the neurosciences, 25(4) (4), 469 - 79, English, International magazine
    Scientific journal

  • Takahiro Yoshikawa, Masaaki Tanaka, Akira Ishii, Yasuyoshi Watanabe
    Fatigue is a common complaint among young adults. We investigated whether eating behaviors are associated with fatigue in this population. The participants consisted of 117 healthy students attending Osaka City University. They completed questionnaires assessing fatigue and eating behaviors. To identify the factors associated with the prevalence of fatigue, multivariate logistic regression analysis adjusted for gender was performed. The Emotional Eating subscale score of the Japanese version of Three-Factor Eating Questionnaire Revised 21-item and stress response in food intake (large decrease vs. no change) were positively associated with the prevalence of fatigue assessed by the Japanese version of the Chalder Fatigue Scale. The finding suggests that emotional eating and decrease in amount of food intake under mental stress were associated with fatigue in healthy young adults. Our findings may help to clarify the mechanisms underlying fatigue-eating coupling as well as the etiology of diseases related to abnormal eating behavior.
    ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD, 2014, Behavioral medicine (Washington, D.C.), 40(4) (4), 149 - 53, English, International magazine
    Scientific journal

  • Akira Ishii, Masaaki Tanaka, Yasuyoshi Watanabe
    Adequate rest is essential to avoid fatigue and disruption of homeostasis. However, the neural mechanisms underlying the decision to rest are not well understood. In the present study, we aimed to clarify the neural mechanisms of this decision-making process using magnetoencephalography. Fifteen healthy volunteers participated in decision and control experiments performed in a cross-over fashion. In the decision experiment, participants performed 1,200 reverse Stroop test trials and were intermittently asked to decide whether they wanted to take a rest or continue. In the control experiments, participants performed 1,200 reverse Stroop test trials and were instructed to press a response button intermittently without making any decision. Changes in oscillatory brain activity were assessed using a narrow-band adaptive spatial filtering method. The levels of decrease in theta (4-8 Hz) band power in left Brodmann's area (BA) 31, alpha (8-13 Hz) band power in left BA 10 and BA 9, and beta (13-25 Hz) band power in right BA 46 and left BA 10 were greater in trials when the participant opted to rest (rest trials) than those in control trials. The decrease in theta band power in BA 31 in the rest trials was positively correlated with the subjective level of fatigue after the decision experiment. These results demonstrated that the dorsolateral prefrontal cortex, frontal pole, and posterior cingulate cortex play a role in the decision to rest in the presence of fatigue. These findings may help clarify the neural mechanisms underlying fatigue and fatigue-related problems.
    2014, PloS one, 9(10) (10), e109740, English, International magazine
    Scientific journal

  • W Ewan Hume, Tomotaka Shingaki, Tadayuki Takashima, Yoshinobu Hashizume, Takashi Okauchi, Yumiko Katayama, Emi Hayashinaka, Yasuhiro Wada, Hiroyuki Kusuhara, Yuichi Sugiyama, Yasuyoshi Watanabe
    In order to develop a new positron emission tomography (PET) probe to study hepatobiliary transport mediated by the multi-drug and toxin extrusion transporter 1 (MATE1), (11)C-labelled metformin was synthesized and then evaluated as a PET probe. [(11)C]Metformin ([(11)C]4) was synthesized in three steps, from [(11)C]methyl iodide. Evaluation by small animal PET of [(11)C]4 showed that there was increased concentrations of [(11)C]4 in the livers of mice pre-treated with pyrimethamine, a potential inhibitor of MATEs, inhibiting the hepatobiliary excretion of metformin. Radiometabolite analysis showed that [(11)C]4 was not degraded in vivo during the PET scan. Biodistribution studies were undertaken and the organ distributions were extrapolated into a standard human model. In conclusion, [(11)C]4 may be useful as a PET probe to non-invasively study the in vivo function of hepatobiliary transport and drug-drug interactions, mediated by MATE1 in future clinical investigations.
    Dec. 2013, Bioorganic & medicinal chemistry, 21(24) (24), 7584 - 90, English, International magazine
    Scientific journal

  • Takeo Sako, Koki Hasegawa, Mie Nishimura, Yousuke Kanayama, Yasuhiro Wada, Emi Hayashinaka, Yilong Cui, Yosky Kataoka, Michio Senda, Yasuyoshi Watanabe
    Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia, and the loss or dysfunction of pancreatic beta cells has been reported before the appearance of clinical symptoms and hyperglycemia. To evaluate beta cell mass (BCM) for improving the detection and treatment of DM at earlier stages, we focused on somatostatin receptors that are highly expressed in the pancreatic beta cells, and developed a positron emission tomography (PET) probe derived from octreotide, a metabolically stable somatostatin analog. Octreotide was conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), a chelating agent, and labeled with (68)Gallium ((68)Ga). After intravenous injection of (68)Ga-DOTA-octreotide, a 90-min emission scan of the abdomen was performed in normal and DM model rats. The PET studies showed that (68)Ga-DOTA-octreotide radioactivity was highly accumulated in the pancreas of normal rats and that the pancreatic accumulation was significantly reduced in the rats administered with an excess amount of unlabeled octreotide or after treatment with streptozotocin, which was used for the chemical induction of DM in rats. These results were in good agreement with the ex vivo biodistribution data. These results indicated that the pancreatic accumulation of (68)Ga-DOTA-octreotide represented specific binding to the somatostatin receptors and reflected BCM. Therefore, PET imaging with (68)Ga-DOTA-octreotide could be a potential tool for evaluating BCM.
    ACADEMIC PRESS INC ELSEVIER SCIENCE, Dec. 2013, Biochemical and biophysical research communications, 442(1-2) (1-2), 79 - 84, English, International magazine
    [Refereed]
    Scientific journal

  • Masaaki Tanaka, Akira Ishii, Yasuyoshi Watanabe
    Central inhibition plays an important role in physical performance during physical fatigue. We tried to clarify the neural mechanism of central inhibition during physical fatigue using the magnetoencephalography (MEG) and a classical conditioning technique. Twelve right-handed volunteers participated in this study. Participants underwent MEG recording during the imagery of maximum grips of the right hand guided by metronome sounds for 10 min. Thereafter, fatigue-inducing maximum handgrip trials were performed for 10 min; the metronome sounds were started 5 min after the beginning of the handgrip trials. We used metronome sounds as conditioned stimuli and maximum handgrip trials as unconditioned stimuli to cause central inhibition. The next day, MEG recording during the imagery of maximum grips of the right hand guided by metronome sounds were measured for 10 min. Levels of the fatigue sensation in the right hand and sympathetic nerve activity on the second day were significantly higher than those on the first day. In the right dorsolateral prefrontal cortex (Brodmann's area 46), the alpha-band event-related desynchronization (ERD) of the second MEG session relative to the first session with the time window of 200 to 300 ms after the onset of handgrip cue sounds was identified. The ERD level in this brain region was positively associated with the change in subjective level of right hand fatigue after the conditioning session and was negatively associated with that of the sympathetic nerve activity. We demonstrated that the right dorsolateral prefrontal cortex is involved in the neural substrates of central inhibition during physical fatigue.
    Nov. 2013, Brain research, 1537, 117 - 24, English, International magazine
    Scientific journal

  • Kishiko Sunami, Akira Ishii, Sakurako Takano, Hidefumi Yamamoto, Tetsushi Sakashita, Masaaki Tanaka, Yasuyoshi Watanabe, Hideo Yamane
    In daily communication, we can usually still hear the spoken words as if they had not been masked and can comprehend the speech when spoken words are masked by background noise. This phenomenon is known as phonemic restoration. Since little is known about the neural mechanisms underlying phonemic restoration for speech comprehension, we aimed to identify the neural mechanisms using magnetoencephalography (MEG). Twelve healthy male volunteers with normal hearing participated in the study. Participants were requested to carefully listen to and understand recorded spoken Japanese stories, which were either played forward (forward condition) or in reverse (reverse condition), with their eyes closed. Several syllables of spoken words were replaced by 300-ms white-noise stimuli with an inter-stimulus interval of 1.6-20.3s. We compared MEG responses to white-noise stimuli during the forward condition with those during the reverse condition using time-frequency analyses. Increased 3-5 Hz band power in the forward condition compared with the reverse condition was continuously observed in the left inferior frontal gyrus [Brodmann's areas (BAs) 45, 46, and 47] and decreased 18-22 Hz band powers caused by white-noise stimuli were seen in the left transverse temporal gyrus (BA 42) and superior temporal gyrus (BA 22). These results suggest that the left inferior frontal gyrus and left transverse and superior temporal gyri are involved in phonemic restoration for speech comprehension. Our findings may help clarify the neural mechanisms of phonemic restoration as well as develop innovative treatment methods for individuals suffering from impaired speech comprehension, particularly in noisy environments.
    Nov. 2013, Brain research, 1537, 164 - 73, English, International magazine
    Scientific journal

  • Kenji Tamura, Hiroaki Kurihara, Kan Yonemori, Hitoshi Tsuda, Junko Suzuki, Yuzuru Kono, Natsuki Honda, Makoto Kodaira, Harukaze Yamamoto, Mayu Yunokawa, Chikako Shimizu, Koki Hasegawa, Yousuke Kanayama, Satoshi Nozaki, Takayuki Kinoshita, Yasuhiro Wada, Shusaku Tazawa, Kazuhiro Takahashi, Yasuyoshi Watanabe, Yasuhiro Fujiwara
    UNLABELLED: The purpose of this study was to determine the safety, distribution, internal dosimetry, and initial human epidermal growth factor receptor 2 (HER2)-positive tumor images of (64)Cu-DOTA-trastuzumab in humans. METHODS: PET was performed on 6 patients with primary or metastatic HER2-positive breast cancer at 1, 24, and 48 h after injection of approximately 130 MBq of the probe (64)Cu-DOTA-trastuzumab. Radioactivity data were collected from the blood, urine, and normal-tissue samples of these 6 patients, and the multiorgan biodistribution and internal dosimetry of the probe were evaluated. Safety data were collected for all the patients after the administration of (64)Cu-DOTA-trastuzumab and during the 1-wk follow-up period. RESULTS: According to our results, the best timing for the assessment of (64)Cu-DOTA-trastuzumab uptake by the tumor was 48 h after injection. Radiation exposure during (64)Cu-DOTA-trastuzumab PET was equivalent to that during conventional (18)F-FDG PET. The radioactivity in the blood was high, but uptake of (64)Cu-DOTA-trastuzumab in normal tissues was low. In 2 patients, (64)Cu-DOTA-trastuzumab PET showed brain metastases, indicative of blood-brain barrier disruptions. In 3 patients, (64)Cu-DOTA-trastuzumab PET imaging also revealed primary breast tumors at the lesion sites initially identified by CT. CONCLUSION: The findings of this study indicated that (64)Cu-DOTA-trastuzumab PET is feasible for the identification of HER2-positive lesions in patients with primary and metastatic breast cancer. The dosimetry and pharmacologic safety results were acceptable at the dose required for adequate PET imaging.
    SOC NUCLEAR MEDICINE INC, Nov. 2013, Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 54(11) (11), 1869 - 75, English, International magazine
    Scientific journal

  • Tomotaka Shingaki, Tadayuki Takashima, Ryosuke Ijuin, Xuan Zhang, Tomohiro Onoue, Yumiko Katayama, Takashi Okauchi, Emi Hayashinaka, Yilong Cui, Yasuhiro Wada, Masaaki Suzuki, Kazuya Maeda, Hiroyuki Kusuhara, Yuichi Sugiyama, Yasuyoshi Watanabe
    We developed a pravastatin derivative, sodium (3R,5R)-3,5-dihydroxy-7-((1S,2S,6S,8S)-6-hydroxy-2-methyl-8-((1-[(11)C]-(E)-2-methyl-but-2-enoyl)oxy)-1,2,6,7,8,8a-hexahydronaphthalen-1-yl)heptanoate ([(11)C]DPV), as a positron emission tomography (PET) probe for noninvasive measurement of hepatobiliary transport, and conducted pharmacokinetic analysis in rats as a feasibility study for future clinical study. Transport activities of DPV in freshly isolated rat hepatocytes and rodent multidrug resistance-associated protein 2 (rMrp2; human, MRP2)-expressing membrane vesicles were similar to those of pravastatin. Rifampicin diminished the uptake of DPV and pravastatin by the hepatocytes, with similar inhibition potency. [(11)C]DPV underwent biotransformation to produce at least two metabolites in rat, but metabolism of [(11)C]DPV occurred negligibly in human hepatocytes during a 90-minute incubation. After intravenous injection, [(11)C]DPV was mainly distributed to the liver and kidneys, where the tissue uptake clearances (CLuptake,liver and CLuptake,kidney) were blood-flow-limited (73.6 ± 4.8 and 24.6 ± 0.6 ml/min per kilogram, respectively). Systemic elimination of [(11)C]DPV was delayed in rifampicin-treated rat and an Mrp2-deficient mutant rat, Eisai hyperbilirubinemic mutant rat (EHBR). Rifampicin treatment decreased both CLuptake,liver and CLuptake,kidney of [(11)C]DPV by 30% (P < 0.05), whereas these parameters were unchanged in EHBR. Meanwhile, the canalicular efflux clearance (CLint,bile) of [(11)C]DPV, which was 12.2 ± 1.5 ml/min per kilogram in the control rat, decreased by 60% and 89% in rifampicin-treated rat and EHBR (P < 0.05), respectively. These results indicate that [(11)C]DPV is taken up into the liver by organic anion-transporting polypeptides (rodent, Oatps; human, OATP) and excreted into bile by Mrp2 in rat, and that rifampicin may inhibit Mrp2 as well as Oatps, and consequently increase systemic exposure of [(11)C]DPV. PET using [(11)C]DPV is feasible for studies prior to the future clinical investigation of OATP and MRP2 functionality, especially for personalized medicine.
    Oct. 2013, The Journal of pharmacology and experimental therapeutics, 347(1) (1), 193 - 202, English, International magazine
    [Refereed]
    Scientific journal

  • Akira Ishii, Masaaki Tanaka, Yoshihito Shigihara, Etsuko Kanai, Masami Funakura, Yasuyoshi Watanabe
    Mental fatigue, manifest as a reduced efficiency for mental work load, is prevalent in modern society. It is important to understand the neural mechanisms of mental fatigue and to develop appropriate methods for evaluating mental fatigue. In this study we quantified the effect of a long-duration mental fatigue-inducing task on neural activity. We used magnetoencephalography (MEG) to examine the time course change of neural activity over the long duration of the task trials. Nine healthy male volunteers participated in this study. They performed two mental fatigue-inducing tasks on separate days. The order of task presentation was randomized in a single-blinded, crossover fashion. Each task consisted of 25-min mental fatigue-inducing 0- or 2-back task session for three times. Subjective rating of mental fatigue sensation and electrocardiogram, and resting state MEG measurements were performed just before and after each task session. MEG data were analyzed using narrow-band adaptive spatial filtering methods. Alpha band (8-13 Hz) power in the visual cortex decreased after performing the mental fatigue-inducing tasks, and the decrease of alpha power was greater when they performed 2-back task trials. The decrease in alpha power was positively associated with the self-reported level of mental fatigue sensation and sympathetic nerve activity level. These results demonstrate that performing the prolonged mental fatigue-inducing task causes overactivation of the visual cortex, manifest as decreased alpha power in this brain region. Our results increase understanding of the neural mechanisms of mental fatigue and can be used to develop new quantitative methods to assess mental fatigue.
    Sep. 2013, Brain research, 1529, 105 - 12, English, International magazine
    Scientific journal

  • Mari Miyajima, Hiroyuki Kusuhara, Kayo Takahashi, Tadayuki Takashima, Takamitsu Hosoya, Yasuyoshi Watanabe, Yuichi Sugiyama
    The brain distribution of nonsteroidal aromatase inhibitors was investigated in mice to understand their interactions with brain aromatase. The brain-to-plasma ratio (Kp,brain , mL/g brain) of anastrozole was 0.0299 ± 0.0068, which was lower than that of letrozole (0.383 ± 0.048) and vorozole (0.185 ± 0.031) despite their similar physicochemical properties. The brain-to-plasma unbound concentration ratio of anastrozole, measured using microdialysis, was 0.118 ± 0.037 mL/g brain. In situ mouse brain perfusion also demonstrated that the uptake clearance [mL/(min·g brain)] of anastrozole by the brain (0.108 ± 0.018) was lower than that for letrozole and vorozole (0.422 ± 0.068 and 0.910 ± 0.152, respectively). Anastrozole and vorozole were transported by P-glycoprotein (P-gp) in vitro, whereas none of the compounds were transported by breast cancer resistance protein (BCRP). The Kp,brain of anastrozole and vorozole were increased by 12- and 3.3-fold, respectively, in Mdr1a/b/Bcrp(-/-) mice. IC50 (nM) of anastrozole and letrozole against human aromatase was 12.9 ± 0.7 and 3.59 ± 0.75, respectively. Taken together, these results suggest that active efflux mediated by P-gp at the blood-brain barrier limits the effect of anastrozole in the central nervous system, whereas vorozole and letrozole easily traverse the barrier.
    Sep. 2013, Journal of pharmaceutical sciences, 102(9) (9), 3309 - 19, English, International magazine
    Scientific journal

  • 佐古 健生, 岡内 隆, 向井 英史, 松村 一史, 和田 康弘, 林中 恵美, 崔 翼龍, 千田 道雄, 渡辺 恭良
    (一社)日本核医学会, Sep. 2013, 核医学, 50(3) (3), S236 - S236, Japanese

  • Fujii H, Koyama H, Fukuda S, Tokai H, Tajima S, Koizumi J, Yamaguti K, Kuratsune H, Watanabe Y, Hirayama Y, Shoji T, Inaba M, Nishizawa Y
    OBJECTIVE: In the present study, we assessed the associations among fatigue, quality of life (QOL), clinical parameters, and body mass index (BMI) with autonomic function in end-stage renal disease (ESRD) patients undergoing hemodialysis as well as fatigue-free healthy subjects. DESIGN AND METHODS: This was a case-control study. This study compared autonomic function in ESRD patients (n = 192) to that of healthy subjects (n = 282) and evaluated its association with fatigue, QOL, and clinical parameters such as glucose, albumin, cholesterol, and BMI. Fatigue was evaluated by a recently established fatigue questionnaire and performance status, and QOL was evaluated with the kidney disease QOL questionnaire. With regards to autonomic function, spontaneous beat-to-beat variations were measured, according to time- (standard deviation of all normal a-wave intervals [CVa-a%]) and frequency domains (low frequency [LF] power, high frequency [HF] power, and LF/HF ratio) with acceleration plethysmography. RESULTS: CVa-a%, LF power, HF power, and LF/HF ratio were significantly lower in ESRD patients than healthy subjects. There were significant inverse correlations between these factors and age in healthy subjects, but not in ESRD patients. Although the fatigue score was not associated with any autonomic parameters, ESRD patients with impaired performance status exhibited a significantly lower LF/HF ratio. Moreover, in ESRD patients, the LF/HF ratio was significantly and positively associated with several components of QOL, including physical functioning and role emotional, independent of other clinical parameters and BMI. CONCLUSIONS: Impaired autonomic function is significantly associated with fatigue and impaired QOL in dialysis patients.
    Sep. 2013, Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation, 23(5) (5), 340 - 347, English, International magazine
    [Refereed]
    Scientific journal

  • Takahiro Yoshikawa, Masaaki Tanaka, Akira Ishii, Yasuyoshi Watanabe
    BACKGROUND: We aimed to determine the brain areas related to food motivation and to examine individual variability using magnetoencephalography (MEG) during a fasted state. Correlation analysis was performed between MEG responses and the subscale and aggregated scores of the Power of Food Scale (PFS) and body mass index (BMI). MATERIAL AND METHODS: Eight healthy, right-handed males [age, 29.0±10.4 years; BMI, 22.7±2.4 kg/m2 (mean ±SD)] were enrolled. The MEG experiment consisted of 2 food sessions and 2 control sessions in an alternating and counterbalanced order. During the MEG recordings, participants viewed a set of food pictures (food session) or mosaic pictures (control session) projected on a screen. RESULTS: When participants viewed pictures of food items, we were able to estimate equivalent current dipoles (ECDs) in the insular cortex in all participants peaked approximately 300 ms after the onset of each picture presentation. When they viewed mosaic pictures, 1 of 8 participants exhibited corresponding ECDs. Of note, significant correlations were observed between the intensities of the MEG responses and the subscale scores of Factor 1 (food available) (r=0.846, P=0.008) and those of Factor 2 (food present) (r=0.875, P=0.004), the aggregated scores of PFS (r=0.820, P=0.013), and BMI (r=0.898, P=0.002). CONCLUSIONS: We demonstrated the involvement of the immediate neural responses of the insular cortex in individual differences in appetitive motivation. The signal intensities of the insular cortex were associated with self-awareness of appetitive motive.
    INT SCIENTIFIC INFORMATION, INC, Aug. 2013, Medical science monitor : international medical journal of experimental and clinical research, 19, 631 - 40, English, International magazine
    Scientific journal

  • Hidefumi Mukai, Yasuhiro Wada, Yasuyoshi Watanabe
    Targeted photodynamic therapy (PDT) is necessary for preventing the side effects associated with PDT, such as photosensitivity caused by the distribution of photosensitizers into normal tissues. In the development of targeted PDT agents, a simple evaluation system of in vivo pharmacokinetics, as well as target cell uptake, is absolutely imperative. We hypothesized that Cu-64 chelation with porphyrin photosensitizer-biomacromolecule conjugates may become a simple and versatile labeling strategy for this purpose.Protoporphyrin IX (PPIX) and a bombesin (BBN) analog, that interacts with the gastrin-released peptide (GRP) receptor, were used as a photosensitizer and tumor-targeting peptide, respectively. Then, a conjugate of PPIX and BBN analog linked via short polyethylene glycol (PPIX-PEG6-BBN analog) was synthesized and used as a targeted PDT agent. In addition, a Cu-64-chelated PPIX-PEG6-BBN analog was synthesized under optimized reaction conditions. Lastly, cell uptake study and PET image-based pharmacokinetic analyses of the PPIX-PEG6-BBN analog were carried out in a human prostate cancer cell line, PC-3, which highly expresses the GRP receptor, and PC-3 tumor-bearing mice.It was confirmed that degradation (thought to be based on radiolysis) occurs, and large amounts of Cu-64-labeling compounds are wasted in the reaction mixture. Interestingly, the addition of ethanol into the reaction mixture provides an effective solution for this problem. As for cell uptake study, the [Cu-64]PPIX-PEG6-BBN analog demonstrated significantly higher uptake for PC-3 cells than [Cu-64]PPIX and, in addition, the uptake of [Cu-64]PPIX-PEG6-BBN analog was significantly inhibited by adding excess cold BBN analog peptide. PET image-based pharmacokinetic evaluation revealed that [Cu-64]PPIX-PEG6-BBN analog and [Cu-64]PPIX rapidly accumulate into the liver and kidney, circulate in blood for a long time compared with normal peptides, and distribute at a low level in the tumor. This result suggested that in vivo biodistribution of PPIX-PEG6-BBN analog is mainly dependent on the lipophilicity of PPIX. Ex vivo measurements of radioactivity distribution after PET studies showed that although there was no remarkable difference in the tumor/skin ratio of radioactivity between [Cu-64]PPIX-PEG6-BBN analog and [Cu-64]PPIX, the pancreas (an organ that also expresses GRP receptors)/skin ratio was significantly higher in the case of [Cu-64]PPIX-PEG6-BBN analog.We report on the successful synthesis of Cu-64-chelated porphyrin photosensitizers and their tumor-targeting peptide conjugates under conditions in which radiolysis is suppressed. This labeling strategy with porphyrin photosensitizers may be of value for the rapid development of ideal targeted PDT agents.
    SPRINGER, Aug. 2013, ANNALS OF NUCLEAR MEDICINE, 27(7) (7), 625 - 639, English, Domestic magazine
    [Refereed]
    Scientific journal

  • Emi Yamano, Masaaki Tanaka, Akira Ishii, Nobuo Tsuruoka, Keiichi Abe, Yasuyoshi Watanabe
    BACKGROUND: Fatigue is a common symptom in modern society. There has been a recent resurgence of interest in traditional remedies for fatigue. Chicken essence, which is rich in anserine and carnosine, has been widely taken in Asian countries as a traditional remedy with various aims, including attenuation of physical and mental fatigue. However, the evidence for its efficacy specifically for mental fatigue remains unclear. We examined the effect of essence of chicken on mental fatigue in humans, using our established fatigue-inducing task and evaluation methods. MATERIAL AND METHODS: In this placebo-controlled crossover study, 20 healthy male volunteers were randomized to receive daily oral administration of essence of chicken or placebo drink provided by Cerebos Pacific Ltd. via Suntory holdings Ltd. for 4 weeks. The participants performed 2-back test trials as a fatigue-inducing mental task and then had a rest session. Just before and after each session, they completed cognitive task trials focusing on selective attention to evaluate the level of mental fatigue. RESULTS: After essence of chicken intake for 1 and 4 weeks, the reaction times on the cognitive task trials after the rest session were significantly shorter than those at baseline, and significant changes were not observed with placebo intake. The reaction times before and after the fatigue-inducing session were not altered by either essence of chicken or placebo intake. CONCLUSIONS: We showed that daily intake of essence of chicken could be effective for the recovery from mental fatigue and is a promising candidate for use as an anti-fatigue food.
    Jul. 2013, Medical science monitor : international medical journal of experimental and clinical research, 19, 540 - 7, English, International magazine
    Scientific journal

  • Tsutomu Kimura, Takeo Sako, Siqin, Junji Hosokawa-Muto, Yi Long Cui, Yasuhiro Wada, Yosky Kataoka, Hisashi Doi, Suehiro Sakaguchi, Masaaki Suzuki, Yasuyoshi Watanabe, Kazuo Kuwata
    A radiolabeled PET! A (11) C-labeled derivative of N,N'-(methylenedi-4,1-phenylene)bis[2-(1-pyrrolidinyl) acetamide] (GN8), an antiprion agent currently under development, was synthesized by palladium-catalyzed rapid methylation of aryltributylstannane and assessed for brain penetration and organ distribution in rats by positron emission tomography (PET).
    Jul. 2013, ChemMedChem, 8(7) (7), 1035 - 1039, English, International magazine
    [Refereed]
    Scientific journal

  • Akira Ishii, Masaaki Tanaka, Masayoshi Iwamae, Chongsoo Kim, Emi Yamano, Yasuyoshi Watanabe
    BACKGROUND: It has been proposed that an inappropriately conditioned fatigue sensation could be one cause of chronic fatigue. Although classical conditioning of the fatigue sensation has been reported in rats, there have been no reports in humans. Our aim was to examine whether classical conditioning of the mental fatigue sensation can take place in humans and to clarify the neural mechanisms of fatigue sensation using magnetoencephalography (MEG). METHODS: Ten and 9 healthy volunteers participated in a conditioning and a control experiment, respectively. In the conditioning experiment, we used metronome sounds as conditioned stimuli and two-back task trials as unconditioned stimuli to cause fatigue sensation. Participants underwent MEG measurement while listening to the metronome sounds for 6 min. Thereafter, fatigue-inducing mental task trials (two-back task trials), which are demanding working-memory task trials, were performed for 60 min; metronome sounds were started 30 min after the start of the task trials (conditioning session). The next day, neural activities while listening to the metronome for 6 min were measured. Levels of fatigue sensation were also assessed using a visual analogue scale. In the control experiment, participants listened to the metronome on the first and second days, but they did not perform conditioning session. MEG was not recorded in the control experiment. RESULTS: The level of fatigue sensation caused by listening to the metronome on the second day was significantly higher relative to that on the first day only when participants performed the conditioning session on the first day. Equivalent current dipoles (ECDs) in the insular cortex, with mean latencies of approximately 190 ms, were observed in six of eight participants after the conditioning session, although ECDs were not identified in any participant before the conditioning session. CONCLUSIONS: We demonstrated that the metronome sounds can cause mental fatigue sensation as a result of repeated pairings of the sounds with mental fatigue and that the insular cortex is involved in the neural substrates of this phenomenon.
    Jun. 2013, Behavioral and brain functions : BBF, 9, 24 - 24, English, International magazine
    Scientific journal

  • 治療と介入 慢性疲労症候群における還元型コエンザイムQ10の効果 二重盲検群間比較試験
    福田 早苗, 中富 康仁, 山口 浩二, 野島 順三, 近藤 一博, 梶本 修身, 倉恒 弘彦, 渡辺 恭良
    日本疲労学会, Jun. 2013, 日本疲労学会誌, 9(1) (1), 76 - 76, Japanese

  • Tadayuki Takashima, Tomotaka Shingaki, Yumiko Katayama, Emi Hayashinaka, Yasuhiro Wada, Makoto Kataoka, Daiki Ozaki, Hisashi Doi, Masaaki Suzuki, Sho Ishida, Kentaro Hatanaka, Yuichi Sugiyama, Shuji Akai, Naoto Oku, Shinji Yamashita, Yasuyoshi Watanabe
    To develop potent drugs for oral use, information on their pharmacokinetic (PK) properties after oral administration is of great importance. We have recently reported the utility of positron emission tomography (PET) for the analysis of gastrointestinal (GI) absorption of radiolabeled compounds. In this study, PET image analysis was performed in rats using a novel PET probe, [F-18]deoxyfluoropoly(ethylene glycol)s, with an average molecular weight of 2 kDa ([F-18]FPEG), as a nonabsorbable marker to elaborate the GI physiology in more detail, such as segmental transition of the administered water, and fluid volume and distribution in the intestine. After oral administration of [F-18]FPEG solution to rats, a 90 min PET scan with continuous blood sampling was performed, and then the disposition of radioactivity in each part of GI tract was investigated. From blood PK analysis, it was confirmed that the bioavailability of [F-18]FPEG was quite low in rats. PET image analysis showed that the radioactivity after oral administration of [F-18]FPEG solution rapidly passed through the stomach, spread into the proximal small intestine, and then transited toward the distal region of the small intestine without decreasing the radioactivity during GI transition. Radiometabolite analysis revealed that the radioactivity in intestinal mucosal tissues, blood, and urine was mainly derived from unchanged [F-18]FPEG. It was also found that the volume of interest (VOI) after oral administration of the radiotracer enables an understanding of the time-dependent manner of effective fluid volume changes in the stomach and the small intestine. In addition, the rate constant of the intestinal transition of radioactivity in each intestinal segment was calculated by kinetic model analysis, which revealed that PET analysis enables us to determine the GI transit from the same individuals and that it is applicable to determine site-specific intestinal absorption. In conclusion, we demonstrated the high potency of PET imaging technique to elucidate the distribution of orally administered solution in the GI tract in vivo.
    AMER CHEMICAL SOC, Jun. 2013, MOLECULAR PHARMACEUTICS, 10(6) (6), 2261 - 2269, English, International magazine
    [Refereed]
    Scientific journal

  • Yilong Cui, Qing-Hua Li, Hisao Yamada, Yasuyoshi Watanabe, Yosky Kataoka
    The vascular serotonergic system in the brain has been implicated in the pathophysiology of migraine, however, involvement of the serotonergic nervous system of the brain parenchyma in the pathophysiology remains unclear. To investigate whether the brain parenchymal serotonergic nervous system is involved in the etiology of migraine, we prepared an experimental model of migraine by generation of cortical spreading depression (SD), characterized by spreading of neuronal/glial membrane depolarization accompanied by temporal elevation of the cerebral blood flow (CBF) throughout the cerebral cortical hemisphere in rats, which underwent pharmacological treatment for degeneration of serotonergic neurons in the dorsal raphe nucleus. We show here that 1) significant degeneration of serotonergic neurons in the dorsal raphe nucleus and serotonergic fibers in the cerebral cortex was observed in treated rats, 2) spreading velocity of the CBF changes was significantly increased in these rats, and 3) calculated width of the depolarization wave was significantly extended in these rats. These results indicate that the dorsal raphe serotonergic neurons modulate cortical spreading depression and might be involved in migraine pathology via a similar mechanism. (c) 2013 Wiley Periodicals, Inc.
    WILEY, Jun. 2013, JOURNAL OF NEUROSCIENCE RESEARCH, 91(6) (6), 737 - 744, English, International magazine
    [Refereed]
    Scientific journal

  • 経鼻投与を用いた薬物送達法の評価に対するPositron Emission Tomography(PET)の活用
    新垣 友隆, 片山 由美子, 岡内 隆, 林中 恵美, 和田 康弘, 古林 呂之, 坂根 稔康, 崔 翼龍, 渡辺 恭良
    日本DDS学会, Jun. 2013, 日本DDS学会学術集会プログラム予稿集, 29回, 184 - 184, Japanese

  • Kei Mizuno, Masaaki Tanaka, Sanae Fukuda, Kyoko Imai-Matsumura, Yasuyoshi Watanabe
    BACKGROUND: Development of the ability to divide attention is of crucial importance in the transitional period from elementary to junior high school. The relationship between divided attention and the prevalence of fatigue or low academic motivation is observed in junior high school students. In order to clarify the factors underlying decreased ability to divide attention, we examined the relationships between divided attention, as assessed by the kana pick-out test, lifestyle factors, and academic and family conditions in junior high school students. METHODS: The study group consisted of 158 healthy 1st-, 2nd-, and 3rd-grade level junior high school students. Each participant performed the kana pick-out test and questionnaires dealing with lifestyle factors (nocturnal sleeping hours on school days, breakfast, exercise, watching television, and spending time with family members), and academic and family conditions (good friendships at school and praise from family members when participants showed good academic performance). RESULTS: On multiple regression analyses adjusted for grade and gender, scores on the kana pick-out test were positively associated with spending time with family members. In addition, the comprehension score of the kana pick-out test was positively associated with having breakfast every day and praise by family members. The score was negatively associated with watching television. CONCLUSION: The present findings suggest that the ability to divide attention is independently associated with good lifestyles and academic and family conditions in junior high school students.
    May 2013, Brain & development, 35(5) (5), 435 - 40, English, International magazine
    Scientific journal

  • Takayuki Iwata, Katsunori Tanaka, Tsuyoshi Tahara, Satoshi Nozaki, Hirotaka Onoe, Yasuyoshi Watanabe, Koichi Fukase
    A small peptide mimic of the Grb2-SH2 domain, which was previously prepared through the template-assisted click approach and exhibited selective A431 tumor growth inhibition both in vitro and in vivo, was further elaborated on to enhance the interaction with target phosphorylated proteins. A conformationally fixed analog was efficiently synthesized by solid-supported ring-closing metathesis and Cu(i)/His-mediated self-activating Huisgen [3+2] cycloadditon as the key steps, and exhibited a 10-fold enhanced affinity to a phosphorylated peptide, a truncated peptide analog of the Grb2-SH2-interacting phosphoproteins. A stronger interaction with the target phosphorylated proteins gave this cyclic analog cytotoxic activity in A431 cells.
    May 2013, Molecular bioSystems, 9(5) (5), 1019 - 25, English, International magazine
    Scientific journal

  • 片頭痛モデル動物を用いたオピオイド受容体のPETイメージング
    崔 翼龍, 長田 浩子, 佐古 健生, 林中 恵美, 和田 康弘, 土居 久志, 渡辺 恭良
    日本分子イメージング学会, May 2013, JSMI Report, 6(2) (2), 82 - 82, Japanese

  • Positron Emission Tomography(PET)による経鼻吸収評価系の確立
    新垣 友隆, 片山 由美子, 岡内 隆, 林中 恵美, 和田 康弘, 古林 呂之, 坂根 稔康, 崔 翼龍, 渡辺 恭良
    日本分子イメージング学会, May 2013, JSMI Report, 6(2) (2), 94 - 94, Japanese

  • Takahiro Yoshikawa, Keisuke Orita, Yasuyoshi Watanabe, Masaaki Tanaka
    BACKGROUND: We aimed to examine the association of appetitive motives with a non-exercise lifestyle, defined as exercising less than once per year, in a young adult population. MATERIAL AND METHODS: We asked university students to answer questions about their exercise habits. We also assessed their appetitive motives, with or without hunger, by using a simple questionnaire in a preliminary survey, and we assessed the hedonic motives to consume palatable foods by using the Power of Food Scale (PFS) in the main experiment. RESULTS: On multivariate logistic regression analyses in the preliminary survey (n=119) adjusted for age, gender, and body mass index (BMI), appetitive motives under the condition of hunger were positively associated with the non-exercise lifestyle. In the main experiment (n=268), simple regression analyses revealed a positive association between the non-exercise lifestyle and the subscale scores of factor-2 of PFS related to physically present foods. On multiple regression analyses adjusted for age, gender, and BMI, the aggregated scores and the subscale scores of factor-2 of PFS were positively associated with the non-exercise lifestyle. CONCLUSIONS: These findings suggest the intriguing possibility that appetitive motives under the condition "with hunger" and those "with hedonic consumption" can be suppressed even by infrequent exercise.
    INT SCIENTIFIC INFORMATION, INC, Apr. 2013, Medical science monitor : international medical journal of experimental and clinical research, 19, 289 - 94, English, International magazine
    Scientific journal

  • K Nakadate, K Imamura, Y Watanabe
    The roles of the central noradrenergic and serotonergic system in the activity-dependent regulation of ocular dominance plasticity have been a contentious issue. Using c-Fos activity mapping, we have developed a new, straightforward method to measure the strength of ocular dominance plasticity: the number of c-Fos-immunopositive cells in layer IV of rat visual cortex (Oc1B), ipsilateral to the stimulated eye, is a sensitive and reliable measure of the effects of monocular deprivation. Applying this new method, here we studied the unique modification of the degree of c-Fos expression induced in the visual cortex, in that endogenous noradrenaline (NA) and serotonin (5HT) in the cortex were significantly reduced, respectively by specific pharmacological agents. Intraperitoneal injections of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) and p-chlorophenylalanine (pCPA) selectively impair NA- and 5HT-containing nerve terminals and fibers, respectively. In the visual cortex with strongly reduced NA, the number of c-Fos-immunopositive cells was found remaining significantly decreased in response to stimulation of the deprived eye, while by open eye stimulation the expected increase in c-Fos-immunoreactivity was strongly suppressed, showing values not different from those obtained by monocular stimulation in the normal rats. In contrast, in the visual cortex with strongly reduced 5HT no expected decrease was found in response to stimulation of the deprived eye, while, as is usually the case for the normal animals, a significant increase was still induced in response to open eye stimulation. These findings suggest that the noradrenergic and serotonergic system regulate ocular dominance (OD) plasticity differently: in the NA-depleted cortex the expected increase in c-Fos expression by open eye stimulation was not seen due to strong suppression, whereas in 5HT-depletion, the expected decrease in c-Fos expression was not materialized due to strong suppression. The present findings with c-Fos activity mapping method indicated a novel possibility of the differential regulation of OD plasticity by two types of common monoaminergic systems.
    Apr. 2013, Neuroscience, 235, 1 - 9, English, International magazine
    [Refereed]
    Scientific journal

  • 骨粗鬆症治療薬Teriparatideの副作用メカニズム解明のためのPositron Emission Tomography(PET)有用性評価
    新垣 友隆, 片山 由美子, 岡内 隆, 林中 恵美, 和田 康弘, 加藤 直人, 黒田 龍彦, 崔 翼龍, 渡辺 恭良
    (公社)日本薬剤学会, Apr. 2013, 日本薬剤学会年会講演要旨集, 28年会, 282 - 282, Japanese

  • Ikuko Nakamura, Koki Hasegawa, Yasuhiro Wada, Tetsuaki Hirase, Koichi Node, Yasuyoshi Watanabe
    BACKGROUND: Sensitive detection and qualitative analysis of atherosclerotic plaques are in high demand in cardiovascular clinical settings. The leukocyte-endothelial interaction mediated by an adhesion molecule P-selectin participates in arterial wall inflammation and atherosclerosis. METHODS AND RESULTS: A (64)Cu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid conjugated anti-P-selectin monoclonal antibody ((64)Cu-DOTA-anti-P-selectin mAb) probe was prepared by conjugating an anti-P-selectin monoclonal antibody with DOTA followed by (64)Cu labeling. Thirty-six hours prior to PET and CT fusion imaging, 3MBq of (64)Cu-DOTA-anti-P-selectin mAb was intravenously injected into low density lipoprotein receptor-deficient Ldlr-/- mice. After a 180min PET scan, autoradiography and biodistribution of (64)Cu-DOTA-anti-P-selectin monoclonal antibody was examined using excised aortas. In Ldlr-/- mice fed with a high cholesterol diet for promotion of atherosclerotic plaque development, PET and CT fusion imaging revealed selective and prominent accumulation of the probe in the aortic root. Autoradiography of aortas that demonstrated probe uptake into atherosclerotic plaques was confirmed by Oil red O staining for lipid droplets. In Ldlr-/- mice fed with a chow diet to develop mild atherosclerotic plaques, probe accumulation was barely detectable in the aortic root on PET and CT fusion imaging. Probe biodistribution in aortas was 6.6-fold higher in Ldlr-/- mice fed with a high cholesterol diet than in those fed with a normal chow diet. (64)Cu-DOTA-anti-P-selectin mAb accumulated selectively in aortic atherosclerotic plaques and was detectable by PET and CT fusion imaging in Ldlr-/- mice. CONCLUSIONS: P-selectin is a candidate target molecule for early-phase detection by PET and CT fusion imaging of atherosclerotic plaques.
    Mar. 2013, Biochemical and biophysical research communications, 433(1) (1), 47 - 51, English, International magazine
    Scientific journal

  • Sanae Fukuda, Mieko Horiguchi, Kouzi Yamaguti, Yasuhito Nakatomi, Hirohiko Kuratsune, Hiroshi Ichinose, Yasuyoshi Watanabe
    AIMS: Tyrosine hydroxylase (TH) and GTP cyclohydrolase I (GCH) are the rate-limiting enzymes for the biosynthesis of catecholamines and tetrahydrobiopterin (BH4), respectively. Since catecholamines and BH4 are thought to be involved in the pathophysiology of CFS, we explored the genetic factors that influence CFS development and examined the possible association between the SNPs of the TH and GCH genes and the various characteristics of CFS patients. MAIN METHODS: After drawing venous blood from CFS patients and controls, genomic DNA was then extracted from whole blood in accordance with standard procedures. Digestion patterns of the PCR products were used for genotyping the SNPs of GCH (rs841; C+243T) and TH (rs10770141; C-824T). We also performed questionnaires consisting of fatigue-scale and temperament and character inventory scale (TCI) to CFS patients. KEY FINDINGS: Our results demonstrated that the allele differences for the GCH and TH SNPs were not associated with CFS patients. We did find that the GCH gene with the C+243T polymorphism affected harm avoidance, while the TH gene with the C-824T polymorphism affected persistence in the CFS patients. The concept of persistence has been linked to specific personality, such as perfectionism, in CFS. SIGNIFICANCE: Our results suggest that the biosynthetic pathways of the monoamine neurotransmitters that are mediated by TH and GCH might be associated with the CFS clinical findings, because persistence is one of the typical personality traits observed in CFS and patients with major depressive disorder exhibit a higher harm avoidance score.
    Feb. 2013, Life sciences, 92(3) (3), 183 - 6, English, International magazine
    Scientific journal

  • Yoshihito Shigihara, Masaaki Tanaka, Akira Ishii, Seiki Tajima, Etsuko Kanai, Masami Funakura, Yasuyoshi Watanabe
    Fatigue is a common symptom in modern society. To clarify the mechanisms underlying fatigue, we examined task performances and subjective scale scores associated with two different types of mental fatigue. The study group consisted of 20 healthy participants, who performed 0-back or 2-back test trials for 30 min as a fatigue-inducing task session. Just before and after the session, they completed advanced trail making test (ATMT) for 30 min and completed subjective scales to measure fatigue, sleepiness, and other factors. After the 0-back or 2-back task session, impairment of task performance was significant as assessed by increased error count in ATMT. In contrast, although task performance as assessed by mean reaction time during the 2-back task trials did not change over time, longer reaction time was observed over time during the 0-back task trials. After the 0-back task session, subjective levels of fatigue and sleepiness were increased while after the 2-back task session, although subjective level of fatigue was increased, that of sleepiness was not altered. Two different types of mental fatigue produce different styles of task performance. We present a new conceptual hypothesis regarding the mechanism underlying the association between mental fatigue and task performance. © 2012 Elsevier GmbH.
    Feb. 2013, Neurology Psychiatry and Brain Research, 19(1) (1), 5 - 11, English
    [Refereed]
    Scientific journal

  • Tadayuki Takashima, Chunyong Wu, Misato Takashima-Hirano, Yumiko Katayama, Yasuhiro Wada, Masaaki Suzuki, Hiroyuki Kusuhara, Yuichi Sugiyama, Yasuyoshi Watanabe
    UNLABELLED: A quantitative PET imaging method was used to assess the in vivo kinetics of hepatobiliary and renal excretion of the breast cancer resistance protein (Bcrp) substrate (11)C-SC-62807 in mice. METHODS: Serial abdominal PET scans were collected in wild-type and Bcrp knockout (Bcrp(-/-)) mice after intravenous injection of (11)C-SC-62807. Venous blood samples and PET images were obtained at frequent intervals up to 30 min after radiotracer administration. Dynamic PET data were analyzed to determine the canalicular and brush-border efflux clearances in the liver and kidney (CL(int,bile,liver) and CL(int,urine,kidney), respectively). RESULTS: SC-62807 is an in vitro substrate of mouse Bcrp and human BCRP. Radioactivity associated with (11)C-SC-62807 was predominantly found in the blood, liver, bile, and urine 30 min after administration. Both biliary and urinary excretion of radioactivity was markedly lower in Bcrp(-/-) mice than in wild-type mice, suggesting greater systemic exposure in Bcrp(-/-) mice. Both the CL(int,bile,liver) and the CL(int,urine,kidney) were significantly lower in Bcrp(-/-) mice (74% ± 10% and 99% ± 1% lower than controls, respectively). We also found that (11)C-SC-62807 is a substrate of the organic anion-transporting polypeptides OATP1B1 and OATP1B3 in vitro. CONCLUSION: The present study demonstrated that Bcrp plays a significant role in the efflux of (11)C-SC-62807 in mouse liver and kidney. We also demonstrated the feasibility of PET using (11)C-SC-62807 to study the activity of BCRP in humans.
    Feb. 2013, Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 54(2) (2), 267 - 76, English, International magazine
    Scientific journal

  • Takuya Hayashi, Masamitsu Shimazawa, Hiroshi Watabe, Takayuki Ose, Yuta Inokuchi, Yasushi Ito, Hajime Yamanaka, Shin-ichi Urayama, Yasuyoshi Watanabe, Hideaki Hara, Hirotaka Onoe
    BACKGROUND: Neurodegenerative diseases including Parkinson's and Alzheimer's diseases progress slowly and steadily over years or decades. They show significant between-subject variation in progress and clinical symptoms, which makes it difficult to predict the course of long-term disease progression with or without treatments. Recent technical advances in biomarkers have facilitated earlier, preclinical diagnoses of neurodegeneration by measuring or imaging molecules linked to pathogenesis. However, there is no established "biomarker model" by which one can quantitatively predict the progress of neurodegeneration. Here, we show predictability of a model with risk-based kinetics of neurodegeneration, whereby neurodegeneration proceeds as probabilistic events depending on the risk. RESULTS: We used five experimental glaucomatous animals, known for causality between the increased intraocular pressure (IOP) and neurodegeneration of visual pathways, and repeatedly measured IOP as well as white matter integrity by diffusion tensor imaging (DTI) as a biomarker of axonal degeneration. The IOP in the glaucomatous eye was significantly increased than in normal and was varied across time and animals; thus we tested whether this measurement is useful to predict kinetics of the integrity. Among four kinds of models of neurodegeneration, constant-rate, constant-risk, variable-risk and heterogeneity models, goodness of fit of the model and F-test for model selection showed that the time course of optic nerve integrity was best explained by the variable-risk model, wherein neurodegeneration kinetics is expressed in an exponential function across cumulative risk based on measured IOP. The heterogeneity model with stretched exponential decay function also fit well to the data, but without statistical superiority to the variable-risk model. The variable-risk model also predicted the number of viable axons in the optic nerve, as assessed by immunohistochemistry, which was also confirmed to be correlated with the pre-mortem integrity of the optic nerve. In addition, the variable-risk model identified the disintegrity in the higher-order visual pathways, known to underlie the transsynaptic degeneration in this disease. CONCLUSIONS: These findings indicate that the variable-risk model, using a risk-related biomarker, could predict the spatiotemporal progression of neurodegeneration. This model, virtually equivalent to survival analysis, may allow us to estimate possible effect of neuroprotection in delaying progress of neurodegeneration.
    Jan. 2013, Molecular neurodegeneration, 8, 4 - 4, English, International magazine
    Scientific journal

  • Yoshihito Shigihara, Masaaki Tanaka, Akira Ishii, Etsuko Kanai, Masami Funakura, Yasuyoshi Watanabe
    BACKGROUND: Fatigue has a multi-factorial nature. We examined the effects of two types of mental fatigue on spontaneous oscillatory brain activity using magnetoencephalography (MEG). METHODS: Participants were randomly assigned to two groups in a single-blinded, crossover fashion to perform two types of mental fatigue-inducing experiments. Each experiment consisted of a 30-min fatigue-inducing 0- or 2-back test session and two evaluation sessions performed just before and after the fatigue-inducing mental task session. RESULTS: After the 0-back test, decreased alpha power was indicated in the right angular gyrus and increased levels in the left middle and superior temporal gyrus, left postcentral gyrus, right superior frontal gyrus, left inferior frontal gyrus, and right medial frontal gyrus. After the 2-back test, decreased alpha power was indicated in the right middle and superior frontal gyrus and increased levels in the left inferior parietal and superior parietal lobules, right parahippocampal gyrus, right uncus, left postcentral gyrus, left middle frontal gyrus, and right inferior frontal gyrus. For beta power, increased power following the 0-back test was indicated in the left middle temporal gyrus, left superior frontal gyrus, left cingulate gyrus, and left precentral gyrus. After the 2-back test, decreased power was suggested in the left superior frontal gyrus and increased levels in the left middle temporal gyrus and left inferior parietal lobule. Some of these brain regions might be associated with task performance during the fatigue-inducing trials. CONCLUSIONS: Two types of mental fatigue may produce different alterations of the spontaneous oscillatory MEG activities. Our findings would provide new perspectives on the neural mechanisms underlying mental fatigue.
    Jan. 2013, Behavioral and brain functions : BBF, 9, 2 - 2, English, International magazine
    Scientific journal

  • Masaaki Tanaka, Akira Ishii, Yasuyoshi Watanabe
    Chronic fatigue syndrome (CFS) is characterized by a profound, disabling, and unexplained sensation of fatigue lasting an unexplained severe fatigue which lasts for at least 6 months with a combination of various symptoms, and it impairs patients' ability to live their days normally. Patients with CFS complain of neuropsychological symptoms, including cognitive impairment (thinking difficulties, decreased alertness, and impaired memory and concentration), chronic widespread pain (muscle pain, pain in multiple joints, headaches, and sore throat), and depressive symptoms. In addition, many studies have shown abnormalities in the central nervous system (CNS) in patients with CFS. These findings suggest that the CNS is primarily involved in the pathophysiology of CFS. Here, we review data primarily from behavioral, electrophysiological, and neuroimaging experiments related to neural dysfunction in CFS. Dysfunction of a facilitation system and central sensitization and classical conditioning of an inhibition system in the CNS seem to play pivotal roles in the pathophysiology of CFS. We also propose a treatment strategy for CFS on the basis of these suggested underlying neural mechanisms. © 2013 - IOS Press.
    I O S Press, 2013, Advances in Neuroimmune Biology, 4(4) (4), 291 - 300, English
    [Refereed]
    Scientific journal

  • [Molecular imaging-based early-phase and exploratory clinical research].
    Yasuyoshi Watanabe
    In vivo molecular imaging became a key technology for innovative drug development. Especially, positron emission tomography (PET) has been applied to patho-physiological science, pharmacodynamics/pharmacokinetics (PD/PK) studies, and drug delivery system (DDS) studies, and accelerated the paradigm shift not only from experimental animals to human subjects, but also from PK in blood circulation to PK in target tissues, even in human. Our RIKEN Centre for Molecular Imaging Science has been established to promote such innovative drug developmental studies with PET molecular imaging, as a center of excellence for development of molecular probes. The center is creating novel labeling methods on drug candidate molecules with positron-emitting radionuclides, and is providing the molecular probes suitable for targeting bio-functional molecules and cellular functions, which are useful for evaluation of drug efficacy and pharmacokinetics in human subjects. Animal PET studies with mice, rats, rabbits, marmosets, and macaque monkeys have also been promoted both under anesthetic condition and consciousness, which was a really difficult task but important for comparison with human PET studies. In this sense, mutual collaboration between the research consortia in basic PET field and in clinical PET molecular imaging such as Osaka City University Hospital would be of great value. Here, the concept, outline of our activities, and PK/PD studies with efficient application of molecular imaging is presented. In addition, the results of the first cassette-dose and micro-dose clinical trials approved by Pharmaceuticals and Medical Devices Agency (PMDA) (New Energy and Industrial Technology Development Organization (NEDO) project represented by Prof. Yuichi Sugiyama) are described.
    2013, Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan, 133(2) (2), 187 - 95, Japanese, Domestic magazine
    Scientific journal

  • Masaaki Tanaka, Hiromi Yamada, Takayuki Nakamura, Akira Ishii, Yasuyoshi Watanabe
    CONTEXT: Exposure to a natural environment has been reported to be associated with positive effects on mental well-being. However, no report has examined the effects of a house designed with an open space connected to nature on recovery from fatigue. OBJECTIVE: The purpose of this study was to examine the effects of such an open space on recovery from mental fatigue. DESIGN: Placebo-controlled, crossover design. SETTING: Participants were randomized into open (connected to nature) and closed (not connected to nature) conditions. PARTICIPANTS: Sixteen healthy female volunteers were enrolled. INTERVENTION: After a 30-minute fatigue-inducing mental task, participants moved to an open or closed recovery room for 30 minutes. MAIN OUTCOME MEASURES: As fatigue-evaluating mental tasks, participants performed advanced trail making tests for 20 minutes. They were asked to rate their levels of fatigue, relaxation, comfort, and healing on a visual analogue scale from 0 (minimum) to 100 (maximum) to evaluate their subjective mental. They also underwent accelerated plethysmography. RESULTS: After the recovery session, lower total error counts of a cognitive test, greater levels of subjective relaxation, comfort, and healing, and lower levels of waveform index-1 assessed via accelerated plethysmography were observed in participants exposed to the open condition compared with the closed condition. These results provide evidence that the use of a house designed with an open space connected to nature during the recovery session improved cognitive function and subjective mental states. Hence, open space was effective for helping recovery from mental fatigue.
    2013, Explore (New York, N.Y.), 9(2) (2), 82 - 6, English, International magazine
    Scientific journal

  • Novel molecular imaging of atherosclerosis with gallium-68-labeled apolipoprotein A-I mimetic peptide and positron emission tomography.
    Emi Kawachi, Yoshinari Uehara, Koki Hasegawa, Eiji Yahiro, Setsuko Ando, Yasuhiro Wada, Tsuneo Yano, Hiroaki Nishikawa, Masashi Shiomi, Shin-ichiro Miura, Yasuyoshi Watanabe, Keijiro Saku
    BACKGROUND:  High-density lipoprotein (HDL) plays a major role in reverse cholesterol transport. Many researchers have been working to enhance the biochemical function of HDL for use in therapy. Although HDL therapy using injections of apolipoprotein (apo)-A-I mimetics, apo A-I Milano or full-length apo A-I is dramatically effective, it is still unclear whether apo A-I or apo A-I mimetics actually enter atherosclerotic plaque and remove cholesterol from the lipid burden. We synthesized a novel 24-amino acid apo A-I mimetic peptide (known as FAMP) that potently removes cholesterol via specific ATP-binding cassette transporter A1. We then investigated the potential of FAMP to image developing plaque lesions in vivo. METHODS AND RESULTS:  FAMP was modified with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and radiolabeled with gallium-68 ((68)Ga) for noninvasive positron emission tomography (PET) in an animal model (familial hypercholesterolemic myocardial infarction-prone rabbits: WHHL-MI) with atherosclerotic lesions. The (68)Ga-DOTA-FAMP was dramatically taken up by atherosclerotic tissues in the blood vessels and aorta of WHHL-MI rabbits, but not the control rabbits. CONCLUSIONS:  An apo A-I mimetic peptide with (68)Ga-DOTA is a promising candidate diagnostic tracer for PET imaging of the atherosclerotic lipid burden and may contribute to the development of a tool for the diagnosis of plaque with PET.
    2013, Circulation journal : official journal of the Japanese Circulation Society, 77(6) (6), 1482 - 9, English, Domestic magazine
    Scientific journal

  • Kei Mizuno, Yasuyoshi Watanabe
    Neurocognitive impairment is a feature of childhood chronic fatigue syndrome (CCFS). Several studies have demonstrated reduced attention control in CCFS patients in switching and divided attention tasks. In students, the extent of deterioration in task performance depends on the level of fatigue. Poor performance in switching and divided attention is common in both fatigued students and CCFS patients. Additionally, attentional functions show dramatic development from childhood to adolescence, suggesting that abnormal development of switching and divided attention may be induced by chronic fatigue. The brain structures associated with attentional control are situated in the frontal and parietal cortices, which are the last to mature, suggesting that severe fatigue in CCFS patients and students may inhibit normal structural and functional development in these regions. A combination of treatment with cognitive behavioral therapy and antidepressant medication is effective to improve attentional control processing in CCFS patients. Studies identifying the features of neurocognitive impairment in CCFS have improved our current understanding of the neurophysiological mechanisms of CCFS.
    2013, Frontiers in physiology, 4, 87 - 87, English, International magazine
    Scientific journal

  • Masaaki Tanaka, Akira Ishii, Yasuyoshi Watanabe
    Central inhibition plays a pivotal role in determining physical performance during physical fatigue. Classical conditioning of central inhibition is believed to be associated with the pathophysiology of chronic fatigue. We tried to determine whether classical conditioning of central inhibition can really occur and to clarify the neural mechanisms of central inhibition related to classical conditioning during physical fatigue using magnetoencephalography (MEG). Eight right-handed volunteers participated in this study. We used metronome sounds as conditioned stimuli and maximum handgrip trials as unconditioned stimuli to cause central inhibition. Participants underwent MEG recording during imagery of maximum grips of the right hand guided by metronome sounds for 10 min. Thereafter, fatigue-inducing maximum handgrip trials were performed for 10 min; the metronome sounds were started 5 min after the beginning of the handgrip trials. The next day, neural activities during imagery of maximum grips of the right hand guided by metronome sounds were measured for 10 min. Levels of fatigue sensation and sympathetic nerve activity on the second day were significantly higher relative to those of the first day. Equivalent current dipoles (ECDs) in the posterior cingulated cortex (PCC), with latencies of approximately 460 ms, were observed in all the participants on the second day, although ECDs were not identified in any of the participants on the first day. We demonstrated that classical conditioning of central inhibition can occur and that the PCC is involved in the neural substrates of central inhibition related to classical conditioning during physical fatigue.
    2013, PloS one, 8(7) (7), e70949, English, International magazine
    Scientific journal

  • Masaaki Tanaka, Akira Ishii, Yasuyoshi Watanabe
    Fatigue is defined as a condition or phenomenon of declined ability and efficiency of mental and/or physical activities, caused by excessive mental or physical activities, diseases, or syndromes. Acute fatigue is a normal condition that disappears after a period of rest; in contrast, chronic fatigue does not disappear after an ordinary rest. Chronic fatigue impairs daily activities and contributes to various medical conditions and death. In addition, many people complain of chronic fatigue. It would thus be of great value to clarify the mechanisms underlying chronic fatigue and to develop efficient treatment methods to overcome it. Here, we review data primarily from behavioral, neurophysiological, and neuroimaging experiments related to the neural mechanisms underlying chronic fatigue. We propose that repetitive and prolonged overwork and/or stress cause neural damage of a facilitation system, as well as central sensitization and classical conditioning of an inhibition system. We also propose a new treatment strategy for chronic fatigue on the basis of its underlying neural mechanisms.
    2013, Reviews in the neurosciences, 24(6) (6), 617 - 28, English, International magazine
    Scientific journal

  • Kei Mizuno, Tetsuya Yoneda, Masanori Komi, Toshinori Hirai, Yasuyoshi Watanabe, Akemi Tomoda
    Attention-deficit/hyperactivity disorder (ADHD) is neurobehavioral disorder characterized by inattention, hyperactivity/impulsivity and impaired reward system function, such as delay aversion and low reward sensitivity. The pharmacological treatment for ADHD includes methylphenidate (MPH), or osmotic release oral system-MPH (OROS-MPH), which increases extrasynaptic dopamine and noradrenaline levels by blocking their reuptake. Although previous functional magnetic resonance imaging (fMRI) studies revealed that acute treatment with MPH alters activation of the nucleus accumbens during delay aversion in children and adolescents with ADHD, the effects a relatively long period of OROS-MPH treatment on delay aversion as well as reward sensitivity remain unclear. Thus, we evaluated brain activation with fMRI during a reward sensitivity paradigm that consists of high monetary reward and low monetary reward conditions before and after a 3-month treatment with OROS-MPH in 17 children and adolescents with ADHD (mean age, 13.3 ± 2.2) and 17 age- and sex-matched healthy controls (mean age, 13.0 ± 1.9). We found that before treatment there was decreased activation of the nucleus accumbens and thalamus in patients with ADHD during only the low monetary reward condition, which was improved to same level as those of the healthy controls after the treatment. The observed change in brain activity was associated with improved ADHD symptom scores, which were derived from Japanese versions of the ADHD rating scale-IV. These results suggest that treatment with OROS-MPH for a relatively long period is effective in controlling reward sensitivity in children and adolescents with ADHD.
    2013, NeuroImage. Clinical, 2, 366 - 76, English, International magazine
    Scientific journal

  • Masaaki Tanaka, Akira Ishii, Yasuyoshi Watanabe
    An enhanced facilitation system caused by motivational input plays an important role in supporting performance during physical fatigue. We tried to clarify the neural mechanisms of the facilitation system during physical fatigue using magnetoencephalography (MEG) and a classical conditioning technique. Twelve right-handed volunteers participated in this study. Participants underwent MEG recording during the imagery of maximum grips of the right hand guided by metronome sounds for 10 min. Thereafter, fatigue-inducing maximum handgrip trials were performed for 10 min; the metronome sounds were started 5 min after the beginning of the handgrip trials. The metronome sounds were used as conditioned stimuli and maximum handgrip trials as unconditioned stimuli. The next day, they were randomly assigned to two groups in a single-blinded, two-crossover fashion to undergo two types of MEG recordings, that is, for the control and motivation sessions, during the imagery of maximum grips of the right hand guided by metronome sounds for 10 min. The alpha-band event-related desynchronizations (ERDs) of the motivation session relative to the control session within the time windows of 500 to 700 and 800 to 900 ms after the onset of handgrip cue sounds were identified in the sensorimotor areas. In addition, the alpha-band ERD within the time window of 400 to 500 ms was identified in the right dorsolateral prefrontal cortex (Brodmann's area 46). The ERD level in the right dorsolateral prefrontal cortex was positively associated with that in the sensorimotor areas within the time window of 500 to 700 ms. These results suggest that the right dorsolateral prefrontal cortex is involved in the neural substrates of the facilitation system and activates the sensorimotor areas during physical fatigue.
    2013, PloS one, 8(11) (11), e80731, English, International magazine
    Scientific journal

  • 土居 久志, 馬渡 彩, 金澤 奨勝, 野崎 聡, 中谷 友香, 野村 之博, 秋元 浩二, 二宮 伸二, 鈴木 正昭, 渡辺 恭良
    公益社団法人 日本ビタミン学会, 2013, ビタミン, 87(5) (5), 290 - 290, Japanese

  • Cognitive dysfunction in elderly females with depressive symptoms.
    Masaaki Tanaka, Akira Ishii, Emi Yamano, Hiroki Ogikubo, Masatsugu Okazaki, Kazuro Kamimura, Yasuharu Konishi, Shigeru Emoto, Yasuyoshi Watanabe
    BACKGROUND: A depressive state is a common symptom in the elderly and often accompanies cognitive impairment. The coexistence of depressive symptoms and cognitive impairment is a serious problem, as it increases adverse outcomes for health, functional status, and mortality. It would thus be of great value to clarify the cognitive dysfunction associated with depressive symptoms. We aimed to identify the cognitive dysfunction, in particular, impairment of the response inhibition component of executive function, associated with depressive symptoms in elderly females using the Simple Color Reaction Test and Modified Stroop Color-Word Test. MATERIAL/METHODS: The study group consisted of 35 elderly women. They performed cognitive function task trials for 9 min. Univariate logistic regression analyses were performed to identify factors associated with the prevalence of the depressive state. RESULTS: Longer reaction time and lower correction rate of response inhibition trials were related to the prevalence of the depressive symptoms. CONCLUSIONS: Impaired function of response inhibition may be a specific feature of the depressive state. Our findings may help clarify the neural mechanisms underlying the depressive state of elderly females.
    Dec. 2012, Medical science monitor : international medical journal of experimental and clinical research, 18(12) (12), CR706-11, English, International magazine
    Scientific journal

  • Midori Futami, Yasuyoshi Watanabe, Takashi Asama, Hitoshi Murata, Hiroko Tada, Megumi Kosaka, Hidenori Yamada, Junichiro Futami
    Protein cationization techniques are powerful protein transduction methods for mammalian cells. As we demonstrated previously, cationized proteins with limited conjugation to polyethylenimine have excellent ability to enter into cells by adsorption-mediated endocytosis [Futami, J., et al. (2005) J. Biosci. Bioeng. 99, 95-103]. In this study, we show that proteins with extensive and uniform cationization covering the protein surface reach the cytoplasm and nucleus more effectively than proteins with limited cationic polymers or proteins that are fused to cationic peptides. Although extensive modification of carboxylates results in loss of protein function, chicken avidin retains biotin-binding ability even after extensive amidation of carboxylates. Using this cationized avidin carrier system, the protein transduction ability of variously cationized avidins was investigated using biotinylated protein as a probe. The results revealed that cationized avidins bind rapidly to the cell surface followed by endocytotic uptake. Small amounts of uniformly cationized avidin showed direct penetration into the cytoplasm within a 15 min incubation. This penetration route seemed to be energy dependent and functioned under cellular physiological conditions. A biotinylated exogenous transcription factor protein that penetrated cells was demonstrated to induce target gene expression in living cells.
    Oct. 2012, Bioconjugate chemistry, 23(10) (10), 2025 - 31, English, International magazine
    Scientific journal

  • Masaaki Tanaka, Yasuyoshi Watanabe
    OBJECTIVE AND METHODS: In order to survive, organisms must pursue and capture prey to avoid starvation, and must either fight or flight to avoid being killed by predators. The starvation-resistance and risk-management systems were of great importance to humans for survival in ancient times. However, given the evolutionary time scale, humans seem not to be well adapted to modern times. Urbanization often puts the risk-management system in motion due to modern stressors, and can induce over-activation of the risk-management system. RESULTS: As a result, central sensitization and classical conditioning of the over-risk-management can occur due to repeated assaults, fears, or even anticipation of the modern predators. We refer to those diseases as risk-management syndrome, defined as an illness caused by the central sensitization and classical conditioning of over-risk-management without apparent organic damage. CONCLUSION: These syndromes classified by each pathophysiological background, i.e. risk-management and metabolic syndromes are two major syndromes associated with urbanization.
    Oct. 2012, International journal of psychiatry in clinical practice, 16(4) (4), 312 - 5, English, International magazine
    Scientific journal

  • Yasuyoshi Watanabe
    Oct. 2012, Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 53(10) (10), 1497 - 8, English, International magazine
    Scientific journal

  • Masaaki Tanaka, Yoshihito Shigihara, Akira Ishii, Masami Funakura, Etsuko Kanai, Yasuyoshi Watanabe
    BACKGROUND: Fatigue can be classified as mental and physical depending on its cause, and each type of fatigue has a multi-factorial nature. We examined the effect of mental fatigue on the central nervous system using electroencephalography (EEG) in eighteen healthy male volunteers. METHODS: After enrollment, subjects were randomly assigned to two groups in a single-blinded, crossover fashion to perform two types of mental fatigue-inducing experiments. Each experiment consisted of four 30-min fatigue-inducing 0- or 2-back test sessions and two evaluation sessions performed just before and after the fatigue-inducing sessions. During the evaluation session, the participants were assessed using EEG. Eleven electrodes were attached to the head skin, from positions F3, Fz, F4, C3, Cz, C4, P3, Pz, P4, O1, and O2. RESULTS: In the 2-back test, the beta power density on the Pz electrode and the alpha power densities on the P3 and O2 electrodes were decreased, and the theta power density on the Cz electrode was increased after the fatigue-inducing mental task sessions. In the 0-back test, no electrodes were altered after the fatigue-inducing sessions. CONCLUSIONS: Different types of mental fatigue produced different kinds of alterations of the spontaneous EEG variables. Our findings provide new perspectives on the neural mechanisms underlying mental fatigue.
    Sep. 2012, Behavioral and brain functions : BBF, 8, 48 - 48, English, International magazine
    Scientific journal

  • Tanaka Katsunori, Iwata Takayuki, Shirotsuki Sanae, Kageyama Chika, Tahara Tsuyoshi, Nozaki Satoshi, Siwu Eric R.O., Tamura Satoru, Douke Shunsuke, Murakami Nobutoshi, Onoe Hirotaka, Watanabe Yasuyoshi, Fukase Koichi
    Exploring efficient strategies for identifying the natural products and their derivatives that selectively regulate protein/protein interactions is one of the most actively studied topics in chemical biology. Especially, the selective activation and/or inhibition of specific phosphorylation-mediated protein/protein interactions within a signaling pathway may direct a specific biological response on the cellular level. In pursuit of such molecules, we developed a Template-Assisted Transcription Synthesis. The approach is based on our findings that (i) the bis-lysine structure such as 1 interacts with the phosphorylated compounds, and (ii) the benzyl-protected histidine significantly accelerates the peptide-based Huisgen cycloaddition, so that the structure 1 can efficiently be modified by the peptide library to strongly and selectively bind to the target phosphorylated protein in a template-assisted fashion. As a model case, we applied to preparing the Grb2/SH2 domain mimicry. The template-assisted transcription synthesis between the bis-lysine 1 and the acetylene-peptide library 2 was performed in the presence of the cyclic phosphopeptide 3 (known ligand for Grb2/SH2 domain) as the template. The clicked peptides 4a, b, and c as the template-assisted products, exhibited the micromolar-level dissociation constants to the phosphopeptide 3. Conformational restriction of the initial hit structure 4a by the solid-supported ring-closing metathesis gave the cyclic peptide 9, further enhancing the interaction with the peptide 3, i.e., Kd of 590 nM. One of the clicked product 4a, the peptidyl mimic of the Grb2-SH2 domain, was found to be internalized into A431 cancer cells, where the EGFR-induced cellular signalling is operative. It selectively bound to the phosphorylated Shc protein, one of the Grb2-SH2 interacting signaling proteins, induced A431-selective apoptosis and tumor growth inhibition. The clicked peptide 4a even exhibited the A431-selective inhibition of tumor growth without any toxic effects and inflammatory responses in the preliminary animal experiments. The results described in this symposium demonstrate the tailor-made synthesis of artificial receptors using a Template-Assisted Transcription Synthesis that is clearly distinct from previous methods. This approach may efficiently and rapidly provide small-molecular regulators that selectively control a specific cell signaling pathway or protein/protein interactions.
    Symposium on the chemistry of natural products, Sep. 2012, Symposium on the Chemistry of Natural Products, symposium papers, (54) (54), 109 - 114, Japanese

  • Makoto Kataoka, Tadayuki Takashima, Tomotaka Shingaki, Yoshinobu Hashidzume, Yumiko Katayama, Yasuhiro Wada, Hiroyuki Oh, Yoshie Masaoka, Shinji Sakuma, Yuichi Sugiyama, Shinji Yamashita, Yasuyoshi Watanabe
    PURPOSE: To dynamically analyze the processes of oral absorption and hepatobiliary distribution of telmisartan using positron emission tomography (PET). METHODS: (11)C-labeled telmisartan ([(11)C]TEL) was orally administered to rats with or without non-radiolabeled telmisartan (0.5, and 10 mg/kg). PET scanning of abdominal region and whole body was performed under conscious condition. In situ intestinal closed loop study in rats and in vitro permeation study in MDR1-MDCK II cell monolayers were also conducted. RESULTS: After oral administration of [(11)C]TEL, systemic bioavailability and hepatic distribution of radioactivity increased non-linearly with dose. In the intestinal lumen, both telmisartan and its glucuronide were detected and the ratio of telmisartan decreased dramatically at high dose of telmisartan. In situ closed loop study showed most of telmisartan-glucuronide detected in the intestinal lumen was derived from the bile excretion. In addition, in vitro permeation study revealed that telmisartan is a substrate of P-glycoprotein. CONCLUSION: PET imaging analysis successfully demonstrated the processes of intestinal absorption and hepatic distribution of telmisartan. PET study combined with appropriate in situ and in vitro experiments is highly expected to be a potent tool for better understanding of GI absorption and subsequent tissue distribution of various drugs and drug candidates.
    Sep. 2012, Pharmaceutical research, 29(9) (9), 2419 - 31, English, International magazine
    Scientific journal

  • Toshiyuki Kawasaki, Toshiyuki Marumo, Keiko Shirakami, Tomoko Mori, Hisashi Doi, Masaaki Suzuki, Yasuyoshi Watanabe, Shigeyuki Chaki, Atsuro Nakazato, Yukio Ago, Hitoshi Hashimoto, Toshio Matsuda, Akemichi Baba, Hirotaka Onoe
    20-Hydroxyeicosatetraenoic acid (20-HETE), an arachidonic acid metabolite known to be produced after cerebral ischemia, has been implicated in ischemic and reperfusion injury by mediating vasoconstriction. To develop a positron emission tomography (PET) probe for 20-HETE synthase imaging, which might be useful for monitoring vasoconstrictive processes in patients with brain ischemia, we synthesized a (11)C-labeled specific 20-HETE synthase inhibitor, N'(4-dimethylaminohexyloxy)phenyl imidazole ([(11)C]TROA). Autoradiographic study showed that [(11)C]TROA has high-specific binding in the kidney and liver consistent with the previously reported distribution of 20-HETE synthase. Using transient middle cerebral artery occlusion in rats, PET study showed significant increases in the binding of [(11)C]TROA in the ipsilateral hemisphere of rat brains after 7 and 10 days, which was blocked by co-injection of excess amounts of TROA (10 mg/kg). The increased [(11)C]TROA binding on the ipsilateral side returned to basal levels within 14 days. In addition, quantitative real-time PCR revealed that increased expression of 20-HETE synthase was only shown on the ipsilateral side on day 7. These results indicate that [(11)C]TROA might be a useful PET probe for imaging of 20-HETE synthase in patients with cerebral ischemia.
    Sep. 2012, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 32(9) (9), 1737 - 46, English, International magazine
    Scientific journal

  • Effect of a human-type communication robot on cognitive function in elderly women living alone.
    Masaaki Tanaka, Akira Ishii, Emi Yamano, Hiroki Ogikubo, Masatsugu Okazaki, Kazuro Kamimura, Yasuharu Konishi, Shigeru Emoto, Yasuyoshi Watanabe
    BACKGROUND: Considering the high prevalence of dementia, it would be of great value to develop effective tools to improve cognitive function. We examined the effects of a human-type communication robot on cognitive function in elderly women living alone. MATERIAL/METHODS: In this study, 34 healthy elderly female volunteers living alone were randomized to living with either a communication robot or a control robot at home for 8 weeks. The shape, voice, and motion features of the communication robot resemble those of a 3-year-old boy, while the control robot was not designed to talk or nod. Before living with the robot and 4 and 8 weeks after living with the robot, experiments were conducted to evaluate a variety of cognitive functions as well as saliva cortisol, sleep, and subjective fatigue, motivation, and healing. RESULTS: The Mini-Mental State Examination score, judgement, and verbal memory function were improved after living with the communication robot; those functions were not altered with the control robot. In addition, the saliva cortisol level was decreased, nocturnal sleeping hours tended to increase, and difficulty in maintaining sleep tended to decrease with the communication robot, although alterations were not shown with the control. The proportions of the participants in whom effects on attenuation of fatigue, enhancement of motivation, and healing could be recognized were higher in the communication robot group relative to the control group. CONCLUSIONS: This study demonstrates that living with a human-type communication robot may be effective for improving cognitive functions in elderly women living alone.
    Sep. 2012, Medical science monitor : international medical journal of experimental and clinical research, 18(9) (9), CR550-7, English, International magazine
    Scientific journal

  • Keiji Shimizu, Tadayuki Takashima, Tomohiko Yamane, Masahiro Sasaki, Hiromitsu Kageyama, Yoshinobu Hashizume, Kazuya Maeda, Yuichi Sugiyama, Yasuyoshi Watanabe, Michio Senda
    INTRODUCTION: Telmisartan, a nonpeptide angiotensin II AT1 receptor antagonist used as an antihypertensive drug, is specifically taken up by the liver through the OATP1B3. PET imaging with [(11)C]telmisartan is expected to provide information about the whole body pharmacokinetics of telmisartan as well as its transport property by OATP1B3. The purpose of the study was to determine the biodistribution and radiation dosimetry of [(11)C]telmisartan in humans. METHODS: Biodistribution of [(11)C]telmisartan was measured in three rats and six healthy male human volunteers. In the rat study, a dynamic emission scan was performed for 90 min. In the human study, dynamic whole-body PET images were acquired after intravenous injection of [(11)C]telmisartan. ROIs were defined for source organs on the PET images to measure time-course of [(11)C]telmisartan uptake as percentage injected dose and the number of disintegration for each organ. Radiation dosimetry was calculated with OLINDA/EXM. RESULTS: In the rat study, most radioactivity was rapidly taken up by the liver and part of it was excreted into the biliary tract and intestine. Extrapolating from the rat data, the effective dose for the adult human being was estimated to be 3.65±0.01 microSv/MBq (n=3). In the human study, most of the tracer was taken up by the liver as well, although not as rapidly as in the rat. The activity in the gall bladder and intestine increased gradually. The effective dose for the adult human being was 4.24±0.09 microSv/MBq (n=6). CONCLUSIONS: [(11)C]Telmisartan is a safe PET tracer with a dosimetry profile comparable to other common (11)C PET tracers.
    Aug. 2012, Nuclear medicine and biology, 39(6) (6), 847 - 53, English, International magazine
    Scientific journal

  • Takahiro Yoshikawa, Keisuke Orita, Yasuyoshi Watanabe, Masaaki Tanaka
    To validate a Japanese version of Power of Food Scale (PFS-J), and to describe characteristics in appetitive motives among current Japanese young adults, the original English PFS was translated into Japanese and translated back into English, to confirm conceptual and linguistic equivalence, and administered to university students. Test-retest reliability of the PFS-J was evaluated in additional experiments. The PFS-J demonstrated good internal consistency and stability over time. Confirmatory factor analyses demonstrated that the PFS-J has acceptable factor structure. Criterion validity was suggested, in that the relationship between the original PFS and Three-Factor Eating Questionnaire Revised-21 was similar to that between the Japanese versions of the scales. While no association was observed between the scores of PFS-J and Body Mass Index, the scores were higher in women than in men. Characteristics of the appetitive motives in Japan might be different from those in western countries.
    SAGE PUBLICATIONS INC, Aug. 2012, Psychological reports, 111(1) (1), 253 - 65, English, International magazine
    Scientific journal

  • 佐古 健生, 長谷川 功紀, 崔 翼龍, 和田 康弘, 林中 恵美, 片岡 洋祐, 千田 道雄, 渡辺 恭良
    (一社)日本核医学会, Aug. 2012, 核医学, 49(3) (3), S255 - S255, Japanese

  • Takayuki Ose, Hiroshi Watabe, Takuya Hayashi, Nobuyuki Kudomi, Masaaki Hikake, Hajime Fukuda, Noboru Teramoto, Yasuyoshi Watanabe, Hirotaka Onoe, Hidehiro Iida
    INTRODUCTION: Measurement of regional cerebral blood flow (rCBF) in rodents can provide knowledge of pathophysiology of the cerebral circulation, but generally requires blood sampling for analysis during positron emission tomography (PET). We therefore tested the feasibility of using an arteriovenous (AV) shunt in rats for less invasive blood analysis. METHODS: Six anesthetized rats received [15O]H2O and [15O]CO PET scans with their femoral artery and vein connected by an AV shunt, the activity within which was measured with a germanium ortho-oxysilicate scintillation detector. The [15O]H2O was intravenously injected either at a faster or slower injection rate, while animals were placed either with their head or heart centered in the gantry. The time-activity curve (TAC) from the AV shunt was compared with that from the cardiac ventricle in PET image. The rCBF values were calculated by a nonlinear least-square method using the dispersion-corrected AV-shunt TAC as an input. RESULTS: The AV-shunt TAC had higher signal-to-noise ratio, but also had delay and dispersion compared with the image-derived TAC. The delay time between the AV-shunt TAC and image-based TAC ranged from 11 to 21 s, while the dispersion was estimated to be ∼5 s as a time constant of the dispersion model of exponential function, and both were properly corrected. In a steady-state condition of [15O]CO PET, the blood activity concentration by AV-shunt TAC was also comparable in height with the image-based TAC corrected for partial volume. Whole-brain CBF values measured by [15O]H2O were 0.37±0.04 (mean±S.D.) ml/g/min, partition coefficient was 0.73±0.04 ml/g, and the CBF varied in a linear relationship with partial pressure of carbon dioxide during each scan. CONCLUSIONS: The AV-shunt technique allows less invasive, quantitative and reproducible measurement of rCBF in [15O]H2O PET studies in rats than direct blood sampling and radioassay.
    Jul. 2012, Nuclear medicine and biology, 39(5) (5), 730 - 41, English, International magazine
    Scientific journal

  • Kei Mizuno, Masaaki Tanaka, Hiroki C Tanabe, Norihiro Sadato, Yasuyoshi Watanabe
    The kana pick-out test has been widely used in Japan to evaluate the ability to divide attention in both adult and pediatric patients. However, the neural substrates underlying the ability to divide attention using the kana pick-out test, which requires participants to pick out individual letters (vowels) in a story while also reading for comprehension, thus requiring simultaneous allocation of attention to both activities, are still unclear. Moreover, outside of the clinical area, neuroimaging studies focused on the mechanisms of divided attention during complex story comprehension are rare. Thus, the purpose of the present study, to clarify the neural substrates of kana pick-out test, improves our current understanding of the basic neural mechanisms of dual task performance in verbal memory function. We compared patterns of activation in the brain obtained during performance of the individual tasks of vowel identification and story comprehension, to levels of activation when participants performed the two tasks simultaneously during the kana pick-out test. We found that activations of the left dorsal inferior frontal gyrus and superior parietal lobule increase in functional connectivity to a greater extent during the dual task condition compared to the two single task conditions. In contrast, activations of the left fusiform gyrus and middle temporal gyrus, which are significantly involved in picking out letters and complex sentences during story comprehension, respectively, were reduced in the dual task condition compared to during the two single task conditions. These results suggest that increased activations of the dorsal inferior frontal gyrus and superior parietal lobule during dual task performance may be associated with the capacity for attentional resources, and reduced activations of the left fusiform gyrus and middle temporal gyrus may reflect the difficulty of concurrent processing of the two tasks. In addition, the increase in synchronization between the left dorsal inferior frontal gyrus and superior parietal lobule in the dual task condition may induce effective communication between these brain regions and contribute to more attentional processing than in the single task condition, due to greater and more complex demands on voluntary attentional resources.
    Jul. 2012, Neuropsychologia, 50(8) (8), 1998 - 2009, English, International magazine
    Scientific journal

  • Ryosuke Ijuin, Tadayuki Takashima, Yasuyoshi Watanabe, Yuichi Sugiyama, Masaaki Suzuki
    Drug transporters mediate the uptake and elimination of drugs in various organs; therefore, having knowledge of how a transporter functions in the body would play a key role in ensuring drug efficacy in in vivo systems. In this context, we designed and synthesized [(11)C]dehydropravastatin, a novel PET probe that would be potentially useful for evaluation of the functions of the OATP1B1 and MRP2 transporters, based on the use of palladium(0)-mediated rapid C-[(11)C]methylation (viz., the rapid cross-coupling between [(11)C]methyl iodide and a boron intermediate).
    Jun. 2012, Bioorganic & medicinal chemistry, 20(12) (12), 3703 - 9, English, International magazine
    Scientific journal

  • 慢性疲労症候群における還元型コエンザイムQ10の効果 摂取栄養素との関連を含めて
    福田 早苗, 藤井 比佐子, 中富 康仁, 山口 浩二, 野島 順三, 梶本 修身, 倉恒 弘彦, 渡辺 恭良
    日本疲労学会, Jun. 2012, 日本疲労学会誌, 8(1) (1), 42 - 42, Japanese
    [Refereed]
    Scientific journal

  • Yoshihito Shigihara, Masaaki Tanaka, Kei Mizuno, Akira Ishii, Emi Yamano, Masami Funakura, Etsuko Kanai, Yasuyoshi Watanabe
    Fatigue is a common complaint in modern society. As photosensitivity is associated with fatigue, this study aimed to clarify the relationship between neural response to visual stimuli and fatigue using a 160-channel whole-head-type magnetoencephalographic system. Twelve healthy male volunteers were enrolled. Participants were randomly assigned to two groups in a single-blinded, crossover fashion to perform acute fatigue-inducing mental task sessions, i.e., 0-back or 2-back test for 30 min. Visual evoked magnetic field (VEF) intensities were evaluated by standardized low-resolution brain electromagnetic tomography modified for a quantifiable method. VEF consisted of two phases, and although acute fatigue did not alter the VEF intensities and the intensities before the acute fatigue-inducing mental task sessions were not correlated with the Chalder's Fatigue Scale scores in either of the two phases, the intensities after the 0-back test trials for 30 min in Phase 1 and those after the 2-back test trials in Phase 2 were significantly correlated with the fatigue scale scores. The daily level of fatigue was related to VEF intensity after the acute mental fatigue loads. Our findings provide new perspectives to evaluate our daily level of fatigue as well as to clarify the neural mechanisms underlying it.
    May 2012, Brain research, 1457, 44 - 50, English, International magazine
    Scientific journal

  • Akira Ishii, Masaaki Tanaka, Emi Yamano, Yasuyoshi Watanabe
    The neural substrates of the fatigue sensation have not been totally identified. Several lines of evidence demonstrate that seeing emotional changes in others activates brain regions involved in experiencing similar emotions. We hypothesized that there exists a mirror system regarding the fatigue sensation and that brain regions associated with the fatigue sensation may be activated by viewing other individuals expressing fatigue. In this study, we attempted to identify the neural substrates activated by viewing other fatigued individuals using magnetoencephalography (MEG). Twelve healthy participants were enrolled in our study after providing written informed consent. During MEG recordings, they viewed a set of pictures projected on a screen. The pictures, which were presented in a randomized order, were of a person with a fatigued or neutral facial expression. When participants viewed pictures of people with fatigued expressions, we were able to estimate equivalent current dipoles (ECDs) in the posterior cingulate cortex (PCC) in 9 of 12 participants approximately 300 ms after the onset of each picture presentation. When they viewed pictures of people with neutral expressions, we were not able to estimate corresponding ECDs for any participant. The PCC is the brain region activated by viewing others expressing fatigue, suggesting existence of the shared neural substrates of felt and observed fatigue.
    May 2012, Brain research, 1455, 68 - 74, English, International magazine
    Scientific journal

  • Cu-64-DOTA-trastuzumab-PET imaging in patients with HER2-positive breast cancer
    Kenji Tamura, Hiroaki Kurihara, Kan Yonemori, Kazuhiro Takahashi, Yasuhiro Wada, Koki Hasegawa, Fumiaki Koizumi, Hitoshi Tsuda, Makoto Kodaira, Mayu Yunokawa, Chikako Shimizu, Masashi Ando, Yasuyoshi Watanabe, Yasuhiro Fujiwara
    AMER SOC CLINICAL ONCOLOGY, May 2012, JOURNAL OF CLINICAL ONCOLOGY, 30(15) (15), English
    [Refereed]

  • Tadayuki Takashima, Satoshi Kitamura, Yasuhiro Wada, Masaaki Tanaka, Yoshihito Shigihara, Hideki Ishii, Ryosuke Ijuin, Susumu Shiomi, Takahiro Nakae, Yumiko Watanabe, Yilong Cui, Hisashi Doi, Masaaki Suzuki, Kazuya Maeda, Hiroyuki Kusuhara, Yuichi Sugiyama, Yasuyoshi Watanabe
    It is well accepted that drug transporters play a pivotal role in hepatobiliary excretion of anionic drugs, in which drug-drug interactions and genetic polymorphisms are known to cause variations. However, PET probes for in vivo functional characterization of these transporters have not been established yet. We used PET to investigate hepatic uptake and subsequent canalicular efflux of C-11-labeled (15R)-16-m-tolyl-17,18,19,20-tetranorisocarbacyclin methyl ester [(15R)-C-11-TIC-Me)] in healthy subjects. Methods: Serial PET scans of the abdominal region in healthy male subjects were obtained with or without the organic anion-transporting polypeptide (OATP) inhibitor rifampicin after intravenous injection of (15R)-C-11-TIC-Me as a radiotracer. Venous blood samples and PET images were obtained at frequent intervals up to 30 min after administration of the PET tracer. Dynamic imaging data were evaluated by integration plots of data collected for 2-10 min and for 10-30 min after tracer administration for the determination of tissue uptake clearance and biliary efflux clearance, respectively. Results: After rapid hydrolysis in blood, the acid form-C-11-labeled (15R)-16-m-tolyl-17,18,19,20-tetranorisocarbacyclin [(15R)-C-11-TIC]-accumulated in the liver (37% of the dose by 17 min), and the radioactivity was then excreted into the bile (6.2% by 30 min). Rifampicin (600 mg by mouth), a potent OATP inhibitor, significantly reduced the radioactivity excreted into the bile (by 44%) by inhibiting both uptake (by 45%) and subsequent canalicular efflux (by 62%). (15R)-C-11-TIC is an in vitro substrate of OATP1B1 and OATP1B3, and clinically relevant concentrations of rifampicin inhibited uptake by OATP1B1 and OATP1B3. These results demonstrated that in humans, (15R)-C-11-TIC-associated radioactivity is excreted into the bile by organic anion transport systems. Conclusion: We demonstrated that PET image analysis with (15R)-C-11-TIC-Me is useful for investigating variations in OATP function in the human hepatobiliary transport system.
    SOC NUCLEAR MEDICINE INC, May 2012, JOURNAL OF NUCLEAR MEDICINE, 53(5) (5), 741 - 748, English, International magazine
    [Refereed]
    Scientific journal

  • Katsunori Tanaka, Sanae Shirotsuki, Takayuki Iwata, Chika Kageyama, Tsuyoshi Tahara, Satoshi Nozaki, Eric R O Siwu, Satoru Tamura, Shunsuke Douke, Nobutoshi Murakami, Hirotaka Onoe, Yasuyoshi Watanabe, Koichi Fukase
    A new synthetic strategy for obtaining artificial receptors that selectively regulate and/or control specific protein/protein interactions was developed based on the template-assisted and the self-activating click reaction applied to a combinatorial library. Synthetic mimics of the Grb2-SH2 domain, examined as a model case, selectively bound to a target signaling protein to induce cytotoxicity and inhibit tumor growth in vivo.
    Apr. 2012, ACS chemical biology, 7(4) (4), 637 - 45, English, International magazine
    Scientific journal

  • 慢性疲労症候群の実生活への影響調査に関する検討
    福田 早苗, 山口 浩二, 中富 康仁, 藤井 比佐子, 野島 順三, 渡辺 恭良, 倉恒 弘彦
    慢性疲労症候群(CFS)と診断された患者47名を対象、一般コントロール47名を対照として、CFSの実生活への影響を調査し、他の検査項目との対応、既存の質問票・客観的疲労バイオマーカー候補との相関関係について検討し、感度・特異度を計算した。疲労の重症度評価質問票(FP)は、全ての項目の合計得点(FPT)と因子分析の結果5因子に分け、第1因子から順に作成したFPindexのそれぞれを検証した。その結果、それぞれの平均得点はいずれの群でもFPT、FPindexにおいてCFS群の方が有意に得点が高かった。FPTおよび他の質問票との相関関係を調べたところ、CFS群においてFPTおよびFPindexはPSと比較的高い正の相関を示し、FPTおよびFPindexはChalderの疲労スケールCES-Dとも正の相関を示した。一方コントロール群ではPS、VAS、CES-Dとは有意な相関を示さなかったものの、Chalder疲労スケールとは緩やかな正の相関を示した。PSはコントロール群においてVASとやや高い正の相関を示し、CFSにおいて相関を示さなかった。睡眠効率、活動量、DTA、中途覚醒回数、酸化ストレス、抗酸化量、アミラーゼとFPTおよびFPindexの相関関係を調べたところ、いずれも活動度や酸化ストレス、アミラーゼと相関を示した。感度・特異度はPSの感度・特異度に匹敵する値をFPindexで得られ、FPTの感度・特異度はFPindexの感度・特異度よりやや低かった。
    日本疲労学会, Mar. 2012, 日本疲労学会誌, 7(2) (2), 80 - 87, Japanese
    [Refereed]
    Scientific journal

  • Effects of pellet stove on recovery from mental fatigue.
    Masaaki Tanaka, Hiromi Yamada, Takayuki Nakamura, Yasuyoshi Watanabe
    BACKGROUND: Exposure to a warm environment has been reported to be effective for recovery from mental fatigue. However, there have been no reports examining the effects of a pellet stove on recovery from mental fatigue. The purpose of this study was to examine the effects of a pellet stove on recovery from mental fatigue. MATERIAL/METHODS: In this placebo-controlled, crossover experiment, 16 healthy volunteers were randomized into the pellet stove and control groups. After a 30-min fatigue-inducing mental task session, participants moved to a recovery room with (pellet stove condition) or without (control condition) a pellet stove to see the image of a pellet stove for 30 min. RESULTS: After the recovery session, the participants exposed to the pellet stove condition showed lower total error counts of a cognitive test, higher levels of subjective healing, comfort, and warmth, and sympathetic nerve activity and higher parasympathetic nerve activity as compared with the control condition. CONCLUSIONS: These results provide evidence that improved cognitive function, subjective mental states, and balance of the autonomic nervous activities result from using a pellet stove during the recovery session. Hence, the pellet stove was effective for the recovery from mental fatigue.
    Mar. 2012, Medical science monitor : international medical journal of experimental and clinical research, 18(3) (3), CR148-53, English, International magazine
    Scientific journal

  • Yoshihiro Yamakawa, Hiroyuki Shimada, Suzuka Ataka, Akiko Tamura, Hideki Masaki, Hiroshi Naka, Tsuyoshi Tsutada, Aki Nakanishi, Susumu Shiomi, Yasuyoshi Watanabe, Takami Miki
    We described the cases of two patients with dementia associated with motor neuron disease, the former with frontotemporal dementia (FTD) and the latter with Alzheimer's disease (AD), studied by the Pittsburgh compound B-positron emission tomography (PIB-PET). In the FTD patient, the PIB-PET revealed no amyloid accumulation in the cortex, whilst in the AD patient showed amyloid accumulation mainly in the frontal, parietal and lateral temporal lobes, besides the posterior cingulate gyrus and the precuneus. Thus, PIB-PET might facilitate the discrimination of different proteinopathies that cause neurodegenerative diseases, as dementia associated with ALS.
    Feb. 2012, Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 33(1) (1), 87 - 92, English, International magazine
    Scientific journal

  • K Nakadate, K Imamura, Y Watanabe
    We studied the pattern of expression of a protein product (c-Fos) of immediate-early gene (IEG) in the visual cortex of rats and mice. The basal expression of c-Fos was very low and visual exposure revealed a large number of c-Fos immunopositive cells in the visual cortex. We found that monocular deprivation during the sensitive period of ocular dominance (OD) plasticity significantly changed both the amount and pattern of c-Fos expression upon monocular stimulation of either eye. The number of immunopositive cells in layer IV of binocular subfields of the primary visual cortex (Oc1B) ipsilateral to the stimulated eye was found to be the most sensitive index of the effects of monocular deprivation during the sensitive period, that is, opened eye stimulation induced significantly larger numbers of c-Fos immunopositive cells, whereas closed eye stimulation induced significantly smaller numbers compared with those induced by monocular stimulation in control animals. In the lateral geniculate nucleus and superior colliculus, the pattern of expression of c-Fos following monocular stimulation was not affected by preceding monocular deprivation. Monocular deprivation imposed after the sensitive period did not affect the pattern of induction of c-Fos. Notably, in age-matched old animals that had been raised in total darkness and then experienced monocular deprivation, the distribution and numbers of c-Fos-expressing cells in visual cortex exhibited the same alterations as found in young animals during the sensitive period. These findings suggest that the present activity mapping method using c-Fos as a molecular marker is useful for examining the activity-dependent regulation of cortical plasticity, and provides an alternative method to conventional electrophysiological recording. This method is particularly powerful when applied to knockout or transgenic mice in which sampling biases in electrophysiological recording have been considered inevitable. Furthermore, these findings suggest that c-Fos is involved in OD plasticity as an IEG that transfers neuronal activity to late gene expression.
    Jan. 2012, Neuroscience, 202, 17 - 28, English, International magazine
    [Refereed]
    Scientific journal

  • Impaired Selective Attention Caused By Mental Fatigue
    Masaaki Tanaka, Akira Ishii, Yoshihito Shigihara, Seiki Tajima, Masami Funakura, Etsuko Kanai, Yasuyoshi Watanabe
    Objective: Fatigue decreases efficiency in performing daily tasks, and this is a common symptom in modern society. It would thus be of great value to clarify the mechanism underlying fatigue and to develop efficient methods to evaluate fatigue. We examined cognitive function associated with two types of mental fatigue. Methods: Twenty healthy volunteers were randomised to perform rest or fatigue-inducing mental task session (0-back or 2-back test session) for 30 min in a 3-way crossover design. Just before and after each session, participants completed cognitive task trials to evaluate simple and conflict-controlling selective attention (response inhibition). Results: Changes in the reaction time of simple selective attention task after the 2-back test session were longer and changes after the 0-back test session had a trend toward being longer than those after the rest session. In addition, changes in the percent error for Stroop effect after the 2-back test session were significantly higher than those after the rest session, although those after the 0-back test session were not. Conclusions: Different types of mental fatigue produced different styles of deteriorated cognitive performances. Impaired selective attention may be a specific feature of mental fatigue, and a higher mental load may introduce a greater level of impaired conflict control or response inhibition.
    JOURNAL NEUROLOGICAL SCIENCES, 2012, JOURNAL OF NEUROLOGICAL SCIENCES-TURKISH, 29(3) (3), 542 - 553, English
    [Refereed]
    Scientific journal

  • Masaaki Tanaka, Yasuyoshi Watanabe
    Fatigue, defined as difficulty in initiating or sustaining voluntary activities, can be classified as physical or mental, and physical fatigue can be classified as peripheral or central (spinal or supraspinal). It has been reported that during physical fatigue, sensory input from the peripheral system activates an inhibition system to limit motor output from the primary motor cortex (M1) (supraspinal fatigue) while a motivational input activates a facilitation system to increase motor output from M1 in order to overcome supraspinal fatigue. Hence, the motor output from M1 is primarily determined by the balance between the inhibition and facilitation systems. Here, we review data from behavioral, electrophysiological, and neuroimaging experiments related to supraspinal mechanisms that are thought to regulate motor output from M1 during physical fatigue, and we propose a supraspinal model to regulate physical fatigue as well as a hypothetical model of fatigue in human diseases or syndromes.
    Jan. 2012, Neuroscience and biobehavioral reviews, 36(1) (1), 727 - 34, English, International magazine
    Scientific journal

  • Keiji Yashio, Yumiko Katayama, Tadayuki Takashima, Naoki Ishiguro, Hisashi Doi, Masaaki Suzuki, Yasuhiro Wada, Ikumi Tamai, Yasuyoshi Watanabe
    The synthesis and in vivo evaluation of (11)C -labeled uric acid ([(11)C]1), a potential imaging agent for the diagnosis of urate-related life-style diseases, was performed using positron emission tomography (PET) image analysis. First, the synthesis of [(11)C]1 was achieved by reacting 5,6-diaminouracil (2) with (11)C-labeled phosgene ([(11)C]COCl(2)). The radiochemical yield of [(11)C]1 was 37±7% (decay-corrected based on [(11)C]COCl(2)) with specific radioactivities of 96-152GBq/μmol at the end of synthesis (n=6). The average time of radiosynthesis from the end of bombardment, including formulation, was about 30min with >98% radiochemical purity. Second, the synthetic approach to [(11)C]1 was optimized using 5,6-diaminouracil sulfate (3) with [(11)C]COCl(2) in the presence of 1,8-bis(dimethylamino)naphthalene. [(11)C]1 was synthesized in 36±6% radiochemical yield, 89-142GBq/μmol of specific radioactivities, and 98% radiochemical purity by this method (n=5). This allowed the synthesis of [(11)C]1 to be carried out repeatedly and the radiochemical yield, specific radioactivities, average time of synthesis, and radiochemical purity of [(11)C]1 were similar to those obtained using 2. PET studies in rats showed large differences in the accumulation of radioligand in the limbs under normal and hyperuricemic conditions. Thus, an efficient and convenient automated synthesis of [(11)C]1 has been developed, and preliminary PET evaluation of [(11)C]1 confirmed the increased accumulation of radioactivity in the limbs of a rat model of hyperuricemia.
    Jan. 2012, Bioorganic & medicinal chemistry letters, 22(1) (1), 115 - 9, English, International magazine
    Scientific journal

  • Masamitsu Shimazawa, Yasushi Ito, Yuta Inokuchi, Hajime Yamanaka, Tomohiro Nakanishi, Takuya Hayashi, Bin Ji, Makoto Higuchi, Tetsuya Suhara, Kazuyuki Imamura, Makoto Araie, Yasuyoshi Watanabe, Hirotaka Onoe, Hideaki Hara
    We examined lateral geniculate nucleus (LGN) degeneration as an indicator for possible diagnosis of glaucoma in experimental glaucoma monkeys using positron emission tomography (PET). Chronic intraocular pressure (IOP) elevation was induced by laser trabeculoplasty in the left eyes of 5 cynomolgus monkeys. Glial cell activation was detected by PET imaging with [(11)C]PK11195, a PET ligand for peripheral-type benzodiazepine receptor (PBR), before and at 4 weeks after laser treatment (moderate glaucoma stage). At mild, moderate, and advanced experimental glaucoma stages (classified by histological changes based on the extent of axonal loss), brains were stained with cresyl violet, or antibodies against PBR, Iba-1 (a microglial marker), and GFAP (an activated astrocyte marker). In laser-treated eyes, IOP was persistently elevated throughout all observation periods. PET imaging showed increased [(11)C]PK11195 binding potential in the bilateral LGN at 4 weeks after laser treatment; the increase in the ipsilateral LGN was statistically significant (P<0.05, n = 4). Immunostaining showed bilateral activations of microglia and astrocytes in LGN layers receiving input from the laser-treated eye. PBR-positive cells were observed in LGN layers receiving input from laser-treated eye at all experimental glaucoma stages including the mild glaucoma stage and their localization coincided with Iba-1 positive microglia and GFAP-positive astrocytes. These data suggest that glial activation occurs in the LGN at a mild glaucoma stage, and that the LGN degeneration could be detected by a PET imaging with [(11)C]PK11195 during the moderate experimental glaucoma stage after unilateral ocular hypertension. Therefore, activated glial markers such as PBR in the LGN may be useful in noninvasive molecular imaging for diagnosis of glaucoma.
    2012, PloS one, 7(1) (1), e30526, English, International magazine
    Scientific journal

  • Masaaki Tanaka, Yoshihito Shigihara, Masami Funakura, Etsuko Kanai, Yasuyoshi Watanabe
    Fatigue is a common problem in modern society. We attempted to identify moderate- to long-term fatigue-related alterations in the central nervous system using cognitive tasks and electroencephalography (EEG) measures. The study group consisted of 17 healthy male participants. After saliva samples were collected to measure copy number of human herpesvirus (HHV)-6 DNA to assess the level of moderate- to long-term fatigue, subjects were evaluated using EEG, with their eyes open for 2 min, then closed for 1 min sitting quietly. Thereafter, they completed cognitive task trials to evaluate simple selective attention for 3 min (Task 1) and conflict-controlling selective attention for 6 min (Task 2, which included Stroop trials). The percent error of Task 2 for Stroop trials was positively associated with the copy number of saliva HHV-6 DNA, although the simple selective attention measures in Task 1 did not differ significantly. EEG power densities (especially the alpha power density) during the eye-closed condition were negatively associated with the saliva HHV-6 DNA level. Impaired high-level information processing such as that required for conflict-controlling selective attention in the central nervous system may be a characteristic feature of moderate- to long-term fatigue.
    2012, PloS one, 7(4) (4), e34774, English, International magazine
    Scientific journal

  • Clinical features of Pittsburgh compound-B-negative dementia.
    Jun Takeuchi, Hiroyuki Shimada, Suzuka Ataka, Joji Kawabe, Hiroshi Mori, Kei Mizuno, Yasuhiro Wada, Susumu Shiomi, Yasuyoshi Watanabe, Takami Miki
    BACKGROUND/AIMS: We previously found that some cases of clinically diagnosed Alzheimer's disease (AD) were rated as Pittsburgh compound B (PiB) negative by amyloid imaging (i.e. cases of PiB-negative dementia). The present study was designed to analyze the clinical features of PiB-negative dementia patients in detail. METHODS: Of the 64 cases of clinically diagnosed AD, 14 were rated PiB negative. Eleven of these were further analyzed using CSF biomarker levels and findings from MRI, FDG-PET, (123)I-MIBG myocardial scintigraphy and voxel-based morphometry (VBM). RESULTS: When examined by (123)I-MIBG myocardial scintigraphy, the heart/mediastinum ratio was significantly higher in the PiB-negative dementia group than in the dementia with Lewy bodies (DLB) group. Analyses of CSF biomarkers and MRI and FDG-PET findings suggested argyrophilic grain disease (AGD) in 3 cases, frontotemporal lobar degeneration (FTLD) in 3 cases, neurofibrillary tangle-predominant dementia (NFTD) in 1 case, and AD in 2 cases. In the VBM data analysis, the PiB-positive AD group showed significant atrophy of both hippocampi compared with the healthy control group, while the PiB-negative dementia group presented with significant atrophy of the left precuneus. CONCLUSION: PiB-negative dementia is unlikely to include DLB, while it most likely includes diseases of tauopathy, such as FTLD, AGD and NFTD. A better understanding of PiB-negative dementia is expected to further improve the accuracy of the clinical AD diagnosis.
    2012, Dementia and geriatric cognitive disorders, 34(2) (2), 112 - 20, English, International magazine
    Scientific journal

  • Shigeyuki Yamamoto, Yasuomi Ouchi, Daisaku Nakatsuka, Tsuyoshi Tahara, Kei Mizuno, Seiki Tajima, Hirotaka Onoe, Etsuji Yoshikawa, Hideo Tsukada, Masao Iwase, Kouzi Yamaguti, Hirohiko Kuratsune, Yasuyoshi Watanabe
    BACKGROUND: Numerous associations between brain-reactive antibodies and neurological or psychiatric symptoms have been proposed. Serum autoantibody against the muscarinic cholinergic receptor (mAChR) was increased in some patients with chronic fatigue syndrome (CFS) or psychiatric disease. We examined whether serum autoantibody against mAChR affected the central cholinergic system by measuring brain mAChR binding and acetylcholinesterase activity using positron emission tomography (PET) in CFS patients with positive [CFS(+)] and negative [CFS(-)] autoantibodies. METHODOLOGY: Five CFS(+) and six CFS(-) patients, as well as 11 normal control subjects underwent a series of PET measurements with N-[(11)C]methyl-3-piperidyl benzilate [(11)C](+)3-MPB for the mAChR binding and N-[(11)C]methyl-4-piperidyl acetate [(11)C]MP4A for acetylcholinesterase activity. Cognitive function of all subjects was assessed by neuropsychological tests. Although the brain [(11)C](+)3-MPB binding in CFS(-) patients did not differ from normal controls, CFS(+) patients showed significantly lower [(11)C](+)3-MPB binding than CFS(-) patients and normal controls. In contrast, the [(11)C]MP4A index showed no significant differences among these three groups. Neuropsychological measures were similar among groups. CONCLUSION: The present results demonstrate that serum autoantibody against the mAChR can affect the brain mAChR without altering acetylcholinesterase activity and cognitive functions in CFS patients.
    2012, PloS one, 7(12) (12), e51515, English, International magazine
    Scientific journal

  • ソマトスタチンアナログを用いた膵内分泌細胞PETイメージング
    佐古 健生, 長谷川 功紀, 西村 三恵, 崔 翼龍, 和田 康弘, 林中 恵美, 片岡 洋祐, 千田 道雄, 渡辺 恭良
    日本分子イメージング学会, Jan. 2012, JSMI Report, 5(1) (1), 20 - 22, Japanese

  • Makoto Ozawa, Kayo Takahashi, Ko-hei Akazawa, Tadayuki Takashima, Hiroko Nagata, Hisashi Doi, Takamitsu Hosoya, Yasuhiro Wada, Yilong Cui, Yosky Kataoka, Yasuyoshi Watanabe
    Aromatase is a rate-limiting enzyme for estrogen biosynthesis and has been implicated in pathophysiological states of various diseases via estrogen production. This enzyme is known to be widely distributed in extragonadal and gonadal tissues including the stomach. In contrast to circulating estrogen, the functional role of gastric aromatase/estrogen has not been elucidated in detail, because there is no efficient methodology to investigate spatiotemporal changes of gastric aromatase/ estrogen in vivo. Recently, (S)-C-11-6-[(4-chlorophenyl)(H-1-1,2,4- triazole-1-yl)methyl]-1-methyl-H-1-benzotriazole (C-11-labeled vorozole), based on a potent nonsteroidal aromatase inhibitor, has been developed as a tracer to investigate aromatase distribution in living animals and humans using a noninvasive PET technique. In the present study, we investigated gastric aromatase expression by means of PET with C-11-vorozole. Methods: After bolus injection of C-11-vorozole into the tail vein, emission scans were obtained for 90 min on male and female rats under isoflurane anesthesia. Displacement studies with unlabeled vorozole and autoradiographic analysis were conducted for demonstration of specific binding. Immunohistochemistry was performed to confirm aromatase expression. Results: PET scans revealed that C-11-vorozole highly accumulated in the stomach and adrenal glands. Displacement studies and autoradiography demonstrated that aromatase was expressed in the stomach but that the accumulation of C-11-vorozole in the adrenal glands might be through nonspecific binding. Immunohistochemical analysis revealed that aromatase is expressed in gastric parietal cells but not in adrenal glands. Moreover, the accumulation of C-11-vorozole in the stomach was significantly increased in fatigued rats. Conclusion: These results suggest that the C-11-vorozole PET technique is a useful tool for evaluation of gastric aromatase dynamics in vivo, which may provide important information for understanding the molecular mechanisms of gastric aromatase/estrogenrelated pathophysiological processes and for the development of new drugs.
    SOC NUCLEAR MEDICINE INC, Dec. 2011, JOURNAL OF NUCLEAR MEDICINE, 52(12) (12), 1964 - 1969, English, International magazine
    [Refereed]
    Scientific journal

  • 崔 翼龍, 渡辺 恭良, 片岡 洋祐
    先端医療技術研究所, Dec. 2011, PET Journal, (16) (16), 14 - 16, Japanese

  • Kiyoshi Kyono, Tadayuki Takashima, Yumiko Katayama, Toshiyuki Kawasaki, Riyo Zochi, Maki Gouda, Yasuhiro Kuwahara, Kazuhiro Takahashi, Yasuhiro Wada, Hirotaka Onoe, Yasuyoshi Watanabe
    BACKGROUND: We evaluated the utility of L-3,4-dihydroxy-6-[18F]fluoro-phenylalanine ([18F]FDOPA) positron emission tomography (PET) as a method for assessing the severity of dopaminergic dysfunction in unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats by comparing it with quantitative biochemical, immunohistochemical, and behavioral measurements. METHODS: Different doses of 6-OHDA (0, 7, 14, and 28 μg) were unilaterally injected into the right striatum of male Sprague-Dawley rats. Dopaminergic functional activity in the striatum was assessed by [18F]FDOPA-PET, measurement of striatal dopamine (DA) and DA metabolite levels, tyrosine hydroxylase (TH) immunostaining, and methamphetamine-induced rotational testing. RESULTS: Accumulation of [18F]FDOPA in the bilateral striatum was observed in rats pretreated with both aromatic L-amino acid decarboxylase and catechol-O-methyltransferase (COMT) inhibitors. Unilateral intrastriatal injection of 6-OHDA produced a significant site-specific reduction in [18F]FDOPA accumulation. The topological distribution pattern of [18F]FDOPA accumulation in the ipsilateral striatum agreed well with the pattern in TH-stained corresponding sections. A significant positive relationship was found between Patlak plot Ki values and striatal levels of DA and its metabolites (r = 0.958). A significant negative correlation was found between both Ki values (r = -0.639) and levels of DA and its metabolites (r = -0.719) and the number of methamphetamine-induced rotations. CONCLUSIONS: Ki values determined using [18F]FDOPA-PET correlated significantly with the severity of dopaminergic dysfunction. [18F]FDOPA-PET makes it possible to perform longitudinal evaluation of dopaminergic function in 6-OHDA-lesioned rats, which is useful in the development of new drugs and therapies for Parkinson's disease (PD).
    Nov. 2011, EJNMMI research, 1(1) (1), 25 - 25, English, International magazine
    Scientific journal

  • Novel System for the Molecular Imaging of Atherosclerotic Plaque with Ga-68-DOTA-ApoA-I Mimetic Peptide (-FAMP)
    Eiji Yahiro, Yoshinari Uehara, Koki Hasegawa, Emi Kawachi, Tsuneo Yano, Yasuyoshi Watanabe, Shin-ichiro Miura, Keijiro Saku
    LIPPINCOTT WILLIAMS & WILKINS, Nov. 2011, CIRCULATION, 124(21) (21), English
    [Refereed]

  • Junko Kawatani, Kei Mizuno, Seishi Shiraishi, Miyuki Takao, Takako Joudoi, Sanae Fukuda, Yasuyoshi Watanabe, Akemi Tomoda
    OBJECTIVES: Cognitive function was investigated in patients with childhood type chronic fatigue syndrome (CCFS) using the modified advanced trail making test (mATMT). METHODS: mATMT was performed on 19 patients with CCFS and 25 healthy controls of comparable age and sex. The effectiveness of combined treatment with cognitive behavioral therapy (CBT) and pharmacotherapy and its relationship to cognitive function was investigated by evaluation of Chalder's fatigue scale and behavior state before and after treatment for 6 consecutive months. RESULTS: All three tasks (motor skill, selective and alternative attention, and spatial working memory) of the mATMT, especially the difference in reaction time of the alternative attention task, could discriminate CCFS patients from control subjects with 70.5% accuracy (P=0.007). CCFS patients showed significantly lower alternative attention and Chalder's fatigue score before treatment (P=0.037 and 0.002, respectively). A significant improvement in performance status scores was found during the 6 months follow-up period with combined treatment with CBT and medication (P<0.001). Improvement of their cognitive symptoms was significantly correlated with improvement of alternative attention (r=0.653, P=0.002). CONCLUSIONS: Higher-order level cognitive dysfunction affects CCFS pathogenesis. Alternative attention performance evaluated by the mATMT may be used to monitor improvement in patients with CCFS. Combined treatment with CBT and medication may be effective to improve poor attention characteristics associated with CCFS.
    Nov. 2011, Brain & development, 33(10) (10), 832 - 41, English, International magazine
    Scientific journal

  • Masaaki Tanaka, Kei Mizuno, Kouzi Yamaguti, Hirohiko Kuratsune, Akira Fujii, Hiromichi Baba, Kazuya Matsuda, Ayako Nishimae, Toshio Takesaka, Yasuyoshi Watanabe
    BACKGROUND: Fatigue is a common symptom in both sick and healthy people. We examined autonomic nervous alterations associated with fatigue to clarify the mechanisms underlying fatigue. METHODS: The study group consisted of 19 healthy participants who performed a 2-back test for 30 min as a fatigue-inducing mental task session. Before and after the session, they completed the advanced trail making test (ATMT) for 30 min for mental fatigue evaluation, subjective scales to measure fatigue sensation, and underwent electrocardiography to allow assessment of autonomic nerve activities. RESULTS: After the fatigue-inducing task, the total error counts on the ATMT tended to increase (P = 0.076); the ATMT for total trial counts (P = 0.001), the subjective level of fatigue (P < 0.001), and the % low-frequency power (%LF) (P = 0.035) increased significantly; and the % high-frequency power (%HF) decreased compared with before the fatigue-inducing task although this did not reach the statistical significance (P = 0.170). Although LF measured in absolute units did not change significantly before and after the fatigue-inducing task (P = 0.771), and HF measured in absolute units decreased after the task (P = 0.020). The %LF and LF/HF ratio were positively associated with the daily level of fatigue evaluated using Chalder's fatigue scale. In addition, %HF was negatively associated with the fatigue score. CONCLUSIONS: Increased sympathetic activity and decreased parasympathetic activity may be characteristic features of both acute and daily levels of fatigue. Our findings provide new perspectives on the mechanisms underlying fatigue.
    Oct. 2011, Behavioral and brain functions : BBF, 7, 46 - 46, English, International magazine
    Scientific journal

  • Tadayuki Takashima, Yoshinobu Hashizume, Yumiko Katayama, Machiko Murai, Yasuhiro Wada, Kazuya Maeda, Yuichi Sugiyama, Yasuyoshi Watanabe
    Telmisartan, a selective angiotensin II receptor antagonist, is primarily excreted via hepatobiliary transport. The predominant contribution of organic anion transporting polypeptide (OATP) 1B3 in its hepatic uptake of telmisartan has been demonstrated by in vitro transport studies. In the present study, a quantitative positron emission tomography (PET) methodology was developed for in vivo kinetic assessment of hepatobiliary transport of telmisartan. Serial abdominal PET scans were performed in rats following intravenous administration of [(11)C]telmisartan as a radiotracer. PET scans revealed that [(11)C]telmisartan was localized primarily in the liver and some of the radioactivity moved to the intestine, which corresponds to biliary excretion. Radiometabolite analysis by radiometric HPLC showed that [(11)C]telmisartan was converted to its acylglucuronide, which was mainly detected in bile, but little in plasma and liver. Integration plot analysis revealed that [(11)C]telmisartan was taken up into the liver as rapidly as the hepatic blood flow rate, and the radiometabolite was subsequently excreted into the bile. When rifampicin, a typical Oatp inhibitor, was coadministered with [(11)C]telmisartan in rats, hepatic uptake clearance of [(11)C]telmisartan was significantly decreased, whereas biliary efflux clearance was not changed. Coinjection with unlabeled telmisartan (4 and 10 mg/kg) also decreased hepatic uptake clearance of [(11)C]telmisartan. On the other hand, PET imaging analysis revealed a significant increase of biliary efflux when telmisartan dose was increased to more than 4 mg/kg. These results suggested that the hepatic uptake of [(11)C]telmisartan mainly consists of a saturable process mediated by Oatps in rats, according to noninvasive real-time measurement of tissue radioactivity with the use of PET. The present study with rats is expected to provide the feasibility of PET imaging study to quantitatively estimate OATP1B3 function in humans.
    Oct. 2011, Molecular pharmaceutics, 8(5) (5), 1789 - 98, English, International magazine
    Scientific journal

  • Masaaki Tanaka, Yoshihito Shigihara, Yasuyoshi Watanabe
    Central fatigue refers to a progressive decline in the ability to activate muscles voluntarily. Although the existence of central inhibition of the motor area via visual feedback during physical fatigue was noted in a behavioral study, neural evidence has not been presented. The central mechanism to regulate physical fatigue was examined using a magnetoencephalographic (MEG) system. The study group consisted of eight healthy participants. They were randomly assigned to two groups in a crossover fashion to perform fatigue-inducing physical task sessions, in which they performed repetitive grips of a dominant hand at maximal voluntary contraction levels every second without using Ramachandran's mirror box to see the dominant hand or with using the mirror box to see the mirror reflection of the non-dominant hand to perceive that the fatigued dominant hand was not fatigued. Before and after each session, imagery of maximum grips of the dominant hand was performed for the evaluation with MEG. Beta-band event-related desynchronization (ERD) level of motor readiness magnetic field in the sensorimotor area in the contralateral hemisphere to the handgrips was not altered after the fatigue-inducing session without or with the mirror box. In contrast, the ERD level of motor movement-evoked magnetic field in the contralateral sensorimotor area was reduced after the fatigue-inducing session without the mirror box, although it was not altered after the session with the mirror box. We identified neural evidence of the central inhibition and showed that the visual feedback system is involved in the central mechanism regulating motor output.
    Sep. 2011, Brain research, 1412, 37 - 43, English, International magazine
    Scientific journal

  • Goto Miki, Mizuma Hiroshi, Wada Yasuhiro, Suzuki Masaaki, Onoe Hirotaka, Watanabe Yasuyoshi, Doi Hisashi
    Capsaicin is a pungent and orally ingested compound which is included especially in red pepper. Capsaicin has a variety of important biological activities to human health such as thermal sensing, perspiration, and pain relief etc.. Furthermore, capsaicin is a symbolic compound of vanilloid family which is associated with a receptor of vanilloid receptor subtype 1 (TRPV1). With the aim of demonstrating in vivo molecular imaging of capsaicin by positron emission tomography (PET), we have synthesized a PET molecule probe of 'IC-labeled capsaicin ([^<11>C]capsaicin) by 0-[^<11>C]methylation using [^<11>C]methyl iodide and a corresponding catechol precursor 1. The purified [^<11>C]capsaicin was intravenously injected in rat and the in vivo behaviors of [^<11>C]capsaicin in rat brain and whole body were observed by micro-PET. Interestingly, [^<11>C]capsaicin penetrated the blood-brain barrier and then was accumulated in the brain for approximately 10 min after the administration. In addition, [^<11>C]capsaicin was also accumulated in rat body surface which might be due to the binding of [^<11>C]capsaicin to TRPV1 receptor in the skin. Thus, the obtained PET images were positively correlated with the previously-reported in vitro and in vivo biological activities of capsaicin. Based on the synthesis of [^<11>C]capsaicin, we intend to further synthesize the diverse PET probes of ^<11>C-labeled capsaicin analogs with the objective of not only PET molecule imaging such as biologically important dietary constituents but also drug development focusing on TRPV1.
    Symposium on the chemistry of natural products, Sep. 2011, Symposium on the Chemistry of Natural Products, symposium papers, (53) (53), 493 - 498, Japanese

  • Hiroyuki Shimada, Suzuka Ataka, Jun Takeuchi, Hiroshi Mori, Yasuhiro Wada, Yasuyoshi Watanabe, Takami Miki
    Amyloid imaging has been used to detect amyloid deposition in the brain. We performed Pittsburgh compound B (PiB)-positron emission tomography on 63 patients with dementia having cognitive decline or memory disturbance. In addition, we measured the patients' apolipoprotein E4 (apo E4) status and cerebrospinal fluid (CSF) levels of amyloid-β (Aβ)1-42, tau, and P-tau. Finally, the patients were diagnosed as having probable Alzheimer disease (AD) on the basis of their neuropsychological findings and because they met the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria. Among the patients diagnosed with probable AD, 10 patients were PiB negative. The CSF levels of P-tau and tau in PiB-negative patients were significantly lower than those in the PiB-positive patients. In addition, the CSF levels of Aβ1-42 in the PiB-negative patients were significantly higher than those in the PiB-positive patients. None of the PiB-negative patients were apo E4 carriers. These results suggest that the PiB-negative patient group included not only AD patients but also non-AD-type dementia patients. However, our finding is based on a relatively small number of patients and therefore should be replicated in a larger cohort. In addition, it will be necessary to categorize these participants by longitudinal follow-up and postmortem pathological examinations.
    Sep. 2011, Journal of geriatric psychiatry and neurology, 24(3) (3), 123 - 6, English, International magazine
    Scientific journal

  • 佐古 健生, 長谷川 功紀, 西村 三恵, 崔 翼龍, 和田 康弘, 林中 恵美, 片岡 洋祐, 千田 道雄, 渡辺 恭良
    (一社)日本核医学会, Sep. 2011, 核医学, 48(3) (3), S273 - S273, Japanese

  • Miho Shukuri, Misato Takashima-Hirano, Keiko Tokuda, Tadayuki Takashima, Kiyoshi Matsumura, Osamu Inoue, Hisashi Doi, Masaaki Suzuki, Yasuyoshi Watanabe, Hirotaka Onoe
    UNLABELLED: Cyclooxygenase (COX)-1 and -2 are prostanoid-synthesizing enzymes that play important roles in the regulation of neuroinflammation and in the development of neurodegenerative disorders. However, the specific functions of these isoforms are still unclear. We recently developed (11)C-labeled ketoprofen methyl ester as a PET probe that targets the COXs for imaging neuroinflammation, though its responsible isoform is yet to be determined. In the present study, we performed ex vivo and in vivo imaging studies with (11)C-ketoprofen methyl ester and determined the contributions of the COX isoforms during the neuroinflammatory process. METHODS: To identify the COX isoform responsible for (11)C-ketoprofen methyl ester in the brain, we examined the ex vivo autoradiography of (11)C-ketoprofen methyl ester using COX-deficient mice. Time-dependent changes in accumulation of (11)C-ketoprofen methyl ester during the neuroinflammatory process were evaluated by PET in rats with hemispheric neuroinflammation induced by intrastriatal injection of lipopolysaccharide or quinolinic acid. In both rat models, cell-type specificity of COX isoform expression during neuroinflammation was identified immunohistochemically. RESULTS: Ex vivo autoradiographic analysis of COX-deficient mice revealed a significant reduction of (11)C-ketoprofen methyl ester accumulation only in COX-1-deficient mice, not COX-2-deficient mice. PET of rats after intrastriatal injection of lipopolysaccharide showed a significant increase in accumulation of (11)C-ketoprofen methyl ester in the inflamed area. This increase was evident at the early phase of 6 h, peaked at day 1, and then returned to basal levels by day 7. In addition, immunohistochemical analysis revealed that the population of activated microglia and macrophages was elevated at the early phase with COX-1 expression but not COX-2. A significant increase in (11)C-ketoprofen methyl ester accumulation was also observed at day 1 after intrastriatal injection of quinolinic acid, with increased COX-1-expressing activated microglia and macrophages. CONCLUSION: We have identified (11)C-ketoprofen methyl ester as a COX-1-selective PET probe, and using this, we have also demonstrated a time-dependent expression of COX-1 in activated microglia and macrophages during the neuroinflammatory process in the living brain. Thus, COX-1 may play a crucial role in the pathology of neuroinflammation and might be a critical target for the diagnosis and therapy of neurodegenerative disorders.
    Jul. 2011, Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 52(7) (7), 1094 - 101, English, International magazine
    Scientific journal

  • Kei Mizuno, Masaaki Tanaka, Sanae Fukuda, Emi Yamano, Yoshihito Shigihara, Kyoko Imai-Matsumura, Yasuyoshi Watanabe
    BACKGROUND: Fatigue is a common complaint among elementary and junior high school students, and is known to be associated with reduced academic performance. Recently, we demonstrated that fatigue was correlated with decreased cognitive function in these students. However, no studies have identified cognitive predictors of fatigue. Therefore, we attempted to determine independent cognitive predictors of fatigue in these students. METHODS: We performed a prospective cohort study. One hundred and forty-two elementary and junior high school students without fatigue participated. They completed a variety of paper-and-pencil tests, including list learning and list recall tests, kana pick-out test, semantic fluency test, figure copying test, digit span forward test, and symbol digit modalities test. The participants also completed computerized cognitive tests (tasks A to E on the modified advanced trail making test). These cognitive tests were used to evaluate motor- and information-processing speed, immediate and delayed memory function, auditory and visual attention, divided and switching attention, retrieval of learned material, and spatial construction. One year after the tests, a questionnaire about fatigue (Japanese version of the Chalder Fatigue Scale) was administered to all the participants. RESULTS: After the follow-up period, we confirmed 40 cases of fatigue among 118 students. In multivariate logistic regression analyses adjusted for grades and gender, poorer performance on visual information-processing speed and attention tasks was associated with increased risk of fatigue. CONCLUSIONS: Reduced visual information-processing speed and poor attention are independent predictors of fatigue in elementary and junior high school students.
    Jun. 2011, Behavioral and brain functions : BBF, 7, 20 - 20, English, International magazine
    Scientific journal

  • Masaaki Tanaka, Yasuyoshi Watanabe
    Central fatigue refers to a progressive decline in the ability to activate muscles voluntarily. Although the neural mechanisms of central inhibition of the motor area during physical fatigue have been widely investigated, mechanisms supporting motor output during fatigue remain to be clarified. In this study, the compensation mechanisms to regulate physical fatigue were examined using a 160-channel whole-head-type magnetoencephalographic (MEG) system. The study group consisted of nine right-handed healthy participants. After enrollment, participants performed a fatigue-inducing physical task session in which they performed repetitive grips of the right hand at maximal voluntary contraction levels every second. Before and after the session, imagery of maximum grips of the right hand was performed for evaluation with MEG. Although beta-band event-related desynchronization (ERD) level of the motor movement-evoked magnetic field in the left sensorimotor area showed a trend toward reduction after the fatigue session, the ERD level of the motor movement-evoked magnetic field in the right sensorimotor area was increased after the session. The ERD level in the prefrontal area was increased after the fatigue-inducing session. The ERD level in the left sensorimotor area was positively associated with that in the right sensorimotor area after the fatigue-inducing task session. In addition, ERD levels in the left and right sensorimotor areas had trends toward positive correlations with that in the prefrontal area. These results suggest that the ipsilateral sensorimotor and prefrontal areas are brain regions associated with compensation mechanisms to support motor output under the condition of physical fatigue.
    Jun. 2011, Brain research, 1395, 46 - 52, English, International magazine
    Scientific journal

  • Kei Mizuno, Masaaki Tanaka, Sanae Fukuda, Kyoko Imai-Matsumura, Yasuyoshi Watanabe
    BACKGROUND: Fatigue is a common complaint among elementary and junior high school students, and is related to poor academic performance. Since grade-dependent development of cognitive functions also influences academic performance, we attempted to determine whether cognitive functions were associated with the prevalence of fatigue. METHODS: Participants were 148 elementary school students from 4th- to 6th-grades and 152 junior high school students from 7th- to 9th-grades. Participants completed a questionnaire about fatigue (Japanese version of the Chalder Fatigue Scale) and paper-and-pencil and computerized cognitive tests which could evaluate the abilities of motor processing, immediate, delayed and working memory, selective, divided and alternative attention, retrieve learned material, and spatial construction. RESULTS: We found that in multivariate logistic regression analyses adjusted for grade and gender, slow motor processing was positively correlated with the prevalence of fatigue in the elementary school students and decreases in working memory and divided and alternative attention processing were positively correlated with the prevalence of fatigue in the junior high school students. CONCLUSION: The grade-dependent development of cognitive function influences the severity of fatigue in elementary and junior high school students.
    Jun. 2011, Brain & development, 33(6) (6), 470 - 9, English, International magazine
    Scientific journal

  • Hitoshi Iimori, Yoshinobu Hashizume, Masahiro Sasaki, Yoshinobu Kajiwara, Yuichi Sugimoto, Yuichi Sugiyama, Yasuyoshi Watanabe, Michio Senda
    OBJECTIVE: Telmisartan, a nonpeptide angiotensin II AT1 receptor antagonist, is an antihypertensive drug. Positron emission tomography (PET) imaging with [(11)C]Telmisartan is expected to provide information about the whole body pharmacokinetics of telmisartan as well as the transport function of hepatic OATP1B3. We developed a first automatic preparation system of [(11)C]Telmisartan to applicable clinical research using a new (11)C and (18)F multipurpose synthesizer. METHODS: Two milligrams of precursor (1) in 5 μl of 1 M KOH in 0.5 ml of dimethyl sulfoxide was reacted with [(11)C]CH(3)I for 5 min at 120°C. The resultant solution was hydrolyzed with 1 M NaOH at 100°C for 3 min. The neutralization was carried out with acetic acid, followed by purification with high-performance liquid chromatography. The desired radioactive fraction was collected and solvent was replaced by 10 ml saline containing 0.3 ml of EtOH and 0.5 ml of PEG400, and then passed through a sterile 0.22 μm filter (Millex-GV, Millipore) to a pyrogen-free vial as the final product. RESULTS: The yield of [(11)C]Telmisartan for clinical research use was 16.8 ± 2.9% EOB as decay corrected (n = 8, mean ± SD) in 32-36 min. The radiochemical purity of [(11)C]Telmisartan was >97%, and specific activity was higher than 86.3 MBq/nmol. CONCLUSIONS: We succeeded in the first synthesis of [(11)C]Telmisartan for clinical research use by appropriate quality tests.
    Jun. 2011, Annals of nuclear medicine, 25(5) (5), 333 - 7, English, Domestic magazine
    Scientific journal

  • Tadayuki Takashima, Chihiro Yokoyama, Hiroshi Mizuma, Hajime Yamanaka, Yasuhiro Wada, Kayo Onoe, Hiroko Nagata, Shusaku Tazawa, Hisashi Doi, Kazuhiro Takahashi, Masataka Morita, Motomu Kanai, Masakatsu Shibasaki, Hiroyuki Kusuhara, Yuichi Sugiyama, Hirotaka Onoe, Yasuyoshi Watanabe
    P-glycoprotein (P-gp) plays a pivotal role in limiting the penetration of xenobiotic compounds into the brain at the blood-brain barrier (BBB), where its expression increases with maturation in rats. We investigated developmental changes in P-gp function in the BBB of nonhuman primates using PET with R-C-11-verapamil, a PET radiotracer useful for evaluating P-gp function. In addition, developmental changes in the brain penetration of C-11-oseltamivir, a substrate for P-gp, was investigated as practical examples. Methods: PET studies in infant (age, 9 mo), adolescent (age, 24-27 mo), and adult (age, 5.6-6.6 y) rhesus monkeys (Macaca mulatta) were performed with R-C-11-verapamil and also with C-11-oseltamivir. Arterial blood samples and PET images were obtained at frequent intervals up to 60 min after administration of the PET tracer. Dynamic imaging data were evaluated by integration plots using data collected within the first 2.5 min after tracer administration. Results: R-C-11-verapamil rapidly penetrated the brain, whereas the blood concentration of intact R-C-11-verapamil decreased rapidly in all subjects. The maximum brain uptake in infant (0.033% +/- 0.007% dose/g of brain) and adolescent (0.020% +/- 0.002% dose/g) monkeys was 4.1- and 2.5-fold greater, respectively, than uptake in adults (0.0082% +/- 0.0007% dose/g). The clearance of brain R-C-11-verapamil uptake in adult monkeys was 0.056 +/- 0.010 mL/min/g, significantly lower than that in infants (0.11 +/- 0.04 mL/min/g) and adolescents (0.075 +/- 0.023 mL/min/g). C-11-oseltamivir showed little brain penetration in adult monkeys, with a clearance of R-C-11-verapamil uptake of 0.0072 and 0.0079 mL/min/g, slightly lower than that in infant (0.0097 and 0.0104 mL/min/g) and adolescent (0.0097 and 0.0098 mL/min/g) monkeys. Conclusion: These results suggest that P-gp function in the BBB changes with development in rhesus monkeys, and this change may be closely related to the observed difference in drug responses in the brains of children and adult humans.
    SOC NUCLEAR MEDICINE INC, Jun. 2011, JOURNAL OF NUCLEAR MEDICINE, 52(6) (6), 950 - 957, English, International magazine
    [Refereed]
    Scientific journal

  • Kei Mizuno, Masaaki Tanaka, Kouzi Yamaguti, Osami Kajimoto, Hirohiko Kuratsune, Yasuyoshi Watanabe
    BACKGROUND: It is known that chronic fatigue is associated with sympathetic hyperactivity. However, the relationship between autonomic function and mental fatigue caused by a prolonged mental load in healthy humans is still unclear. Thus, in order to clarify the mechanisms underlying mental fatigue, we examined the association between mental fatigue and autonomic functions. METHODS: The study group comprised 10 healthy participants. To induce mental fatigue, participants performed mental tasks, which consisted of the advanced trail making test, kana pick-out test and mirror drawing test, for 8 hr, corresponding to a normal work day. Autonomic functions were measured by accelerated plethysmography before and after the fatigue-inducing mental tasks. As a control, the same participants completed an 8-hr relaxation session 4 weeks before the fatigue session. RESULTS: After the 8-hr relaxation session, low-frequency component power (LF), high-frequency component power (HF) and low-frequency component power/high-frequency component power ratio (LF/HF ratio) were not changed from baseline. In contrast, after the fatigue session, the HF and LF/HF ratio were significantly changed from baseline; specifically, the HF was lower and LF/HF ratio was higher as compared to those after the relaxation session. CONCLUSIONS: Sympathetic hyperactivity based on decreased parasympathetic activity is associated with mental fatigue induced by prolonged cognitive load.
    May 2011, Behavioral and brain functions : BBF, 7, 17 - 17, English, International magazine
    Scientific journal

  • Kayo Takahashi, Kayo Onoe, Hisashi Doi, Hiroko Nagata, Gen Yamagishi, Takamitsu Hosoya, Yasuhisa Tamura, Yasuhiro Wada, Hajime Yamanaka, Chihiro Yokoyama, Hiroshi Mizuma, Tadayuki Takashima, Mats Bergström, Hirotaka Onoe, Bengt Långström, Yasuyoshi Watanabe
    In an earlier study in rodents, we showed that the aromatase that converts androgens to estrogens in the preoptic area and bed nucleus of stria terminalis was significantly increased in concentration after exposure to anabolic-androgenic steroids. To confirm whether this occurs in primates, we conducted a positron emission tomographic study using macaque monkeys. Male rhesus monkeys were treated with nandrolone decanoate for 3 weeks. To measure aromatase concentrations, we performed positron emission tomographic imaging using a 11C-labeled specific aromatase inhibitor, [11C]vorozole. After treatment with nandrolone, significant increase in [11C]vorozole binding was observed in the hypothalamus but not other areas including the amygdala, which is also aromatase enriched. These findings in monkeys are consistent with those we obtained earlier in rats. These findings strongly suggest that aromatase in the hypothalamus may play a crucial role in the emotional instability of anabolic-androgenic steroids abusers.
    LIPPINCOTT WILLIAMS & WILKINS, May 2011, Neuroreport, 22(7) (7), 326 - 30, English, International magazine
    [Refereed]
    Scientific journal

  • 新しい分子標的と分子プローブ創製 新規aromataseイメージングPETプローブ
    高橋 佳代, 細谷 孝充, 尾上 嘉代, 長田 浩子, 土居 久志, 和田 康弘, 高島 忠之, 田村 泰久, 渡辺 由美子, 田中 雅彰, 石井 聡, 鈴木 正昭, 尾上 浩隆, 渡辺 恭良
    日本分子イメージング学会, May 2011, JSMI Report, 4(2) (2), 30 - 30, Japanese

  • Progress in axonal and neuronal degenerations of visual pathways in experimental glaucoma monkeys: Imaging studies with PET and DTI
    Hirotaka Onoe, Takuya Hayashi, Masamitsu Shimazawa, Yuta Inokuchi, Yasushi Ito, Hajime Yamanaka, Yasuyoshi Watanabe, Hideaki Hara
    SOC NUCLEAR MEDICINE INC, May 2011, JOURNAL OF NUCLEAR MEDICINE, 52, English

  • Kei Mizuno, Masaaki Tanaka, Sanae Fukuda, Tetsuya Sasabe, Kyoko Imai-Matsumura, Yasuyoshi Watanabe
    BACKGROUND: When students proceed to junior high school from elementary school, rapid changes in the environment occur, which may cause various behavioral and emotional problems. However, the changes in cognitive functions during this transitional period have rarely been studied. METHODS: In 158 elementary school students from 4th- to 6th-grades and 159 junior high school students from 7th- to 9th-grades, we assessed various cognitive functions, including motor processing, spatial construction ability, semantic fluency, immediate memory, delayed memory, spatial and non-spatial working memory, and selective, alternative, and divided attention. RESULTS: Our findings showed that performance on spatial and non-spatial working memory, alternative attention, divided attention, and semantic fluency tasks improved from elementary to junior high school. In particular, performance on alternative and divided attention tasks improved during the transitional period from elementary to junior high school. CONCLUSION: Our finding suggests that development of alternative and divided attention is of crucial importance in the transitional period from elementary to junior high school.
    May 2011, Brain & development, 33(5) (5), 412 - 20, English, International magazine
    Scientific journal

  • Misato Takashima-Hirano, Tadayuki Takashima, Yumiko Katayama, Yasuhiro Wada, Yuichi Sugiyama, Yasuyoshi Watanabe, Hisashi Doi, Masaaki Suzuki
    Synthesis of [(11)C]celecoxib, a selective COX-2 inhibitor, and [(11)C]SC-62807, a major metabolite of celecoxib, were achieved and the potential of these PET probes for assessing the function of drug transporter in biliary excretion was evaluated. The synthesis of [(11)C]celecoxib was achieved in one-pot by reacting [(11)C]methyl iodide with an excess of the corresponding pinacol borate precursor using Pd(2)(dba)(3), P(o-tolyl)(3), and K(2)CO(3) (1:4:9) in DMF. The radiochemical yield of [(11)C]celecoxib was 63±23% (decay-corrected, based on [(11)C]CH(3)I) (n=7) with a specific radioactivity of 83±23GBq/μmol (n=7). The average time of synthesis from end of bombardment including formulation was 30min with >99% radiochemical purity. [(11)C]SC-62807 was synthesized from [(11)C]celecoxib by further rapid oxidation in the presence of excess KMnO(4) with microwave irradiation. The radiochemical yield of [(11)C]SC-62807 was 55±9% (n=3) (decay-corrected, based on [(11)C]celecoxib) with a specific radioactivity of 39±4GBq/μmol (n=3). The average time of synthesis from [(11)C]celecoxib including formulation was 20min and the radiochemical purity was >99%. PET studies in rats and the metabolite analyzes of [(11)C]celecoxib and [(11)C]SC-62807 showed largely different excretion processes, and consequently, [(11)C]SC-62807 was rapidly excreted via hepatobiliary excretion without further metabolism. [(11)C]SC-62807 was shown to have a high potential as a PET probe for evaluating drug transporter function in biliary excretion.
    May 2011, Bioorganic & medicinal chemistry, 19(9) (9), 2997 - 3004, English, International magazine
    [Refereed]
    Scientific journal

  • 早期緑内障サルの外側膝状体内ミクログリアの活性化
    嶋澤 雅光, 井口 勇太, 伊藤 保志, 山中 創, 林 拓也, 季 斌, 樋口 真人, 須原 哲也, 今村 一之, 新家 眞, 渡辺 恭良, 尾上 浩隆, 原 英彰
    日本分子イメージング学会, May 2011, JSMI Report, 4(2) (2), 130 - 130, Japanese
    [Refereed]

  • 拡散テンソル画像でみた神経変性動態 緑内障視神経障害モデル動物における観察
    林 拓也, 原 英彰, 嶋澤 雅光, 井口 勇太, 伊藤 保志, 合瀬 恭幸, 渡部 浩司, 飯田 英博, 山中 創, 渡辺 恭良, 尾上 浩隆
    日本分子イメージング学会, May 2011, JSMI Report, 4(2) (2), 92 - 92, Japanese
    [Refereed]

  • PETを用いた核酸医薬DDSの動態評価 クリック化学法による18F-標識化オリゴヌクレオチドの有用性の実証
    向井 英史, 尾崎 大起, 長田 浩子, 崔 翼龍, 窪山 剛之, 和田 康弘, 今西 武, 兒玉 哲也, 小比賀 聡, 鈴木 正昭, 土居 久志, 渡辺 恭良
    日本DDS学会, May 2011, Drug Delivery System, 26(3) (3), 294 - 294, Japanese

  • 脳内炎症の分子イメージングと片頭痛病態
    崔 翼龍, 高島 忠之, 高島 好聖, 佐古 健生, 奥山 香里, 林中 恵美, 和田 康弘, 土居 久志, 渡辺 恭良, 片岡 洋祐
    日本分子イメージング学会, May 2011, JSMI Report, 4(2) (2), 47 - 47, Japanese

  • ソマトスタチンアナログを用いた膵内分泌細胞PETイメージング
    佐古 健生, 長谷川 功紀, 西村 三恵, 崔 翼龍, 和田 康弘, 林中 恵美, 片岡 洋祐, 千田 道雄, 渡辺 恭良
    日本分子イメージング学会, May 2011, JSMI Report, 4(2) (2), 98 - 98, Japanese

  • 脳内炎症の分子イメージングと片頭痛病態
    崔 翼龍, 高島 忠之, 高島 好聖, 佐古 健生, 奥山 香里, 林中 恵美, 和田 康弘, 土居 久志, 渡辺 恭良, 片岡 洋祐
    日本分子イメージング学会, May 2011, JSMI Report, 4(2) (2), 126 - 126, Japanese

  • 田沢 周作, 長谷川 功紀, 高橋 和弘, 矢野 恒夫, 渡辺 恭良
    (株)じほう, Mar. 2011, PHARM TECH JAPAN, 27(3) (3), 431 - 440, Japanese

  • Yasushi Ito, Masamitsu Shimazawa, Yuta Inokuchi, Hajime Yamanaka, Kazuhiro Tsuruma, Kazuyuki Imamura, Hirotaka Onoe, Yasuyoshi Watanabe, Makoto Aihara, Makoto Araie, Hideaki Hara
    We investigated whether endoplasmic reticulum (ER) stress was involved in the pathophysiological mechanisms underlying neuronal death of the lateral geniculate nucleus (LGN) after intraocular pressure (IOP) elevation. Five cynomolgus monkeys, four with a glaucomatous left eye after laser photocoagulation treatment and one normal monkey, were studied. At 4, 11, 15 and 24 weeks after the laser photocoagulation treatment, the numbers of LGN neurons and atrophy were immunohistochemically evaluated using anti-parvalbumin-antibody, which was used to specifically label relay neurons connecting to the visual cortex. In addition, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells, polyubiquitin, and production of ER stress-related proteins, such as the phosphorylation of eukaryotic initiation factor 2α (p-eIF2α) and C/EBP-homologous protein (CHOP), were also measured using in situ hybridization and immunostaining. Loss of neurons and/or neuronal atrophy in layers 1, 4 and 6 of the LGN on the contralateral side were observed at 4-24 weeks after the laser photocoagulation treatment. Furthermore, the retinal input from the high IOP eye projected to layers 2 (magnocellular layer), 3 and 5 (parvocellular layer) on the ipsilateral side. Neuronal damage was also confirmed in these layers. In the LGN region, TUNEL-positive cells, polyubiquitin, p-eIF2α and CHOP were also detected at 11-24 weeks after the laser photocoagulation treatment. These findings indicate that ER stress may play a pivotal role in neuronal death of the LGN after IOP elevation.
    Mar. 2011, The European journal of neuroscience, 33(5) (5), 843 - 55, English, International magazine
    Scientific journal

  • Positron Emission Tomography(PET)を用いた薬物の体内動態評価 薬物の消化管吸収過程の解析
    片岡 誠, 高島 忠之, 新垣 友隆, 政岡 祥江, 佐久間 信至, 片山 由美子, 林中 恵美, 崔 翼龍, 和田 康弘, 渡辺 恭良, 山下 伸二
    (公社)日本薬学会, Mar. 2011, 日本薬学会年会要旨集, 131年会(4) (4), 200 - 200, Japanese

  • Kayo Takahashi, Gen Yamagishi, Toshiyuki Hiramatsu, Ayako Hosoya, Kayo Onoe, Hisashi Doi, Hiroko Nagata, Yasuhiro Wada, Hirotaka Onoe, Yasuyoshi Watanabe, Takamitsu Hosoya
    A practical method to prepare precursor of [N-methyl-(11)C]vorozole ([(11)C]vorozole), an efficient positron emission tomography (PET) tracer for imaging aromatase in the living body, was established. Sufficient amount of the racemate including norvorozole, a demethylated vorozole derivative used as a precursor of [(11)C]vorozole, became available by means of high-yield eight-step synthesis. The enantiomers were separated by preparative HPLC using a chiral stationary phase column to give optically pure norvorozole and its enantiomer. From the latter, ent-[(11)C]vorozole, an enantiomer of [(11)C]vorozole, was prepared and used in the PET study for the first time, which was shown to bind very weakly to aromatase in rhesus monkey brain supporting the previous pharmacological results. The stable supply of norvorozole will facilitate further researches on aromatase in the living body including brain by the PET technique.
    Feb. 2011, Bioorganic & medicinal chemistry, 19(4) (4), 1464 - 70, English, International magazine
    Scientific journal

  • Shinji Yamashita, Tadayuki Takashima, Makoto Kataoka, Hiroyuki Oh, Shinji Sakuma, Masayuki Takahashi, Norio Suzuki, Emi Hayashinaka, Yasuhiro Wada, Yilong Cui, Yasuyoshi Watanabe
    This study assessed the process of gastrointestinal drug absorption in vivo using PET. Methods: F-18-FDG was used as a model probe and was orally administered to rats as a solution. PET scans were obtained of the whole body and abdominal region under conscious and anesthetized conditions. Blood samples were routinely taken from the femoral vein during scanning. The rate of gastric emptying and intestinal absorption of F-18-FDG was estimated from the time profiles of radioactivity in the stomach and small intestine. In addition, nonradiolabeled 2-fluoro-2-deoxy-D-glucose (2-FDG) was used in an intestinal closed-loop experiment to compare the intestinal permeability of 2-FDG with that of D-glucose. Results: In conscious rats, gastrointestinal absorption of F-18-FDG was rate-limited by the process of intestinal membrane permeation, because the permeability of 2-FDG through the intestinal membrane was low compared with that of D-glucose. In anesthetized rats, the gastric emptying rate of F-18-FDG decreased dramatically whereas the intestinal absorption rate constant was not significantly different from that in conscious rats. As a result, the rate-limiting step of gastrointestinal absorption of F-18-FDG was shifted to the gastric emptying process by anesthesia. Conclusion: PET technology is a powerful tool for in vivo analysis of the gastrointestinal absorption of orally administered drugs.
    SOC NUCLEAR MEDICINE INC, Feb. 2011, JOURNAL OF NUCLEAR MEDICINE, 52(2) (2), 249 - 256, English, International magazine
    [Refereed]
    Scientific journal

  • Kei Mizuno, Masaaki Tanaka, Sanae Fukuda, Kyoko Imai-Matsumura, Yasuyoshi Watanabe
    BACKGROUND: Decrease in intrinsic motivation is a common complaint among elementary and junior high school students, and is related to poor academic performance. Since grade-dependent development of cognitive functions also influences academic performance by these students, we examined whether cognitive functions are related to the prevalence of decrease in intrinsic academic motivation. METHODS: The study group consisted of 134 elementary school students from 4th to 6th grades and 133 junior high school students from 7th to 9th grades. Participants completed a questionnaire on intrinsic academic motivation. They also performed paper-and-pencil and computerized cognitive tests to measure abilities in motor processing, spatial construction, semantic fluency, immediate memory, short-term memory, delayed memory, spatial working memory, and selective, alternative, and divided attention. RESULTS: In multivariate logistic regression analyses adjusted for grade and gender, scores of none of the cognitive tests were correlated with the prevalence of decrease in intrinsic academic motivation in elementary school students. However, low digit span forward test score and score for comprehension of the story in the kana pick-out test were positively correlated with the prevalence of decrease in intrinsic academic motivation in junior high school students. CONCLUSIONS: The present findings suggest that decrease in capacity for verbal memory is associated with the prevalence of decrease in intrinsic academic motivation among junior high school students.
    Jan. 2011, Behavioral and brain functions : BBF, 7, 4 - 4, English, International magazine
    Scientific journal

  • Akira Ishii, Masaaki Tanaka, Emi Yamano, Yasuyoshi Watanabe
    ELSEVIER IRELAND LTD, 2011, NEUROSCIENCE RESEARCH, 71, E268 - E268, English
    [Refereed]

  • Yasuhito Nakatomi, Kei Mizuno, Akira Ishii, Yasuhiro Wada, Masaaki Tanaka, Shusaku Tazawa, Kayo Onoe, Sanae Fukuda, Joji Kawabe, Kazuhiro Takahashi, Yosky Kataoka, Susumu Shiomi, Kouzi Yamaguti, Masaaki Inaba, Hirohiko Kuratsune, Yasuyoshi Watanabe
    ELSEVIER IRELAND LTD, 2011, NEUROSCIENCE RESEARCH, 71, E199 - E199, English
    [Refereed]

  • Current Practice of producing Cu-64-DOTA-Trastuzumab Injections in RIKEN CMIS according to GMP for Investigational Products
    Shusaku Tazawa, Koki Hasegawa, Yousuke Kanayama, Riyo Zochi, Yoko Morimoto, Kazutaka Hayashi, Akiko Tachibana, Kazuhiro Takahashi, Tsuneo Yano, Yasuyoshi Watanabe
    WILEY-BLACKWELL, 2011, JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS, 54, S160 - S160, English
    [Refereed]

  • Takeshi Kuboyama, Motoi Nakahara, Masafumi Yoshino, Yilong Cui, Takeo Sako, Yasuhiro Wada, Takeshi Imanishi, Satoshi Obika, Yasuyoshi Watanabe, Masaaki Suzuki, Hisashi Doi
    A novel method for (18)F-radiolabeling of oligodeoxynucleotides (ODNs) by a Cu-catalyzed Huisgen reaction has been developed by using the lowest possible amount of the precursor biomolecule for the realization of stoichiometry-oriented PET (positron emission tomography) chemistry. Under the optimized cyclization conditions of p- or m-azido([(18)F]fluoromethyl)benzene and alkyne-substituted ODN (20nmol) at 40°C for 15min in the presence of CuSO(4), TBTA [tris((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)amine], and sodium ascorbate (2:1:2), the synthesis of (18)F-labeled ODNs with sufficiently high radioactivities of 2.1-2.5GBq and specific radioactivities of 1800-2400GBq/μmol have been accomplished for use in animal and human PET studies.
    Jan. 2011, Bioorganic & medicinal chemistry, 19(1) (1), 249 - 55, English, International magazine
    Scientific journal

  • Masayuki Kobayashi, Tetsuya Sasabe, Yoshihito Shigihara, Masaaki Tanaka, Yasuyoshi Watanabe
    Our experience and prejudice concerning food play an important role in modulating gustatory information processing; gustatory memory stored in the central nervous system influences gustatory information arising from the peripheral nervous system. We have elucidated the mechanism of the "top-down" modulation of taste perception in humans using functional magnetic resonance imaging (fMRI) and demonstrated that gustatory imagery is mediated by the prefrontal (PFC) and insular cortices (IC). However, the temporal order of activation of these brain regions during gustatory imagery is still an open issue. To explore the source of "top-down" signals during gustatory imagery tasks, we analyzed the temporal activation patterns of activated regions in the cerebral cortex using another non-invasive brain imaging technique, magnetoencephalography (MEG). Gustatory imagery tasks were presented by words (Letter G-V) or pictures (Picture G-V) of foods/beverages, and participants were requested to recall their taste. In the Letter G-V session, 7/9 (77.8%) participants showed activation in the IC with a latency of 401.7±34.7 ms (n = 7) from the onset of word exhibition. In 5/7 (71.4%) participants who exhibited IC activation, the PFC was activated prior to the IC at a latency of 315.2±56.5 ms (n = 5), which was significantly shorter than the latency to the IC activation. In the Picture G-V session, the IC was activated in 6/9 (66.7%) participants, and only 1/9 (11.1%) participants showed activation in the PFC. There was no significant dominance between the right and left IC or PFC during gustatory imagery. These results support those from our previous fMRI study in that the Letter G-V session rather than the Picture G-V session effectively activates the PFC and IC and strengthen the hypothesis that the PFC mediates "top-down" control of retrieving gustatory information from the storage of long-term memories and in turn activates the IC.
    2011, PloS one, 6(7) (7), e21736, English, International magazine
    Scientific journal

  • Positron Emission Tomography (PET) study for the evaluation of in vivo hepatobiliary transport using [11C] telmisartan
    Tadayuki Takashima, Yoshinobu Hashizume, Hisashi Doi, Yasuhiro Wada, Yasuyoshi Watanabe, Michio Senda, Tomohiko Yamane, Masahiro Sasaki, Keiji Shimizu, Akemi Iwamoto, Hiromitsu Kageyama, Kazuya Maeda, Hiroyuki Kusuhara, Yuichi Sugiyama
    Dec. 2010, Japanese Pharmacology and Therapeutics, 38(2) (2), S103 - S109, Japanese
    International conference proceedings

  • Narumi Katsuyama, Kazuyuki Imamura, Hirotaka Onoe, Hide-Ki Tanaka, Kayo Onoe, Hideo Tsukada, Yasuyoshi Watanabe
    Physiological and lesion studies have shown that the anterior inferior temporal (IT) cortex (aITC) is involved in the color vision of macaque monkeys. However, some functional imaging studies using awake monkeys contradicted the involvement of aITC in color vision. Thus, in most of the imaging studies, cortical activation has been observed during a fixation task. However, because the neuronal activity of aITC is highly affected by the behavioral task, it is desirable to investigate cortical activity during a color discrimination task to determine the functional role of aITC in the color vision of macaque monkeys. In this study, we investigated the cortical activity of aITC of macaque monkeys during color discrimination by positron emission tomography. Two monkeys were trained in a color discrimination task. Cortical areas involved in color processing were investigated by comparing activities during the color discrimination and lever release tasks. In addition to area V4 and the posterior IT cortex (pITC), we found color-related activities in the anterior IT gyrus. Consistent activation was observed in the region posterior to the anterior medial temporal sulcus (AMTS), although the exact location and the size of activations differed between monkeys and hemispheres. We also found color-related activities in the anterior portion of the superior temporal sulcus (STS), suggesting its involvement in the color vision. The present results revealed that aITC is involved in the color vision of macaque monkeys by a functional imaging technique.
    Nov. 2010, Neuroscience letters, 484(3) (3), 168 - 73, English, International magazine
    Scientific journal

  • Tadayuki Takashima, Hiroko Nagata, Takahiro Nakae, Yilong Cui, Yasuhiro Wada, Satoshi Kitamura, Hisashi Doi, Masaaki Suzuki, Kazuya Maeda, Hiroyuki Kusuhara, Yuichi Sugiyama, Yasuyoshi Watanabe
    A quantitative positron emission tomography (PET) methodology was developed for in vivo kinetic analysis of hepatobiliary transport. Serial abdominal PET scans were performed on normal and multidrug resistance-associated protein 2 (Mrp2)-deficient rats after intravenous injection of (15R)-16-m-[C-11]tolyl-17,18,19,20-tetranorisocarbacyclin methyl ester (15R-[C-11]TIC-Me) as a radiotracer. 15R-[C-11]TIC-Me was rapidly converted to its acid form in blood within 10 s. PET scans revealed that 15R-[C-11]TIC was localized mainly in the liver within 5 min of injection. By 90 min, total radioactivity in bile of Mrp2-deficient rats was significantly reduced compared with controls. Metabolite analysis by thin-layer chromatography autoradiography showed that 15R-[C-11]TIC is converted to at least three metabolites (M1, M2, and M3), and M2 and M3 are the major metabolites in plasma and bile, respectively. Hepatic uptake clearance of total radioactivity in normal rats was close to the hepatic blood flow rate and slightly higher than that in Mrp2-deficient rats. The intrinsic canalicular efflux clearance of M3 (CLint,bile,M3) in Mrp2-deficient rats was decreased to 12% of controls, whereas clearance of M2 was moderately decreased (54%). An in vitro transport assay detected ATP-dependent uptake of both M2 and M3 by rat Mrp2-expressing membrane vesicles. These results demonstrated that M3 is excreted primarily into the bile by Mrp2 in normal rats. We conclude that PET studies using 15R-[C-11]TIC-Me could be useful for in vivo analyses of Mrp2-mediated hepatobiliary transport.
    AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS, Nov. 2010, JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 335(2) (2), 314 - 323, English, International magazine
    [Refereed]
    Scientific journal

  • Katsunori Tanaka, Eric R O Siwu, Kaori Minami, Koki Hasegawa, Satoshi Nozaki, Yousuke Kanayama, Koichi Koyama, Weihsu C Chen, James C Paulson, Yasuyoshi Watanabe, Koichi Fukase
    Oct. 2010, Angewandte Chemie (International ed. in English), 49(44) (44), 8195 - 200, English, International magazine
    Scientific journal

  • [Microdose clinical trial--impact of PET molecular imaging].
    Tsuneo Yano, Yasuyoshi Watanabe
    Microdose (MD) clinical trial and exploratory IND study including sub-therapeutic dose and therapeutic dose which are higher than microdoses are expected to bring about innovations in drug development. The outlines of guidances for microdose clinical trial and ICH-M3 (R2) issued by the MHLW in June, 2008, and February, 2010, are first explained, respectively, and some examples of their application to clinical developments of therapeutic drugs in the infection and cancer fields are introduced. Especially, thanks to the progress of molecular imaging research, a new field of drug development is explored by using imaging biomarkers for efficacy or safety evaluation which visualize biomarkers by PET imaging agents. Finally, the roadmap for drug development in infection and cancer fields utilizing PET molecular imaging is discussed.
    Oct. 2010, Gan to kagaku ryoho. Cancer & chemotherapy, 37(10) (10), 1839 - 48, Japanese, Domestic magazine
    Scientific journal

  • Tanaka Katsunori, Minami Kaori, Siwu Eric R. O., Masuyama Tatsuro, Koyama Koichi, Yokoi Satomi, Hasegawa Koki, Tahara Tsuyoshi, Mizuma Hiroshi, Nozaki Satoshi, Kanayama Yousuke, Wada Yasuhiro, Onoe Hirotaka, Watanabe Yasuyoshi, Fukase Koichi
    New labeling probes of fluorescenced and ^<68>Ga-DOTA, as the positron emission nucleus for PET, througn rapid 6π-azaelectrocyclization were designed and synthesized, (E)-ester aldehydes 1. The high reactivity of these probes enabled the labeling of lysine residues in peptides, proteins, and even the amino groups on the cell surfaced at very low concentration (-10^<-8>M) within a short recation time (-10min) to result in "selective" and "non-destructive" labeling of the more accessible amines. The first microPET of glycoproteins, ^<68>Ga-DOTA-orosomucoid and asialoorosomucoid successfully visualized the differences in the circulatory residence of glycoproteins, in the presence or absence of the sialic acids. New N-glycan clusters with MW of 50KDa were also developed and their in vivo dynamics, being affected significantly by their glycan structures, could be visualized through the present amine-labeling & PET and/or noninvasive fluorescence imaging. The azaelectrocyclization-based biocojugation is also applicable to the engineering of the proteins and/or the cell surfaces by the oligosacchrides; the chemically engineered lymphocytes by N-glycan sussessfully traget the tumor tissue implanted in the BALB/c nude mice, based on the noninvasive fluorescence imaging.
    Symposium on the chemistry of natural products, Sep. 2010, Symposium on the Chemistry of Natural Products, symposium papers, (52) (52), 25 - 30, Japanese

  • Goto Miki, Mizuma Hiroshi, Wada Yasuhiro, Onoe Hirotaka, Watanabe Yasuyoshi, Suzuki Masaaki, Doi Hisashi
    Flavonoids are orally ingested compounds, which contained ubiquitously in plant foods. Their benefits to human health are attributed to a variety of the biological activities such as antioxidant, anticarcinogenic, anti-inflammatory, immune-stimulating, and arteriosclerosis inhibiting effects etc. With the aim of in vivo molecular imaging of flavonoids by positron emission tomography (PET), we have syntehsized a PET probe of ^<11>C-labeld flavone [^<11>C]-2 in high yield by our Pd^0-mediated rapic C-[^<11>C]-methylation using [^<11>C]methyl iodide and a corresponding organoboron precursor 1. [^<11>C]-2 was intravenous injected in rat, and in vivo behavior of [^<11>C]-2 in the brain and whole body were observed by micro-PET. As results, [^<11>C]-2 penetrated the blood-brain barrier and then was accumulated in the brain at 1-5 min after the administration. On the other hand, a metabolite of ^<11>C-labeld flavone [^<11>C]-2 was accumulated in the nasal cavity. These PET images are currently in the process of analyzing, compared to the previously-reported biological activities of flavonids. Based on the synthesis of [^<11>C]-2, we intend to construct the PET prove library of flavonoids, which will be useful for development of new methodologies for disease and promotion of drug development process.
    Symposium on the chemistry of natural products, Sep. 2010, Symposium on the Chemistry of Natural Products, symposium papers, (52) (52), 259 - 264, Japanese

  • PETプローブ経口投与時のPET撮像の検討
    和田 康弘, 高島 忠之, 林中 恵美, 片岡 誠, 片山 由美子, 新垣 友隆, 崔 翼龍, 山下 伸二, 渡邊 恭良
    (一社)日本核医学会, Sep. 2010, 核医学, 47(3) (3), 390 - 391, Japanese

  • Nobue Shishioh-Ikejima, Tokiko Ogawa, Kouzi Yamaguti, Yasuyoshi Watanabe, Hirohiko Kuratsune, Hiroshi Kiyama
    BACKGROUND: Despite extensive research, no reliable biological marker for chronic fatigue syndrome (CFS) has yet been identified. However, hyperactivation of melanotrophs in the pituitary gland and increased levels of plasma alpha-melanocyte-stimulating hormone (alpha-MSH) have recently been detected in an animal model of chronic stress. Because CFS is considered to be caused partly by chronic stress events, increased alpha-MSH plasma levels may also occur in CFS patients. We therefore examined alpha-MSH levels in CFS patients. METHODS: Fifty-five CFS patients, who were previously diagnosed within 10 years of with the disease, were enrolled in this study. Thirty healthy volunteers were studied as controls. Fasting bloods samples were collected in the morning and evaluated for their plasma levels of alpha-MSH, adrenocorticotropic hormone (ACTH), serum cortisol and dehydroepiandrosterone sulfate (DHEA-S). Mean levels of alpha-MSH were compared between the CFS and control groups using Welch's t test. RESULTS: The mean plasma alpha-MSH concentration in the CFS group (17.9 +/- 1.0 pg/mL) was significantly higher than that in healthy controls (14.5 +/- 1.0 pg/mL, p = 0.02). However, there was a wide range of values in the CFS group. The factors correlated with the plasma alpha-MSH values were analyzed using Spearman's rank correlation. A negative correlation was found between the duration of the CFS and the plasma alpha-MSH values (p = 0.04, rs = -0.28), but no correlations with ACTH, cortisol or DHEA-S levels were identified (p = 0.55, 0.26, 0.33, respectively). The CFS patients were divided into two groups: patients diagnosed for Aug. 2010, BMC neurology, 10, 73 - 73, English, International magazine
    Scientific journal

  • Noriyasu Kamei, Mariko Morishita, Yousuke Kanayama, Koki Hasegawa, Mie Nishimura, Emi Hayashinaka, Yasuhiro Wada, Yasuyoshi Watanabe, Kozo Takayama
    Molecular imaging technique by use of positron emission tomography (PET) is a noninvasive tool that allows one to quantitatively analyze the function of endogenous molecules and the pharmacokinetics of therapeutic agents in vivo. This technique is expected to be useful for evaluating the effectiveness of diverse drug delivery systems. We demonstrated previously that intestinal insulin absorption is increased significantly by coadministration of cell-penetrating peptides (CPPs), which are taken up effectively by several cells. However, the distribution behavior of insulin whose absorption is increased by CPPs is not clear. We used PET imaging and quantitatively analyzed the intestinal absorption and subsequent distribution of insulin and the effect of CPPs on its absorption and distribution. An unlabeled insulin solution containing tracer insulin, (68)Ga-DOTA-insulin, was administered with or without CPPs into a rat ileal closed loop. PET imaging showed that the CPPs, particularly D-R8 and L-penetratin, significantly increased the (68)Ga-DOTA-insulin level in the liver, kidney, and circulation. After absorption from the intestine, the (68)Ga-DOTA-insulin passed rapidly through the liver and accumulated in the kidney. The increase in the hepatic and renal distribution of (68)Ga-DOTA-insulin by each CPP coadministration was similar manner as that in intestinal absorption, suggesting that the increased accumulation of insulin in the liver and kidney induced by coadministration of CPPs was associated with the increased intestinal absorption of insulin. This is the first study to show that PET imaging enables one to quantitatively analyze the distribution behavior of intestinally absorbed insulin in several organs. This imaging methodology is likely to be useful for developing effective drug delivery systems targeted to specific organs.
    Aug. 2010, Journal of controlled release : official journal of the Controlled Release Society, 146(1) (1), 16 - 22, English, International magazine
    Scientific journal

  • Masaaki Tanaka, Yasuyoshi Watanabe
    Chronic fatigue syndrome is an illness characterized by a profound, disabling, and unexplained sensation of fatigue lasting at least 6 months, which severely impairs daily functioning and is accompanied by a combination of non-specific symptoms. Many potential causes of chronic fatigue syndrome have been investigated, including viral infections, immune dysfunctions, abnormal neuroendocrine responses, central nervous system abnormalities, autonomic dysfunctions, impaired exercise capacities, sleep disruptions, genetic backgrounds, psychiatric abnormalities, personality, and abnormal psychological processes. However, no etiology, specific physical signs or laboratory test abnormalities have been found. It is essential to establish a conceptual theory of chronic fatigue syndrome that can explain its pathophysiology in order to identify the clinical entity and to develop effective treatment methods. In this article, a new conceptual hypothesis about the pathophysiology of chronic fatigue syndrome, the co-conditioning theory, is presented: after repetitive overwork and/or stress, alarm signal to rest and fatigue sensation may cause in response to an unconditioned stimulus (impaired homeostasis and function) that has been paired with a conditioned stimulus (overwork and/or stress). In the future, a new treatment strategy for patients with chronic fatigue syndrome, re-co-conditioning therapy, may be developed on the basis of the co-conditioning theory. In addition, this theory will likely contribute to a better understanding of the pathophysiology of chronic fatigue syndrome.
    Aug. 2010, Medical hypotheses, 75(2) (2), 244 - 9, English, International magazine
    Scientific journal

  • 片頭痛病態モデルラットを用いた疼痛伝達回路の解析(Analysis of nociceptive pathway in a rat model of migraine using small-animal PET)
    崔 翼龍, 佐古 健生, 豊田 浩士, 奥山 香里, 尾上 嘉代, 林中 恵美, 和田 康弘, 渡辺 恭良, 片岡 洋祐
    日本神経化学会, Aug. 2010, 神経化学, 49(2-3) (2-3), 757 - 757, English

  • Hiroshi Mizuma, Miho Shukuri, Takuya Hayashi, Yasuyoshi Watanabe, Hirotaka Onoe
    UNLABELLED: In vivo imaging, such as PET, requires restriction of body movements and is generally conducted under sedation by anesthetic agents in studies using laboratory animals. Because anesthetics reduce neural activity and metabolism, physiologic neural functions are difficult to assess in animal PET studies. Therefore, use of an appropriate method in conscious animals is important and is a practical requirement for physiologic in vivo brain imaging studies. Here, we established an in vivo imaging system for conscious mice to reveal the physiologic regional cerebral glucose metabolic rate (rCMRglu) with (18)F-FDG PET. METHODS: We first developed a head holder to enable brain PET of a conscious mouse. To obtain optimal rCMRglu, we examined the effects of physical and psychologic stresses caused by ambient temperature, intravenous injection, and acclimation to the apparatus and immobile state. Finally, quantitative kinetic analysis was performed for rCMRglu based on a 2-tissue-compartment model with an input function of arterial blood sampling under both conscious and anesthetized (1.5% isoflurane) conditions. RESULTS: Increasing the ambient temperature increased uptake of (18)F-FDG in the brain significantly while reducing the uptake in skeletal muscle and brown adipose tissue that was caused by shivering. The reduction of brain (18)F-FDG uptake caused by tail holding and manual injection was significantly ameliorated by the use of an automated slow injection. Although brain uptake of (18)F-FDG varied at the first session of PET, uptake at the second and subsequent sessions was stable, even after long-term acclimation. After these beneficial changes, brain uptake of (18)F-FDG improved significantly, to approximately 260% above the preconditioned state, which is comparable with that obtained in mice that have been allowed to move freely about their home cages. Quantitative kinetic analyses revealed that isoflurane anesthesia lowered rCMRglu in the cerebral cortex, striatum, thalamus, and cerebellum by 66%, 59%, 62%, and 22%, respectively, mainly by reducing the k(3) value, a rate constant for phosphorylation by hexokinase. CONCLUSION: To our knowledge, this is the first study to report quantitative kinetic analysis of rCMRglu in mice that have been conscious throughout PET. This investigation will open avenues for research into in vivo functional brain molecular imaging in both normal and genetically manipulated mice.
    Jul. 2010, Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 51(7) (7), 1068 - 75, English, International magazine
    Scientific journal

  • 長谷川 功紀, 渡辺 恭良
    (有)科学評論社, Jul. 2010, 腫瘍内科, 6(1) (1), 86 - 92, Japanese

  • Toshikatsu Shimizu, Hiroshi Hoshino, Shugo Nishi, Satoshi Nozaki, Yasuyoshi Watanabe
    The anti-fatigue effect of dicethiamine hydrochloride (DCET) was assessed and compared to that of thiamine hydrochloride (VB(1)HCl) in rats. The absorbability and tissue distribution of thiamine after oral administration of DCET and VB(1)HCl were also examined. To create fatigued animals, male SD rats were placed in plastic cages containing 1.5cm of water for 5 consecutive days. The extent of fatigue was evaluated by a weight-loaded forced swimming test. After oral administration of DCET or VB(1)HCl to non-fatigued rats, blood and tissues were serially collected to determine the concentrations of thiamine and its phosphate esters. Pharmacokinetic analysis was performed to examine the thiamine profile in the body after administration of DCET or VB(1)HCl. Swimming time was significantly shorter for the fatigued vehicle group than the non-fatigued group. DCET (30 and 100mg/kg) significantly prolonged the swimming time compared to the fatigued vehicle group. The anti-fatigue effect of VB(1)HCl (70.1mg/kg) was not significant in our set of results. Both DCET and VB(1)HCl were rapidly absorbed into the circulating blood as thiamine and eventually became localized in the organs. Thiamine was distributed at higher concentrations to the blood, heart, thigh muscles, cerebellum, hippocampus, and thalamus after administration of DCET compared to VB(1)HCl. These results indicate that DCET is a vitamin B(1) derivative that has excellent absorbability and transformability in tissues and suggest that DCET as an oral therapy may be useful against combined mental and physical fatigue, such as that often encountered in contemporary society.
    Jun. 2010, European journal of pharmacology, 635(1-3) (1-3), 117 - 23, English, International magazine
    Scientific journal

  • Katsunori Tanaka, Kaori Minami, Tsuyoshi Tahara, Yohei Fujii, Eric R O Siwu, Satoshi Nozaki, Hirotaka Onoe, Satomi Yokoi, Koichi Koyama, Yasuyoshi Watanabe, Koichi Fukase
    Jun. 2010, ChemMedChem, 5(6) (6), 841 - 5, English, International magazine
    Scientific journal

  • Sanae Fukuda, Ryota Hashimoto, Kazutaka Ohi, Kouzi Yamaguti, Yasuhito Nakatomi, Yuka Yasuda, Kouzin Kamino, Masatoshi Takeda, Seiki Tajima, Hirohiko Kuratsune, Yoshiki Nishizawa, Yasuyoshi Watanabe
    AIMS: Disrupted-in schizophrenia 1 (DISC1), identified in a pedigree with a familial psychosis with the chromosome translocation (1:11), is a putative susceptibility gene for psychoses such as schizophrenia and major depressive disorder (MDD). Patients with chronic fatigue syndrome (CFS) report having continuous severe fatigue and many overlapping symptoms with MDD; however, the mechanism and effective treatment of CFS are still unclear. We focused on the overlapping symptoms between CFS and MDD and performed an association study of the functional single-nucleotide polymorphism (SNP) in the DISC1 gene with CFS. MAIN METHODS: Venous blood was drawn from CFS patients and controls and genomic DNA was extracted from the whole blood according to standard procedures. Ser704Cys DISC1 SNP was genotyped using the TaqMan 5'-exonuclease allelic discrimination assay. KEY FINDINGS: We found that the Cys704 allele of Ser704Cys SNP was associated with an increased risk of CFS development compared with the Ser704 allele. SIGNIFICANCE: DISC1 Ser704Cys might be a functional variant that affects one of the mechanisms implicated in the biology of CFS. Some patients with CFS showed a phenotype similar to that of patients with MDD, but further studies are needed to clarify the biological mechanism, because this study is of a rather preliminary nature. Despite the variety of patients with CFS, DISC1 Ser704Cys has an association with CFS, which may also suggest that DISC1 plays a central role in the induction of various psychiatric diseases.
    May 2010, Life sciences, 86(19-20) (19-20), 722 - 5, English, International magazine
    Scientific journal

  • PETを用いた緑内障早期診断法の確立
    嶋澤 雅光, 井口 勇太, 伊藤 保志, 山中 創, 林 拓也, 季 斌, 樋口 真人, 須原 哲也, 今村 一之, 新家 眞, 渡辺 恭良, 尾上 浩隆, 原 英彰
    日本分子イメージング学会, May 2010, JSMI Report, 3(2) (2), 138 - 138, Japanese
    [Refereed]

  • 緑内障視神経障害モデル動物における拡散テンソル画像
    林 拓也, 原 英彰, 嶋澤 雅光, 井口 勇太, 伊藤 保志, 合瀬 恭幸, 飯田 英博, 山中 創, 渡辺 恭良, 尾上 浩隆
    日本分子イメージング学会, May 2010, JSMI Report, 3(2) (2), 102 - 102, Japanese
    [Refereed]

  • Misato Takashima-Hirano, Miho Shukuri, Tadayuki Takashima, Miki Goto, Yasuhiro Wada, Yasuyoshi Watanabe, Hirotaka Onoe, Hisashi Doi, Masaaki Suzuki
    Cyclooxygenase (COX) is a critical enzyme in prostaglandin biosynthesis that modulates a wide range of biological functions, such as pain, fever, and so on. To perform in vivo COX imaging by positron emission tomography (PET), we developed a method to incorporate (11)C radionuclide into various 2-arylpropionic acids that have a common methylated structure, particularly among nonsteroidal anti-inflammatory drugs (NSAIDs). Thus, we developed a novel (11)C-radiolabeling methodology based on rapid C-[(11)C]methylation by the reaction of [(11)C]CH(3)I with enolate intermediates generated from the corresponding esters under basic conditions. One-pot hydrolysis of the above [(11)C]methylation products also allows the synthesis of desired (11)C-incorporated acids. We demonstrated the utility of this method in the syntheses of six PET tracers, [(11)C]Ibuprofen, [(11)C]Naproxen, [(11)C]Flurbiprofen, [(11)C]Fenoprofen, [(11)C]Ketoprofen, and [(11)C]Loxoprofen. Notably, we found that their methyl esters were particularly useful as proradiotracers for a study of neuroinflammation. The microPET studies of rats with lipopolysaccharide (LPS)-induced brain inflammation clearly showed that the radioactivity of PET tracers accumulated in the inflamed region. Among these PET tracers, the specificity of [(11)C]Ketoprofen methyl ester was demonstrated by a blocking study. Metabolite analysis in the rat brain revealed that the methyl esters were initially taken up in the brain and then underwent hydrolysis to form pharmacologically active forms of the corresponding acids. Thus, we succeeded in general (11)C-labeling of 2-arylpropionic acids and their methyl esters as PET tracers of NSAIDs to construct a potentially useful PET tracer library for in vivo imaging of inflammation involved in COXs expression.
    Apr. 2010, Chemistry (Weinheim an der Bergstrasse, Germany), 16(14) (14), 4250 - 8, English, International magazine
    Scientific journal

  • Personality and fatigue in medical students.
    Masaaki Tanaka, Kei Mizuno, Sanae Fukuda, Yasuyoshi Watanabe
    Among medical students, fatigue is a common complaint and is related to poor academic outcomes. Associations of scores on personality traits and fatigue in medical students were examined. A group of 125 healthy second-year medical students completed a questionnaire about fatigue, the Japanese version of the Chalder Fatigue Scale, and the Temperament and Character Inventory. On simple regression analyses, the Temperament and Character Inventory dimension of Harm Avoidance was positively associated with Fatigue scores and those on Self-directedness were negatively associated. Similarly, on multiple regression analyses adjusted for age and sex, scores on the Temperament and Character Inventory dimension of Harm Avoidance were positively associated with Fatigue scores, and those for Self-directedness were negatively associated. These correlations were evident even after adjustment for other Temperament and Character Inventory dimensions. The temperament dimension of Harm Avoidance and the character dimension of Self-directedness were both associated with Fatigue in medical students.
    Apr. 2010, Psychological reports, 106(2) (2), 567 - 75, English, International magazine
    Scientific journal

  • Koyama H, Fukuda S, Shoji T, Inaba M, Tsujimoto Y, Tabata T, Okuno S, Yamakawa T, Okada S, Okamura M, Kuratsune H, Fujii H, Hirayama Y, Watanabe Y, Nishizawa Y
    BACKGROUND AND OBJECTIVES: Despite potential significance of fatigue and its underlying components in the occurrence of cardiovascular diseases, epidemiologic data showing the link are virtually limited. This study was designed to examine whether fatigue symptoms or fatigue's underlying components are a predictor for cardiovascular diseases in high-risk subjects with ESRD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: 788 volunteer patients under hemodialysis therapy (506 male, 282 female) completed the survey between October and November 2005, with the follow-up period up to 26 months to monitor occurrence of fatal or nonfatal cardiovascular events. The questionnaire consisted of 64 questions, and promax rotation analysis of the principal component method conceptualized eight fatigue-related factors: fatigue itself, anxiety and depression, loss of attention and memory, pain, overwork, autonomic imbalance, sleep problems, and infection. RESULTS: 14.7% of the patients showed fatigue scores higher than twice the SD of the mean for healthy volunteers. These highly fatigued patients exhibited a significantly higher risk for cardiovascular events (hazard ratio: 2.17; P < 0.01), with the relationship independent of the well-known risk factors, including age, diabetes, cardiovascular disease history, and inflammation and malnutrition markers. Moreover, comparisons of the risk in key subgroups showed that the risk of high fatigue score for cardiovascular events was more prominent in well-nourished patients, including lower age, absence of past cardiovascular diseases, higher serum albumin, and high non-HDL cholesterol. CONCLUSIONS: Fatigue can be an important predictor for cardiovascular events in patients with ESRD, with the relationship independent of the nutritional or inflammatory status.
    Apr. 2010, Clinical journal of the American Society of Nephrology : CJASN, 5(4) (4), 659 - 666, English, International magazine
    [Refereed]
    Scientific journal

  • Katsunori Tanaka, Kaori Minami, Tsuyoshi Tahara, Eric R. O. Siwu, Koichi Koyama, Satoshi Nozaki, Hirotaka Onoe, Yasuyoshi Watanabe, Koichi Fukase
    [image omitted]Graphical Abstract Combined azaelectrocyclization and Staudinger ligation allowed proteins and living cells to be modified by small molecules (i.e., biotin or N-glycans). Chemically engineered lymphocytes modified by complex-type N-glycan targeted DLD-1 tissues implanted in nude mice at the whole-body level.
    TAYLOR & FRANCIS INC, 2010, JOURNAL OF CARBOHYDRATE CHEMISTRY, 29(3) (3), 118 - 132, English
    [Refereed]
    Scientific journal

  • Sanae Fukuda, Hirohiko Kuratsune, Seiki Tajima, Shoko Takashima, Kouzi Yamagutchi, Yoshiki Nishizawa, Yasuyoshi Watanabe
    BACKGROUND: Using the Temperament and Character Inventory (TCI), we examined personality characteristics in patients with chronic fatigue syndrome (CFS) compared with healthy control subjects, and CFS patients with and without psychiatric diseases. There have been no previous reports assessing personality in CFS patients using the TCI. METHODS: A total of 211 CFS patients and 90 control subjects completed the TCI and the Chalder Fatigue Scale questionnaires. RESULTS: Compared with control subjects, CFS patients demonstrated significantly lower premorbid Novelty Seeking, and higher Harm Avoidance and persistence. The fatigue score for CFS patients with psychiatric diseases was higher than that for CFS patients without psychiatric diseases. Patients with CFS with psychiatric diseases showed lower premorbid Self-Directedness when compared with CFS patients without psychiatric diseases. The fatigue score was negatively correlated with premorbid Self-Directedness and Cooperativeness, and positively correlated with Harm Avoidance among CFS patients. CONCLUSION: This study supported the stereotyped image of CFS patients as perfectionists, which is similar to the Persistence score, and neurotics, which is similar to the Harm Avoidance score. Patients displaying greater neuroticisms and poorer social and communication skills, similar to the Self-Directedness and Cooperativeness scores, tend to have intercurrent psychiatry diseases and show more severe symptoms of CFS.
    2010, Comprehensive psychiatry, 51(1) (1), 78 - 85, English, International magazine
    Scientific journal

  • Effects of mild-stream bathing on recovery from mental fatigue.
    Kei Mizuno, Masaaki Tanaka, Kanako Tajima, Naoki Okada, Kazumasa Rokushima, Yasuyoshi Watanabe
    BACKGROUND: Bathing in hot water is very common in Japan; people bathe in order to clean their bodies and to recover from physical and mental fatigue. However, there have been few reports examining the effects of bathing on recovery from mental fatigue. The purpose of this study was to examine the effects of mild-stream bathing on recovery from mental fatigue. MATERIAL/METHODS: During mild-stream bathing, a mild stream continuously passes from the sole to the calf, thigh, waist and back, thus providing a massage function. In a double-blinded, placebo-controlled, crossover experiment, 14 male healthy volunteers were randomized into normal bathing and mild-stream bathing experiments. After a fatigue-inducing mental task for 4 hours, subjects took a normal or mild-stream bath. RESULTS: Heart rate was higher, muscle stiffness in the waist was lower and plasma cortisol levels tended to be lower after mild-stream bathing when compared to normal bathing. In addition, after mild-stream bathing, mental task performance, as assessed by reaction times on an advanced trail making test, was better than that after normal bathing. CONCLUSIONS: The present results suggest that improved working memory processing, diminished waist muscle tone, and attenuated mental stress are induced by mild-stream bathing. Therefore, mild-stream bathing appears to be more effective for alleviating mental fatigue than normal bathing.
    Jan. 2010, Medical science monitor : international medical journal of experimental and clinical research, 16(1) (1), CR8-14, English, International magazine
    Scientific journal

  • Emi Yamano, Sanae Fukuda, Takako Joudoi, Kei Mizuno, Masaaki Tanaka, Yosky Kataoka, Junko Kawatani, Miyuki Takano, Akemi Tomoda, Kyoko Imai-Matsumura, Teruhisa Miike, Fumihiko Matsuda, Yasuyoshi Watanabe
    OBJECTIVE: This 1-year follow-up study was performed to examine the association of temperament and character dimensions with new onset of fatigue-induced symptoms among school children in Japan, focusing on the transition from childhood to early adolescence. METHOD: This study prospectively reviewed data from 1512 school children from four elementary and four junior high schools in Japan. The survey was conducted in 2006 and 2007. Multivariate logistic regression analyses were performed to examine the association of psychological dimensions, assessed by the Junior Temperament and Character Inventory, with fatigue-induced symptoms. RESULTS: The correlation between temperament and character dimensions with new-onset of fatigue-induced symptoms differed as the students advanced into higher grades. In terms of physical symptoms in males, traits correlated with fatigue-induced symptoms included Novelty Seeking (headaches OR, 1.36; 95% CI, 1.07-1.73) or Reward Dependence (extreme tiredness OR, 1.84; 95% CI, 1.09-3.12; muscle weakness OR, 2.32; 95% CI, 1.28-4.20) during elementary school, whereas in females, Novelty Seeking was mainly associated with both physical (morning fatigue OR, 1.40; 95% CI, 1.10-1.77; headaches OR, 1.22; 95% CI, 1.04-1.43) and mental (mood changes OR, 1.30; 95% CI, 1.09-1.56) symptoms. Among ninth graders, more mental symptoms of fatigue were associated with Harm Avoidance (males, poor motivation OR, 1.20; 95% CI, 1.02-1.42; females, mood changes OR, 1.25; 95% CI, 1.06-1.49) and Self Directedness (males, poor motivation OR, 0.75; 95% CI, 0.59-0.96; females, difficulty thinking OR, 0.78; 95% CI, 0.62-0.98). CONCLUSION: Confirmation that the correlation between personality traits and fatigue-induced symptoms changes with grade at school has implications for screening susceptible children and adolescents and may help prevent the occurrence of such symptoms at an early stage.
    2010, Comprehensive psychiatry, 51(3) (3), 256 - 65, English, International magazine
    Scientific journal

  • Sanae Fukuda, Emi Yamano, Takako Joudoi, Kei Mizuno, Masaaki Tanaka, Junko Kawatani, Miyuki Takano, Akemi Tomoda, Kyoko Imai-Matsumura, Teruhisa Miike, Yasuyoshi Watanabe
    We examined relationships among fatigue, sleep quality, and effort-reward imbalance for learning in school children. We developed an effort-reward for learning scale in school students and examined its reliability and validity. Self-administered surveys, including the effort reward for leaning scale and fatigue scale, were completed by 1,023 elementary school students (grades 4-6) and 1,361 junior high school students (grades 7-9) at the end of 2006. Effort-reward imbalance for learning was associated with a high incidence of fatigue and sleep problems in elementary and junior high school students of both genders. A good relationship with family was associated with a low fatigue score in junior high school boys, and a good relationship with friends was associated with a low fatigue score in junior high school girls by multiple regression analysis. Fatigue score was associated with effort-reward imbalance and fatigue and quality of sleep in schoolchildren. Fatigue may lead to a decline in school performance, negative health outcomes, or refusal to attend school. These results suggest that it is desirable to consider social support, quality of sleep, and effort-reward imbalance when managing fatigue in school children.
    2010, Behavioral medicine (Washington, D.C.), 36(2) (2), 53 - 62, English, International magazine
    Scientific journal

  • Yoshihito Shigihara, Masaaki Tanaka, Yasuyoshi Watanabe
    It is considered that photosensitivity is one of the most important factors to cause video-game epilepsy. Since photosensitivity is thought to cause various signs of hypersensitivity in the central nervous system and hypersensitivity is believed to be related to fatigue, whether fatigue is associated with photosensitivity was determined. The study group consisted of 68 healthy medical students attending Osaka City University Graduate School of Medicine. They completed questionnaires dealing with fatigue (Chalder Fatigue Scale) and photosensitivity. On simple regression analyses, fatigue score was positively associated with photosensitivity score. Similarly, on multiple regression analyses adjusted for age, gender, and sleeping hours, fatigue score was positively associated with photosensitivity score. Fatigue is associated with photosensitivity. Our findings provide new perspectives on fatigue.
    2010, Behavioral medicine (Washington, D.C.), 36(4) (4), 109 - 12, English, International magazine
    Scientific journal

  • Seiki Tajima, Shigeyuki Yamamoto, Masaaki Tanaka, Yosky Kataoka, Masao Iwase, Etsuji Yoshikawa, Hiroyuki Okada, Hirotaka Onoe, Hideo Tsukada, Hirohiko Kuratsune, Yasuomi Ouchi, Yasuyoshi Watanabe
    Fatigue is an indispensable bioalarm to avoid exhaustive state caused by overwork or stresses. It is necessary to elucidate the neural mechanism of fatigue sensation for managing fatigue properly. We performed H 15 2 O positron emission tomography scans to indicate neural activations while subjects were performing 35-min fatigue-inducing task trials twice. During the positron emission tomography experiment, subjects performed advanced trail-making tests, touching the target circles in sequence located on the display of a touch-panel screen. In order to identify the brain regions associated with fatigue sensation, correlation analysis was performed using statistical parametric mapping method. The brain region exhibiting a positive correlation in activity with subjective sensation of fatigue, measured immediately after each positron emission tomography scan, was located in medial orbitofrontal cortex (Brodmann's area 10/11). Hence, the medial orbitofrontal cortex is a brain region associated with mental fatigue sensation. Our findings provide a new perspective on the neural basis of fatigue. Copyright © 2010 Seiki Tajima et al.
    Hindawi Publishing Corporation, 2010, Neurology Research International, 2010, 1421 - 1425, English, International magazine
    [Refereed]
    Scientific journal

  • Victor L Villemagne, Suzuka Ataka, Toshiki Mizuno, William S Brooks, Yasuhiro Wada, Masaki Kondo, Gareth Jones, Yasuyoshi Watanabe, Rachel Mulligan, Masanori Nakagawa, Takami Miki, Hiroyuki Shimada, Graeme J O'Keefe, Colin L Masters, Hiroshi Mori, Christopher C Rowe
    BACKGROUND: Supported by compelling genetic data regarding early-onset familial Alzheimer disease (AD), the amyloid beta-peptide (Abeta)-centric theory holds that Abeta is involved in the pathogenesis of sporadic AD. Mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes lead to increased Abeta levels before symptoms arise. OBJECTIVES: To evaluate the pattern of Pittsburgh Compound B (PiB) retention in subjects with different autosomal dominant mutations associated with familial AD vs that in healthy age-matched control subjects and subjects with probable sporadic AD, to correlate Abeta burden as measured by PiB with available clinical and cognitive data, and to compare the regional brain patterns of PiB retention and fluorodeoxyglucose F 18 (FDG) uptake. DESIGN: Correlation analysis of positron emission tomography (PET) imaging studies. SETTING: Academic research. PARTICIPANTS: Seven PSEN1 mutation carriers and 1 APP mutation carrier underwent PiB and FDG PET imaging. Amyloid beta-peptide burden and FDG uptake were established using standardized uptake values normalized to pons. MAIN OUTCOME MEASURE: Primary outcomes were PET results, which were compared with those of a well-characterized cohort of 30 healthy control subjects and 30 subjects with probable sporadic AD. RESULTS: All mutation carriers had high PiB retention in the striatum, with some also having cortical PiB retention in ventrofrontal and posterior cingulate/precuneus areas. The striatal pattern of PiB retention was similar in the PSEN1 and APP mutation carriers. Neither striatal nor cortical Abeta burden was related to cognitive status. CONCLUSIONS: Consistent with previous studies, the pattern of Abeta deposition in familial AD differs from that in sporadic AD, with higher striatal and somewhat lower cortical PiB retention in familial AD. The pattern and degree of Abeta deposition were not associated with mutation type nor cognitive status.
    Dec. 2009, Archives of neurology, 66(12) (12), 1537 - 44, English, International magazine
    Scientific journal

  • Satoshi Nozaki, Hiroshi Mizuma, Masaaki Tanaka, Guanghua Jin, Tsuyoshi Tahara, Kei Mizuno, Masanori Yamato, Kaori Okuyama, Asami Eguchi, Kouji Akimoto, Takahito Kitayoshi, Noriko Mochizuki-Oda, Yosky Kataoka, Yasuyoshi Watanabe
    Impaired energy metabolism is considered a possible cause of fatigue The thiamine derivative, thiamine tetrahydrofurfuryl disulfide (TTFD), is prescribed and is also an over-die-counter drug for the attenuation of fatigue. It is readily absorbed from the intestinal tract and converted into thiamine pyrophosphate (TPP), which plays an important role as a cofactor for enzymes of metabolic pathways involved in the production of adenosine triphosphate (ATP). We postulated that TTFD has all anti-fatigue effect by improving energy metabolism during physical-fatigue loading Here, we initially used the forced swimming test to determine whether daily TTFD or thiamine for 5 days has anti-fatigue effects on weight-loaded rats. The swimming duration of TTFD-, but not of thiamine-treated rats, was significantly longer than that of control rats (P < 05). Based on these findings, we examined changes in the levels of thiamine and its phosphate esters in various organs and the effect of TTFD on ATP levels in skeletal muscle after forced swimming, to determine the cellular mechanisms of the anti-fatigue effect of TTFD. Daily TTFD resulted in a characteristic distribution of thiamine and its phosphate esters in rat skeletal muscle, liver, kidney, heart, brain, and plasma. Furthermore, daily TTFD attenuated the decrease in ATP content in the skeletal muscle caused by forced swimming with a weight load for a defined period (150 s) These results indicate that TTFD exerts anti-fatigue effects by improving energy metabolism during physical fatigue. (C) 2009 Elsevier Inc. All rights reserved.
    PERGAMON-ELSEVIER SCIENCE LTD, Dec. 2009, NUTRITION RESEARCH, 29(12) (12), 867 - 872, English, International magazine
    [Refereed]
    Scientific journal

  • 高島 忠之, 長田 浩子, 中江 崇敬, 橋爪 良信, 土居 久志, 和田 康弘, 崔 翼龍, 鈴木 正昭, 渡辺 恭良, 北村 吏司, 前田 和哉, 楠原 洋之, 杉山 雄一
    ライフサイエンス出版(株), Dec. 2009, 薬理と治療, 37(Suppl.1) (Suppl.1), S - 69, Japanese

  • 杉山 雄一, 北村 吏司, 前田 和哉, 楠原 洋之, 高島 忠之, 長田 浩子, 橋爪 良信, 土居 久志, 中江 崇敬, 和田 康弘, 崔 翼龍, 鈴木 正昭, 渡辺 恭良
    ライフサイエンス出版(株), Dec. 2009, 薬理と治療, 37(Suppl.1) (Suppl.1), S - 78, Japanese

  • Yilong Cui, Tadayuki Takashima, Misato Takashima-Hirano, Yasuhiro Wada, Miho Shukuri, Yasuhisa Tamura, Hisashi Doi, Hirotaka Onoe, Yosky Kataoka, Yasuyoshi Watanabe
    Neurogenic inflammation triggered by extravasation of plasma protein has been hypothesized as a key factor in the generation of the pain sensation associated with migraine. The principal immune cell that responds to this inflammation is the parenchymal microglia of the central nervous system. Methods: Using a PET technique with C-11-(R)-[1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)3-isoquinolinecarboxamide] (C-11-PK11195), a PET ligand for peripheral type-benzodiazepine receptor, we evaluated the microglial activation in the rat brain after generation of unilateral cortical spreading depression, a stimulation used to bring up an experimental animal model of migraine. Results: We found a significant increase in the brain uptake of C-11-PK11195, which was completely displaceable by the excess amounts of unlabeled ligands, in the ipsilateral hemisphere of the spreading depression generated rats. Moreover, the binding potential of C-11-PK11195 in the spreading depression-generated rats was significantly higher than that in the sham-operated control rats. Conclusion: These results suggest that as an inflammatory reaction, microglial cells are activated in response to the nociceptive stimuli induced by cortical spreading depression in the rat brain. Therefore, the C-11-PK11195 PET technique could have a potential for diagnostic and therapeutic monitoring of neurologic disorders related to neuroinflammation such as migraine.
    SOC NUCLEAR MEDICINE INC, Nov. 2009, JOURNAL OF NUCLEAR MEDICINE, 50(11) (11), 1904 - 1911, English, International magazine
    [Refereed]
    Scientific journal

  • Bengt Långström, Anders Grahnen, Per Hartvig Honoré, Jürgen Borlak, Mats Bergstrom, Bengt Nielsen, Jeanluc Vanderheyden, Yasuyoshi Watanabe, Raymond Josephsson, Poul F Høilund-Carlsen, Markus Schwaiger, Steven M Larson, David M Goldenberg, Andreas Melzer, Henry Engler, Rodney Hicks, Anders Sundin, Marko Seppänen, Göran Hedenstierna, Agneta Nordberg, David Brooks
    Oct. 2009, European journal of nuclear medicine and molecular imaging, 36(10) (10), 1693 - 4, English, International magazine

  • 11Cで標識した非ステロイド性抗炎症薬(NSAIDs)によるPETイメージング
    宿里 充穂, 高島 好聖, 徳田 景子, 佐古 健生, 崔 翼龍, 後藤 美樹, 土居 久志, 鈴木 正昭, 渡辺 恭良, 尾上 浩隆
    (一社)日本核医学会, Sep. 2009, 核医学, 46(3) (3), 319 - 320, Japanese

  • Increased cerebral uptake of [18F]fluoro-deoxyglucose but not [1-14C]glucose early following traumatic brain injury in rats.
    Niklas Marklund, Sven Sihver, David A Hovda, Bengt Långström, Yasuyoshi Watanabe, Gunnar Ronquist, Mats Bergström, Lars Hillered
    Following experimental and clinical traumatic brain injury (TBI), the local cerebral metabolic rate of glucose (lCMR(Glc)) is commonly estimated using the 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG) method. The adequate estimation of lCMR(Glc) using FDG requires a correction factor, the lumped constant (LC), to convert FDG net uptake into lCMR(Glc). The LC, and thus lCMR(Glc) calculations, require a steady-state that may be disrupted following TBI. In the present report, we hypothesized that [1-(14)C]glucose uptake would accurately reflect glucose dynamics early post-injury, and was compared to the regional uptake of FDG in 44 rats subjected to moderate (2.4-2.6 atm) lateral fluid percussion brain injury (FPI) or sham injury. Cortical energy state and adenylate (ATP, ADP, and AMP) levels were also measured. Early (7-42 min) after FPI, FDG uptake was increased in the ipsilateral cortex and hippocampus (p < 0.05). In contrast, no change in [1-(14)C]glucose uptake (7 and 17 min post-injury) or cortical adenylate content (42 min post-injury) was observed. At 12 h following FPI, the ipsilateral FDG and [1-(14)C]glucose uptake were decreased in the cortex and hippocampus, and the ipsilateral cortical ATP concentration was decreased in comparison to sham-injured controls (p < 0.05). Under the present experimental conditions, the rate of cerebral uptake of FDG and of [1-(14)C]glucose differed, and indicated that following TBI, regional changes in the LC may occur in the immediate, but not in the late, post-injury phase. These results should be considered when interpreting results obtained using FDG for the estimation of lCMR(Glc) early following experimental TBI.
    Aug. 2009, Journal of neurotrauma, 26(8) (8), 1281 - 93, English, International magazine
    Scientific journal

  • Evaluation of Intestinal Absorption Kinetics after Oral Administration Using Positron Emission Tomography (PET)
    Tadayuki Takashima, Makoto Kataoka, Shunichi Kitajima, Machiko Murai, Hiroyuki Ou, Yasuhiro Wada, Emi Hayashinaka, Yilong Cui, Shinji Yamashita, Yasuyoshi Watanabe
    TAYLOR & FRANCIS INC, Aug. 2009, DRUG METABOLISM REVIEWS, 41, 66 - 67, English
    [Refereed]

  • Tokiko Ogawa, Nobue Shishioh-Ikejima, Hiroyuki Konishi, Tetsuya Makino, Hiroyoshi Sei, Sumiko Kiryu-Seo, Masaaki Tanaka, Yasuyoshi Watanabe, Hiroshi Kiyama
    Prolonged stress affects homeostasis in various organs and induces stress-associated disorders. We examined the cellular changes of pituitary gland under the continuous stress condition using a rat model in which rats were kept in a cage filled with water to a height of 1.5 cm for up to 5 days. Among the pituitary hormone mRNAs, proopiomelanocortin mRNA was up-regulated specifically in the intermediate lobe (IL) of this rat model. Additionally, the peripheral blood levels of alpha-melanocyte stimulating hormone (alpha-MSH), a major product of proopiomelanocortin in IL were increased. The alpha-MSH secreting cells, melanotrophs, showed a markedly developed endoplasmic reticulum and Golgi apparatus in the early phase of the experiment. Subsequent continuous stress caused remarkable dilation of the endoplasmic reticulum, disruption of the Golgi structure, and the degeneration of some melanotrophs. In addition the dopaminergic nerve fibers from hypothalamus were markedly decreased in IL. A dopamine antagonist elicited the similar morphologic changes of melanotroph in normal rat. These findings suggest that prolonged stress suppressed hypothalamus-derived dopamine release in IL, which elicited over-secretion of alpha-MSH from the melanotrophs. The present study also suggests that prolonged hyperactivation of endocrine cells could lead to disorder of secretion mechanisms and eventual degeneration.
    Jun. 2009, Journal of neurochemistry, 109(5) (5), 1389 - 99, English, International magazine
    Scientific journal

  • Guanghua Jin, Yosky Kataoka, Masaaki Tanaka, Hiroshi Mizuma, Satoshi Nozaki, Tsuyoshi Tahara, Kei Mizuno, Masanori Yamato, Yasuyoshi Watanabe
    OBJECTIVE: Fatigue can be classified as physical or mental, depending on its cause. In physical fatigue, changes in the plasma levels of some amino acids have been reported. However, complex fatigue, which is experienced in daily life, is a combination of physical and mental fatigue. We aimed to identify changes in amino acid levels in the plasma, skeletal muscle, liver, and brain in an animal model of complex fatigue. METHODS: Rats were kept in a cage filled with water to a height of 2.2 cm for 5 d. Because rats showed a reduction of body weight when the model was developed, we also included a food-restricted group showing a similar profile in weight reduction as the water-immersed rats. A non-treated control group was also included. RESULTS: Results indicated that levels of branched-chain amino acids (valine, leucine, and isoleucine) were increased in plasma (valine, leucine, and isoleucine; P < 0.01), skeletal muscle (valine, leucine, and isoleucine; P < 0.01), the liver (valine; P < 0.05), and brain (isoleucine; P < 0.05), whereas a reduction in other amino acid levels (total amino acids and glutamine in the plasma, skeletal muscle, and liver; and phenylalanine, tyrosine, arginine, and threonine in the brain; P < 0.01) was seen in animals with complex fatigue. CONCLUSION: Complex fatigue may bring about systemic changes in amino acid metabolism in multiple organs.
    May 2009, Nutrition (Burbank, Los Angeles County, Calif.), 25(5) (5), 597 - 607, English, International magazine
    Scientific journal

  • Masaaki Tanaka, Kei Mizuno, Sanae Fukuda, Seiki Tajima, Yasuyoshi Watanabe
    OBJECTIVES: Motivation is one of the most important psychological concepts in education and is related to academic outcomes in medical students. In this study, the relationships between personality traits and intrinsic academic motivation were examined in medical students. METHODS: The study group consisted of 119 Year 2 medical students at Osaka City University Graduate School of Medicine. They completed questionnaires dealing with intrinsic academic motivation (the Intrinsic Motivation Scale toward Learning) and personality (the Temperament and Character Inventory [TCI]). RESULTS: On simple regression analyses, the TCI dimensions of persistence, self-directedness, co-operativeness and self-transcendence were positively associated with intrinsic academic motivation. On multiple regression analysis adjusted for age and gender, the TCI dimensions of persistence, self-directedness and self-transcendence were positively associated with intrinsic academic motivation. CONCLUSIONS: The temperament dimension of persistence and the character dimensions of self-directedness and self-transcendence are associated with intrinsic academic motivation in medical students.
    Apr. 2009, Medical education, 43(4) (4), 384 - 7, English, International magazine
    Scientific journal

  • Yukiko Hakariya Kato, Masanobu Yamate, Muneo Tsujikawa, Hiromi Nishigaki, Yukie Tanaka, Mikihiro Yunoki, Hirohiko Kuratsune, Yasuyoshi Watanabe, Kazuyoshi Ikuta
    Mar. 2009, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology, 44(3) (3), 246 - 7, English, International magazine

  • Hiroshi Mizuma, Masaaki Tanaka, Satoshi Nozaki, Kei Mizuno, Tsuyoshi Tahara, Suzuka Ataka, Tomohiro Sugino, Tomoko Shirai, Yoshitaka Kajimoto, Hirohiko Kuratsune, Osami Kajimoto, Yasuyoshi Watanabe
    This study compared the effects of placebo with a carotenoid compound, crocetin, as well as an antioxidant, ascorbic acid, on physical fatigue in humans. In this double-blind, placebo-controlled, 3-way crossover study, 14 Japanese healthy volunteers (7 men and 7 women) were randomized to oral administration of crocetin (15 mg), ascorbic acid (3,000 mg), or placebo for 8 days. Subjects performed workload tests on a bicycle ergometer at fixed workloads for 120 minutes at 2 times (a total of 240 minutes) as a fatigue-inducing physical task. During the physical task, subjects performed nonworkload tests at maximum velocity (MV) of 10 seconds at 30 minutes (30-minute test) after the start of the physical task and at 30 minutes before the end of the task (210-minute test). The change in MV from the 30- to the 210-minute test was significantly higher in men who received crocetin compared with men who received placebo (P < .05). This effect of crocetin was specific to males. Administration of ascorbic acid did not change in MV from the 30-minute to the 210-minute test on males or females. These results suggest that daily administration of crocetin may attenuate physical fatigue in men.
    Mar. 2009, Nutrition research (New York, N.Y.), 29(3) (3), 145 - 50, English, International magazine
    Scientific journal

  • Masaaki Tanaka, Kei Mizuno, Seiki Tajima, Tetsuya Sasabe, Yasuyoshi Watanabe
    AIMS: Fatigue is a common symptom in modern society. In order to clarify the mechanisms underlying fatigue, we examined the association between central nervous system fatigue and autonomic nerve activity. MAIN METHODS: The study group consisted of 20 healthy subjects. They performed the 2-back test for 30 min to induce fatigue. Just before and after the fatigue-inducing session, they completed the advanced trail making test (ATMT) for 30 min as a fatigue-evaluating task session. In order to measure autonomic nerve activity, electrocardiograms were monitored continuously throughout the experiment. KEY FINDINGS: After the fatigue-inducing task session, impaired task performance was demonstrated based on the total trial number and error counts of the ATMT. During the task session, although task performance as measured using the accuracy and the mean reaction time of the 2-back test was almost unchanged, electrocardiographic R-R wave interval analyses showed a decreased high-frequency component power and an increasing trend in the low-frequency component power/high-frequency component power ratio. SIGNIFICANCE: Decreased vagal nerve activity and increased sympathetic nerve activity are associated with central nervous system fatigue.
    Feb. 2009, Life sciences, 84(7-8) (7-8), 235 - 9, English, International magazine
    Scientific journal

  • Masanori Yamato, Yosky Kataoka, Hiroshi Mizuma, Yasuhiro Wada, Yasuyoshi Watanabe
    (18)F-FDG PET is used mainly in clinical settings for imaging focal cancer sites, but the usefulness of the modality in imaging gastrointestinal ulcers has not been established. We investigated whether PET can be used for noninvasive monitoring of indomethacin-induced small-intestine ulceration. Methods: Intestinal ulcers were induced in rats by subcutaneous administration of indomethacin. An 18F-FDG PET scan was obtained at 1, 2, and 7 d after indomethacin administration. (18)F-FDG uptake in the small intestine was quantified by gamma-counting, and macro- and microautoradiographic studies were performed to determine the site of (18)F-FDG uptake in tissue and at the cellular level. Results: Ulcers observed in the intestine (mainly in the ileum) 1-4 d after indomethacin administration were most severe at 1 d after administration and were almost healed at day 7. The PET study showed increased (18)F-FDG uptake in the intestine correlating to the severity of ulceration, returning to the basal level on day 7. Ex vivo imaging and gamma-counting showed that these regions of high uptake corresponded to regions of ulceration. A microautoradiographic study combined with immunohistochemistry revealed heavy accumulation of 1(8F)-FDG in inflammatory cells containing peroxidase on day 1 and in cells forming granulation tissue (alpha-smooth muscle actin-positive myofibroblasts and ED2-positive macrophages) on days 2-4 in and around ulcers. Proliferating (Ki67-immunopositive) intestinal crypt cells were also densely labeled with (18)F-FDG in intact intestinal tissue taken from the indomethacin-treated and the control animals. Conclusion: Our experimental data suggest that (18)F-FDG PET may be useful for evaluating the occurrence of small-intestine ulcers. Ulceration could be visualized early by the prominent uptake of (18)F-FDG by inflammatory cells and by the formation of granulation tissue by cells in and around ulcers.
    SOC NUCLEAR MEDICINE INC, Feb. 2009, JOURNAL OF NUCLEAR MEDICINE, 50(2) (2), 266 - 273, English, International magazine
    [Refereed]
    Scientific journal

  • Kazuyuki Imamura, Hirotaka Onoe, Masamitsu Shimazawa, Satoshi Nozaki, Yasuhiro Wada, Koichi Kato, Hideki Nakajima, Hiroshi Mizuma, Kayo Onoe, Takazumi Taniguchi, Masaaki Sasaoka, Hideaki Hara, Shigeru Tanaka, Makoto Araie, Yasuyoshi Watanabe
    Experimentally induced changes in the central visual pathway were studied by using positron emission tomography in monkeys with unilateral hypertension glaucoma. In 2-[18F]fluoro-2-deoxy-glucose studies, monocular visual stimulation of the affected eye yielded significantly reduced neural responses in the occipital visuocortical areas. The response reduction was limited to the visual cortex ipsilateral to the affected eye, indicating the unique vulnerability of ipsilateral visual cortex in experimental unilateral glaucoma. In addition, in [11C]PK11195 positron emission tomography and immunohistochemical studies, selective accumulation of activated microglia, a sign of neural degeneration, was found bilaterally in lateral geniculate nuclei. The present findings establish the usefulness of noninvasive molecular imaging for early diagnosis of glaucoma by providing a sharper surrogate end point for an early phase of glaucoma.
    Jan. 2009, Neuroreport, 20(2) (2), 139 - 44, English, International magazine
    Scientific journal

  • 6. Investigation of canalicular efflux mechanisms of SC-62807, a major metabolite of celecoxib
    Chunyong Wu, Hiroyuki Kusuhara, Yuichi Sugiyama, Tadayuki Takashima, Misato Takashima-Hirano, Hisashi Doi, Masaaki Suzuki, Yasuyoshi Watanabe
    2009, Japanese Pharmacology and Therapeutics, 37(1) (1), S-37 - S42, English
    Scientific journal

  • Positron emission tomography (PET) study for the evaluation of in vivo hepatobiliary transport using 15R-[11C]TIC-Me
    Tadayuki Takashima, Hiroko Nagata, Takahiro Nakae, Yoshinobu Hashizume, Hisashi Doi, Yasuhiro Wada, Yilong Cui, Masaaki Suzuki, Satoshi Kitamura, Kazuya Maeda, Hiroyuki Kusuhara, Yuichi Sugiyama, Yasuyoshi Watanabe
    2009, Japanese Pharmacology and Therapeutics, 37(1) (1), S-65 - S-69, Japanese
    Scientific journal

  • Tomohiro Ohira, Tomohisa Okuma, Toshiyuki Matsuoka, Yasuhiro Wada, Kenji Nakamura, Yasuyoshi Watanabe, Yuichi Inoue
    The objective of this study was to evaluate the early changes after radiofrequency ablation (RFA) in VX2 rabbit tumors implanted into the back muscles by diffusion-weighted magnetic resonance (MR) imaging and (18)F-2-fluoro-2-deoxy-D-glucose positron emission tomography ((18)F-FDG PET). Percutaneous CT-guided RFA was conducted in seven rabbits with implanted VX2 tumors. VX2 tumors on the other side were untreated and served as the control. MR imaging was performed with a clinical 1.5-T instrument 2 days after RFA, and FDG-PET, using a high-resolution PET scanner for small animals, was obtained 3 days after the procedure. The mean apparent diffusion coefficient (ADC) values and radioactivity count of untreated and ablated tumors were calculated. Untreated VX2 tumors showed hyperintensity on T1-, T2-, and diffusion-weighted MR images, ring-enhanced on contrast-enhanced T1-weighted imaging, and ring-shaped FDG accumulation on FDG-PET. Ablated VX2 tumors showed slight hyperintensity on T1-, T2-, and diffusion-weighed images, slight enhancement on contrast-enhanced T1-weighted images, and low accumulation on FDG-PET. The ADC value of ablated VX2 tumors (1.52 +/- 0.24 x 10(-3) mm(2)/s) was significantly higher than that of untreated tumors (1.09 +/- 0.12 x 10(-3); p < 0.05). The tumor/muscle ratio of ablated tumors (0.5 +/- 0.3) was significantly lower than that of untreated tumors (11.6 +/- 3.2; p < 0.05). Histopathological examination confirmed the lack of viable tumor cells in the ablated lesions. The results indicate that both ADC value and FDG-PET are potentially useful markers for monitoring the early effects of RFA.
    Jan. 2009, Cardiovascular and interventional radiology, 32(1) (1), 114 - 20, English, International magazine
    Scientific journal

  • Satoshi Nozaki, Masaaki Tanaka, Kei Mizuno, Suzuka Ataka, Hiroshi Mizuma, Tsuyoshi Tahara, Tomohiro Sugino, Tomoko Shirai, Asami Eguchi, Kaori Okuyama, Kaoru Yoshida, Yoshitaka Kajimoto, Hirohiko Kuratsune, Osami Kajimoto, Yasuyoshi Watanabe
    OBJECTIVE: To confirm fatigue-related biochemical alterations, we measured various parameters just before and after relaxation and fatigue-inducing mental or physical sessions. METHODS: Fifty-four healthy volunteers were randomized to perform relaxation and fatigue-inducing mental and physical sessions for 4 h in a double-blind, three-crossover design. Before and after each session, subjects were asked to rate their subjective sensations of fatigue, and blood, saliva, and urine samples were taken. RESULTS: After the fatigue-inducing mental and physical sessions, subjective scores of fatigue were increased. After the fatigue-inducing mental session, the vanillylmandelic acid level in urine was higher and plasma valine level was lower than after the relaxation session. In contrast, after the fatigue-inducing physical session, serum citric acid, triacylglycerol, free fatty acid, ketone bodies, total carnitine, acylcarnitine, uric acid, creatine kinase, aspartate aminotransferase, lactate dehydrogenase, cortisol, dehydroepiandrosterone, dehydroepiandrosterone sulfate, plasma branched-chain amino acids, transforming growth factor-beta1 and -beta2, white blood cell and neutrophil counts, saliva cortisol and amylase, and urine vanillylmandelic acid levels were higher and serum free carnitine and plasma total amino acids and alanine levels were lower than those after the relaxation session. CONCLUSION: Some mental or physical fatigue-related biochemical changes were determined. Various biochemical alterations reflecting homeostatic perturbation and its responses might be shown. We believe that our results contribute to clarifying the mechanism of fatigue, developing evaluation methods, and establishing a basis for treatment.
    Jan. 2009, Nutrition (Burbank, Los Angeles County, Calif.), 25(1) (1), 51 - 7, English, International magazine
    Scientific journal

  • Masaaki Tanaka, Sanae Fukuda, Kei Mizuno, Hirohiko Kuratsune, Yasuyoshi Watanabe
    Fatigue is a common complaint among medical students and researchers consider it to be related to poor academic outcomes. The authors' goal in the present study was to determine whether stress and coping strategies were associated with fatigue in medical students. The study group consisted of 73 second-year healthy students attending the Osaka City University Graduate School of Medicine. Participants completed a questionnaire about fatigue (Japanese version of Chalder Fatigue Scale), stress, stress coping (Japanese version of the Coping Inventory for Stressful Situations), overwork, and nocturnal sleeping hours. On univariate and multivariate logistic regression analyses adjusted for age and gender, stress was positively associated with fatigue. In addition, after adjustment for age, gender, and emotion- and task-oriented stress coping activities, avoidance-oriented stress coping activity was associated with fatigue. The results suggest that stress and the coping style are correlated with fatigue in medical students.
    2009, Behavioral medicine (Washington, D.C.), 35(3) (3), 87 - 92, English, International magazine
    Scientific journal

  • Yasuhisa Tamura, Guanghua Jin, Yilong Cui, Yasuyoshi Watanabe, Yosky Kataoka
    ELSEVIER IRELAND LTD, 2009, NEUROSCIENCE RESEARCH, 65, S157 - S157, English

  • Identification of transporters involved in the hepatobiliary transport of PET probe, 15R- [11C]TIC, change in its plasma and hepatic concentration by drug interaction in humans and its prediction from in vitro experiments
    Yuichi Sugiyama, Satoshi Kitamura, Kazuya Maeda, Hiroyuki Kusuhara, Tadayuki Takashima, Hiroko Nagata, Yoshinobu Hashizume, Hisashi Doi, Takanori Nakae, Yasuhiro Wada, Yilong Cui, Masaaki Suzuki, Yasuyoshi Watanabe
    2009, Japanese Pharmacology and Therapeutics, 37(SUPPL. 1) (SUPPL. 1)
    Scientific journal

  • Ou Hiroyuki, Doi Hisashi, Watanabe Yasuyoshi, Yamashita Shinji, Masaoka Yoshie, Kataoka Makoto, Sakuma Shinji, Takashima Tadayuki, Hashizume Yoshinobu, Wada Yasuhiro, Hayashinaka Emi, Cui Yilong
    The Japanese Society for the Study of Xenobiotics, 2009, Abstracts of Annual meeting of Japanese Society for the Study of Xenobiotics, 24(0) (0), 138 - 138, Japanese

  • Reliability and validity of the Japanese version of the Chalder Fatigue Scale among youth in Japan.
    Masaaki Tanaka, Sanae Fukuda, Kei Mizuno, Kyoko Imai-Matsumura, Takako Jodoi, Junko Kawatani, Miyuki Takano, Teruhisa Miike, Akemi Tomoda, Yasuyoshi Watanabe
    In the present study, the reliability and construct validity of the Japanese version of the Chalder Fatigue Scale was evaluated as a measure of severity of fatigue among young students in Japan. A healthy group comprised 27 Grade 6 primary school students and 28 Grade 1 junior high school students. The severely fatigued group were hospital outpatients with childhood chronic fatigue syndrome (n = 21). Principal components analysis with varimax rotation identified 4 factors which accounted for 63.2% of the total variance, as in the original English version. Internal consistency (Cronbach coefficient alpha) was .73, and test-retest reliability measured using Spearman rank correlation coefficient was .55. Scale scores of the healthy subjects were lower than those of the patients with childhood chronic fatigue syndrome. The reliability (alpha) and construct validity of the Japanese version of the scale among healthy students in Japan were satisfactory for research studies among healthy school students.
    Dec. 2008, Psychological reports, 103(3) (3), 682 - 90, English, International magazine
    Scientific journal

  • First Positron Emission Tomography (PET) Imaging of Glycoproteins and Glycodendrimers by Efficient Chemical Labeling with [Ga-68]-DOTA
    Katsunori Tanaka, Eric Richard Oktavianus Siwu, Kaori Minami, Koki Hasegawa, Yousuke Kanayama, Hiroshi Mizuma, Yasuhiro Wada, Yasuyoshi Watanabe, Koichi Fukase
    OXFORD UNIV PRESS INC, Nov. 2008, GLYCOBIOLOGY, 18(11) (11), 981 - 981, English
    [Refereed]

  • Masaaki Tanaka, Kei Mizuno, Sanae Fukuda, Yoshihito Shigihara, Yasuyoshi Watanabe
    OBJECTIVE: Fatigue, which is a common complaint among medical students, is related to poor academic outcomes. Because impaired dietary habits, such as skipping breakfast and taking meals irregularly, are correlated with poor school performances, whether those dietary habits were associated with the prevalence of fatigue was determined in medical students. METHODS: The study group consisted of 127 healthy second-year medical students attending Osaka City University Graduate School of Medicine. They completed a questionnaire dealing with fatigue (Japanese version of the Chalder Fatigue Scale), lifestyle, and academic performance. RESULTS: On multivariate logistic regression analyses adjusted for age, gender, body mass index, and nocturnal sleeping hours, skipping breakfast (completely skipping breakfast everyday versus having breakfast everyday; odds ratio 7.81, 95% confidence interval 2.00-30.52, P = 0.003) and taking meals irregularly (completely irregular versus always regular; odds ratio 6.89, 95% confidence interval 1.20-39.55, P = 0.030) were positively correlated with the prevalence of fatigue. CONCLUSION: Skipping breakfast and taking meals irregularly are associated with the prevalence of fatigue in medical students.
    Oct. 2008, Nutrition (Burbank, Los Angeles County, Calif.), 24(10) (10), 985 - 9, English, International magazine
    Scientific journal

  • Kei Mizuno, Masaaki Tanaka, Akira Ishii, Hiroki C Tanabe, Hirotaka Onoe, Norihiro Sadato, Yasuyoshi Watanabe
    We have used functional magnetic resonance imaging to study the neural correlates of motivation, concentrating on the motivation to learn and gain monetary rewards. We compared the activation in the brain obtained during reported high states of motivation for learning, with the ones observed when the motivation was based on monetary reward. Our results show that motivation to learn correlates with bilateral activity in the putamen, and that the higher the reported motivation, as derived from a questionnaire that each subject filled prior to scanning, the greater the change in the BOLD signals within the putamen. Monetary motivation also activated the putamen bilaterally, though the intensity of activity was not related to the monetary reward. We conclude that the putamen is critical for motivation in different domains and the extent of activity of the putamen may be pivotal to the motivation that drives academic achievement and thus academic successes.
    Aug. 2008, NeuroImage, 42(1) (1), 369 - 78, English, International magazine
    Scientific journal

  • 疲労と意欲の脳科学 動物モデルを用いた中枢神経疲労の分子・神経メカニズムの解析(Neural mechanism of central fatigue in the animal models)
    崔 翼龍, 片岡 洋祐, 渡辺 恭良
    日本神経化学会, Aug. 2008, 神経化学, 47(2-3) (2-3), 220 - 220, English

  • Masaaki Tanaka, Yoshitake Baba, Yosky Kataoka, Noriaki Kinbara, Yuko M Sagesaka, Takami Kakuda, Yasuyoshi Watanabe
    OBJECTIVE: Fatigue can be classified as physical and mental depending on the cause. However, in our daily lives, combined fatigue, which is the combination of physical and mental fatigue, is most often experienced. In this study, the effects of (-)-epigallocatechin gallate (EGCg) on combined fatigue were assessed. METHODS: To produce an animal model of combined fatigue, rats were kept in a cage filled with water to a height of 1.5 cm for 5 d. To evaluate the extent of fatigue, the rats swam with a load of steel rings that weighed approximately 8% of their body weight and were attached to their tails. RESULTS: Fatigued rats treated with EGCg (50 or 100 mg/kg intraperitoneally [not for 25 mg/kg]) for 5 d could swim longer than fatigued animals given saline. Although levels of thiobarbituric acid-reactive substances in the plasma, brain, and skeletal muscle were not different between control and fatigued rats, thiobarbituric acid-reactive substance levels were higher in livers of fatigued animals than in livers of control animals. Oral intake of EGCg (50 or 100 mg/kg) for 5 d significantly decreased thiobarbituric acid-reactive substance levels in livers of fatigued animals. CONCLUSION: These results suggest that EGCg (50 or 100 mg/kg) is effective for attenuating fatigue. EGCg given orally appears to have an antioxidant effect on the oxidatively damaged liver of fatigued animals.
    Jun. 2008, Nutrition (Burbank, Los Angeles County, Calif.), 24(6) (6), 599 - 603, English, International magazine
    Scientific journal

  • Masaaki Tanaka, Yasuyoshi Watanabe
    Recently, the authors established an animal model of fatigue. The fatigued animals showed reduced 2-[18F]fluoro-2-deoxy-D-glucose uptake in their brain, although their blood glucose level did not differ from that of the control animals. For further clarification, the study measured regional cerebral blood flow, ATP level, and the ability of mitochondria to produce ATP in the brain of the fatigued and control rats. The fatigued animals showed almost equal regional cerebral blood flow, a significantly higher ATP level, and almost equal mitochondria ability to produce ATP. These data suggest that decreased energy utilization in the brain is a feature of fatigue.
    May 2008, The International journal of neuroscience, 118(5) (5), 683 - 92, English, International magazine
    Scientific journal

  • Kei Mizuno, Masaaki Tanaka, Satoshi Nozaki, Hiroshi Mizuma, Suzuka Ataka, Tsuyoshi Tahara, Tomohiro Sugino, Tomoko Shirai, Yoshitaka Kajimoto, Hirohiko Kuratsune, Osami Kajimoto, Yasuyoshi Watanabe
    OBJECTIVE: This study examined the effects of coenzyme Q10 administration on physical fatigue. METHODS: In a double-blinded, placebo-controlled, three crossover design, 17 healthy volunteers were randomized to oral coenzyme Q10 (100 or 300 mg/d) or placebo administration for 8 d. As a fatigue-inducing physical task, subjects performed workload trials on a bicycle ergometer at fixed workloads twice for 2 h and then rested for 4 h. During the physical tasks, subjects performed non-workload trials with maximum velocity for 10 s at 30 min (30-min trial) after the start of physical tasks and 30 min before the end of the tasks (210-min trial). RESULTS: The change in maximum velocity from the 30- to the 210-min trial in the 300-mg coenzyme Q10-administered group was higher than that in the placebo group. In addition, subjective fatigue sensation measured on a visual analog scale in the 300-mg coenzyme Q10-administered group after the fatigue-inducing physical task and recovery period was alleviated when compared with that in the placebo group. CONCLUSION: Oral administration of coenzyme Q10 improved subjective fatigue sensation and physical performance during fatigue-inducing workload trials and might prevent unfavorable conditions as a result of physical fatigue.
    Apr. 2008, Nutrition (Burbank, Los Angeles County, Calif.), 24(4) (4), 293 - 9, English, International magazine
    Scientific journal

  • Kayo Takahashi, Yasuhisa Tamura, Yasuyoshi Watanabe, Bengt Långström, Mats Bergström
    In a previous study, we demonstrated that androgenic-anabolic steroids increased aromatase expression in the bed nucleus of stria terminalis and preoptic area in rat brain, as evaluated using autoradiography with [11C]vorozole, a potential positron emission tomography tracer for aromatase. In this study, we explored whether the increase in aromatase binding is mediated via androgen receptors and whether this increase occurs in neurons or glial cells. Rats were given nandrolone decanoate (15 mg/kg body weight once every 3 days) and flutamide (20 mg/kg/day) alone or in combination for 20 days. Results indicated a significant increase of [11C]vorozole binding by nandrolone decanoate in the bed nucleus of the stria terminalis and preoptic area, as in our previous study. Flutamide treatment, on the other hand, decreased [11C]vorozole binding in the bed nucleus of the stria terminalis, preoptic area, and medial amygdala. Immunohistochemical examination demonstrated that upregulation of aromatase expression occurred in neurons. Our findings suggest that aromatase is regulated through an androgen receptor-mediated system. This aromatase-specific tracer and the positron emission tomography technique could be useful for exploring the role of aromatase in anabolic androgenic steroids abusers.
    Mar. 2008, Neuroreport, 19(4) (4), 431 - 5, English, International magazine
    Scientific journal

  • CBEX-Dr配合飲料の健常者における抗疲労効果
    田中 雅彰, 鴫原 良仁, 藤井 比佐子, 平山 佳伸, 渡辺 恭良
    疲労負荷時の不快感(疲労感)を緩和させる目的で開発されたchicken breast extract(CBEX)-Dr配合飲料の抗疲労効果について健常成人を被験者として、ランダム化二重盲検プラセボ対照クロスオーバー試験により検討した。被験者は20歳以上60歳未満の健常成人20名(男性10名、女性10名)で、試験食はCBEX-Dr配合飲料60ml(イミダゾールペプチドとして400mg含有)で、プラセボは熱量・ナトリウムなどの含量が試験食と大差ないように作製され、そのいずれかを4週間毎日60ml摂取した。検査方法は身体的パフォーマンス検査として10秒間ハイパワーテスト・physical working capacity(PWC)テストを行い、副次評価としてvisual analogue scale(VAS)による疲労感の評価を行い、作用機序の解明と疲労によって起こる変化の把握のため血液検査・尿検査・理学的検査及び診察・問診を行った。その結果、CBEX-Dr配合飲料60mlを4週間摂取後の4時間身体作業負荷の条件下において、身体的パフォーマンスの低下抑制作用及び疲労感上昇の低減作用がみられ、抗疲労効果が示された。その作用機序は本飲料に含まれるイミダゾールペプチドがもつ抗酸化作用によるものと推測された。以上より、CBEX-Dr配合飲料は肉体的疲労を感じる人に適した食品と考えられた。
    ライフサイエンス出版(株), Mar. 2008, 薬理と治療, 36(3) (3), 199 - 212, Japanese

  • Suzuka Ataka, Masaaki Tanaka, Satoshi Nozaki, Hiroshi Mizuma, Kei Mizuno, Tsuyoshi Tahara, Tomohiro Sugino, Tomoko Shirai, Yoshitaka Kajimoto, Hirohiko Kuratsune, Osami Kajimoto, Yasuyoshi Watanabe
    OBJECTIVE: We examined the effects of administering two different candidate antifatigue substances, caffeine and D-ribose, on mental fatigue. METHODS: In a double-blinded, placebo-controlled, three-way crossover design, 17 healthy volunteers were randomized to oral caffeine (200 mg/d), D-ribose (2000 mg/d), or placebo for 8 d. As fatigue-inducing mental tasks, subjects performed a 30-min Uchida-Kraepelin psychodiagnostic test and a 30-min advanced trail-making test on four occasions. RESULTS: During the tasks, the task performance of the caffeine group was better than that of the placebo group. However, after the fatigue-inducing tasks, although subjective perception of fatigue, motivation, or sleepiness was not significantly different, plasma branched-chain amino acid levels in the caffeine group were lower than those of the placebo group. Administration of D-ribose had no effect. CONCLUSION: Because plasma branched-chain amino acid levels are decreased by mental fatigue, these results suggest that administration of caffeine improved task performance through the enhancement of central nervous system activity without increasing the sensation of fatigue. However, further decreases in branched-chain amino acid levels indicate that caffeine might promote deeper fatigue than placebo. Unfortunately, research subsequent to our study design has shown that D-ribose dosing higher than we used is needed to see a clinical effect and therefore no conclusions can be made from this study as to the efficacy of D-ribose.
    Mar. 2008, Nutrition (Burbank, Los Angeles County, Calif.), 24(3) (3), 233 - 8, English, International magazine
    Scientific journal

  • Takami Tomiyama, Tetsu Nagata, Hiroyuki Shimada, Rie Teraoka, Akiko Fukushima, Hyoue Kanemitsu, Hiroshi Takuma, Ryozo Kuwano, Masaki Imagawa, Suzuka Ataka, Yasuhiro Wada, Eito Yoshioka, Tomoyuki Nishizaki, Yasuyoshi Watanabe, Hiroshi Mori
    OBJECTIVE: Soluble oligomers of amyloid beta (Abeta), rather than amyloid fibrils, have been proposed to initiate synaptic and cognitive dysfunction in Alzheimer's disease (AD). However, there is no direct evidence in humans that this mechanism can cause AD. Here, we report a novel amyloid precursor protein (APP) mutation that may provide evidence to address this question. METHODS: A Japanese pedigree showing Alzheimer's-type dementia was examined for mutations in APP, PSEN1, and PSEN2. In addition, 5,310 Japanese people, including 2,121 patients with AD, were screened for the novel APP mutation. The pathogenic effects of this mutation on Abeta production, degradation, aggregation, and synaptotoxicity were also investigated. RESULTS: We identified a novel APP mutation (E693Delta) producing variant Abeta lacking gulutamate-22 (E22Delta) in Japanese pedigrees showing Alzheimer's-type dementia and AD. Although the secretion of total Abeta was markedly reduced by this mutation, the variant Abeta was more resistant to proteolytic degradation. The mutant peptides showed the unique aggregation property of enhanced oligomerization but no fibrillization, and inhibited hippocampal long-term potentiation more potently than wild-type peptide in rats in vivo. Consistent with the nonfibrillogenic property of the variant Abeta, a very low amyloid signal was observed in the patient's brain on positron emission tomography using Pittsburgh compound-B. INTERPRETATION: The E693Delta mutation has been suggested as a cause of dementia because of enhanced formation of synaptotoxic Abeta oligomers. Our findings may provide genetic validation in humans for the emerging hypothesis that the synaptic and cognitive impairment in AD is primarily caused by soluble Abeta oligomers.
    Mar. 2008, Annals of neurology, 63(3) (3), 377 - 87, English, International magazine
    Scientific journal

  • Yilong Cui, Yosky Kataoka, Takashi Inui, Takatoshi Mochizuki, Hirotaka Onoe, Kiyoshi Matsumura, Yoshihiro Urade, Hisao Yamada, Yasuyoshi Watanabe
    Cortical spreading depression is an excitatory wave of depolarization spreading throughout cerebral cortex at a rate of 2-5 mm/min and has been implicated in various neurological disorders, such as epilepsy, migraine aura, and trauma. Although sleepiness or sleep is often induced by these neurological disorders, the cellular and molecular mechanism has remained unclear. To investigate whether and how the sleep-wake behavior is altered by such aberrant brain activity, we induced cortical spreading depression in freely moving rats, monitoring REM and non-REM (NREM) sleep and sleep-associated changes in cyclooxygenase (COX)-2 and prostaglandins (PGs). In such a model for aberrant neuronal excitation in the cerebral cortex, the amount of NREM sleep, but not of REM sleep, increased subsequently for several hours, with an up-regulated expression of COX-2 in cortical neurons and considerable production of PGs. A specific inhibitor of COX-2 completely arrested the increase in NREM sleep. These results indicate that up-regulated neuronal COX-2 would be involved in aberrant brain excitation-induced NREM sleep via production of PGs. © 2007 Wiley-Liss, Inc.
    4, Mar. 2008, Journal of Neuroscience Research, 86(4) (4), 929 - 936, English, International magazine
    [Refereed]
    Scientific journal

  • A method for the synthesis of an oseltamivir PET tracer.
    Masataka Morita, Toshihiko Sone, Kenzo Yamatsugu, Yoshihiro Sohtome, Shigeki Matsunaga, Motomu Kanai, Yasuyoshi Watanabe, Masakatsu Shibasaki
    A protocol applicable for the synthesis of an oseltamivir positron emission tomography (PET) tracer was developed. Acetylation of amine 3 with CH(3)COCl, followed by deprotection and aqueous workup, produced oseltamivir 4 from 3 within 10 min. The obtained 4 was sufficiently pure for PET studies. This method can be extended to PET tracer synthesis using CH(3)(11)COCl.
    Jan. 2008, Bioorganic & medicinal chemistry letters, 18(2) (2), 600 - 2, English, International magazine
    Scientific journal

  • Sanae Fukuda, Shoko Takashima, Masao Iwase, Kouzi Yamaguti, Hirohiko Kuratsune, Yasuyoshi Watanabe
    The objective of our study was to develop a new fatigue scale for the assessment of patients with chronic fatigue syndrome (CFS) as well as people who feel they are chronically fatigued but do not meet the diagnostic criteria for CFS. A new fatigue scale was developed by one psychiatrist and two physicians who specialize in CFS. This scale consists of various psychosomatic symptoms, psychiatric symptoms, and diagnostic criteria for CFS. It was completed by 325 patients with CFS, 311 fatigue patients who did not fulfill the diagnostic criteria for CFS, 92 healthy workers, and 80 university students. The Chalder fatigue scale, the profile of mood states (POMS), the performance status (PS), which is included in the Japanese diagnostic criteria for CFS, and the visual analogue scale (VAS) for fatigue were also assessed with the agreement of patients who consulted our center from December 2004 to April 2006. Seventy-two university students also completed the questionnaire, including this new scale, the Chalder fatigue scale, and other lifestyle factors, and we reconfirmed the effectiveness of the new scale among fatigue patients with and without CFS and normal controls. There was a high degree of internal consistency in the results, and principal components analysis supported the notion of an 8-factor solution (42 items covering fatigue, anxiety and depression, loss of attention and memory, pain, overwork, autonomic imbalance, sleep problems, and infection). Only anxiety and depression, pain, and infection factors were able to distinguish CFS from not CFS. The sensitivity and specificity of CFS were 67.7 and 64.4, respectively, using a cut-off score of 25 points for this subscore. We concluded that the new fatigue scale used in this study was useful for differentiating CFS patients from not CFS patients and fatigued people from a healthy sample. © 2008 Springer Japan.
    Springer Japan, 2008, Fatigue Science for Human Health, 89 - 102, English
    [Refereed]
    In book

  • A submicrogram-scale protocol for biomolecule-based PET imaging by rapid 6pi-azaelectrocyclization: visualization of sialic acid dependent circulatory residence of glycoproteins.
    Katsunori Tanaka, Tatsuro Masuyama, Koki Hasegawa, Tsuyoshi Tahara, Hiroshi Mizuma, Yasuhiro Wada, Yasuyoshi Watanabe, Koichi Fukase
    2008, Angewandte Chemie (International ed. in English), 47(1) (1), 102 - 5, English, International magazine
    Scientific journal

  • Masahiro Yoshida, Masaaki Tanaka, Kei Mizuno, Akira Ishii, Kumi Nozaki, Ayako Urakawa, Yuki Cho, Yosky Kataoka, Yasuyoshi Watanabe
    Motivation is an important psychological concept in academic learning. Subjects performed jigsaw puzzle and square puzzle sessions (as difficulty variant task) and 80%, 50%, and 20% completion sessions (as completion variant task). After square puzzle or 20% completion sessions, subjective motivation decreased. Although baseline scores on an academic motivation scale were negatively correlated with changes in subjective motivation for the square puzzle session, a positive correlation was observed for the 20% completion session. These suggest that while continual completion of facile task trials may support the motivation of college students with lower academic motivation, attempting difficult task trials may sustain that of those with higher academic motivation.
    INFORMA HEALTHCARE, 2008, INTERNATIONAL JOURNAL OF NEUROSCIENCE, 118(10) (10), 1400 - 1411, English, International magazine
    [Refereed]
    Scientific journal

  • Morphological changes of cortical NG2+cells in cerebral neocortex of aged rats
    Yasuhisa Tamura, Mitsuyo Maeda, Kayo Takahashi, Yilong Cui, Yasuyoshi Watanabe, Yosky Kataoka
    ELSEVIER IRELAND LTD, 2008, NEUROSCIENCE RESEARCH, 61, S158 - S158, English

  • Takashima Tadayuki, kusuhara Hiroyuki, Sugiyama Yuichi, Watanabe Yasuyoshi, Kitamura Satoshi, Nagata Hiroko, Doi Hisashi, Nakae Takahiro, Wada Yasuhiro, Cui Yilong, Suzuki Masaaki, Maeda Kazuya
    The Japanese Society for the Study of Xenobiotics, 2008, Abstracts of Annual meeting of Japanese Society for the Study of Xenobiotics, 23(0) (0), 76 - 76, Japanese

  • Kataoka Yosky, Cui Yilong, Tamura Yasuhisa, Yamato Masanori, Jin Guanghua, Watanabe Yasuyoshi
    Two experimental animal models for central fatigue have been developed by excessive activation of the central nervous system of rats; induction of cortical spreading depression, the propagation of neuronal membrane depolarization throughout the cerebral cortex, and long-term intracranial self-stimulation. We have reported that prostaglandins including PGD2, PGE2, and PGF were produced by COX-2 expression in neurons in the cerebral cortex following cortical spreading depression. In such a model for neuronal excitation in the cortex, the amount of non-REM sleep, but not of REM sleep, increased subsequently for several hours in the animals, and the increase was completely attenuated by application of NS-398, a COX-2 inhibitor. In a long-term intracranial self-stimulation study, resting behavior and non-REM sleep appeared a few hours after the start of stimulation, and such behavioral changes were also inhibited by application of an inhibitor of COX-2. These observations indicate that arachidonic acid cascade plays an important role in a common molecular and neural system in such animal models for fatigue following neuronal activation in the central nervous system, and relieves excessive brain activity by inducing resting behavior and non-REM sleep. [J Physiol Sci. 2008;58 Suppl:S18]
    PHYSIOLOGICAL SOCIETY OF JAPAN, 2008, Proceedings of Annual Meeting of the Physiological Society of Japan, 2008(0) (0), 18 - 18

  • Nojima J, Masuda Y, Iwatani Y, Suehisa E, Futsukaichi Y, Kuratsune H, Watanabe Y, Takano T, Hidaka Y, Kanakura Y
    Our aim was to clarify the role of anti-phospholipid antibodies in the pathogenesis of monocyte tissue factor (TF) expression and thromboembolic complications (TE) in patients with SLE. We examined cell surface expression of TF on monocytes in 93 SLE patients. Monocyte TF expression was significantly higher in SLE patients who had TE than in other SLE patients, and confirmed that the high expression of monocyte TF was a strong risk factor for TE. Furthermore, the presence of anti-cardiolipin/beta2-glycoprotein I antibodies (anti-CL/beta2-GPI) was strongly associated with the high expression of monocyte TF. We therefore studied the in vitro effect of IgG anti-CL/beta2-GPI on lipopolysaccharide (LPS)-induced expression of TF on monocytes in healthy peripheral blood and found that purified IgG containing anti-CL/beta2-GPI significantly enhanced LPS-induced monocyte TF expression. These results suggest that anti-CL/beta2-GPI cause persistently high TF expression on monocyte, which may contribute to the risk of thromboembolic events in SLE patients.
    2008, Biochem Biophys Res Commun., 365(1) (1), 195 - 200, Japanese, International magazine
    [Refereed]
    Others

  • Nojima J, Masuda Y, Iwatani Y, Kuratsune H, Watanabe Y, Suehisa E, Takano T, Hidaka Y, Kanakura Y
    2008, Rheumatology, 47, 684 - 689, Japanese
    [Refereed]
    Scientific journal

  • Effects of increased endogenous serotonin on the in vivo binding of [11C]DASB to serotonin transporters in conscious monkey brain.
    Shigeyuki Yamamoto, Hirotaka Onoe, Hideo Tsukada, Yasuyoshi Watanabe
    Using a combination of positron emission tomography (PET) and the microdialysis technique, the effects of increased endogenous serotonin (5-hydroxytryptamine; 5-HT) on the binding of [(11)C]DASB to 5-HT transporters (5-HTT) were investigated in the conscious monkey brain. Five rhesus monkeys (Macaca mulatta) were scanned with [(11)C]DASB under the control condition and the increased endogenous 5-HT condition, in which 5-hydroxy-L-tryptophan (5-HTP) was administered (20 mg/kg, i.v.) before the PET scan. Compared with the control scan, the 5-HTP administration significantly decreased the binding potential (BP) (BP = B(max)/K(d)) of [(11)C]DASB in several brain regions. The mean % decrease of BP was biggest in the caudate and putamen. Two monkeys were scanned with [(11)C]5-HTP to assess the amino acid decarboxylase (AADC) activity in the brain, resulting in the high activity in the caudate and putamen. Microdialysis measurements showed that although 5-HTP administration (20 mg/kg, i.v.) increased the extracellular 5-HT levels in both the prefrontal cortex and caudate, the increase of the 5-HT level in the caudate was 27 times higher than that in the prefrontal cortex. These results suggest that the caudate and putamen, both of which show high AADC activity, convert 5-HTP to 5-HT at a high rate, and the increased 5-HT competes with [(11)C]DASB for the 5-HTT.
    Sep. 2007, Synapse (New York, N.Y.), 61(9) (9), 724 - 31, English, International magazine
    Scientific journal

  • Y. Tamura, Y. Kataoka, Y. Cui, Y. Takamori, Y. Watanabe, H. Yamada
    Glutathione S-transferase (GST)-pi is a cytosolic isoenzyme used as a marker for mature oligodendrocytes in the mammalian brain. However, the cellular properties of GST-pi-immunoreactive [GST-pi (+)] cells in adult brain are not completely understood. We immunohistochemically demonstrated the existence of two subtypes of GST-pi (+) cells in the cerebral cortex of adult rats: one subtype exhibited GST-pi in the cytoplasm (C-type cells), while the other did mainly in the nucleus (N-type cells). The GST-pi (+) C-type cells were also immunopositive for 2 ',3 '-cyclic nucleotide 3 '-phosphodiesterase and RIP, indicating that they were mature oligodendrocytes, while the GST-pi (+) N-type cells expressed NG2, indicating that they were oligodendrocyte progenitor cells. Furthermore, observation of the fate of newly-generated cells by 5-bromodeoxyuridine-labeling revealed that the GST-pi (+) N-type cells differentiated into C-type cells. These findings indicate translocation of GST-pi from the nucleus to the cytoplasm during oligodendrocyte maturation. (c) 2007 IBRO. Published by Elsevier Ltd. All rights reserved.
    PERGAMON-ELSEVIER SCIENCE LTD, Aug. 2007, NEUROSCIENCE, 148(2) (2), 535 - 540, English
    [Refereed]
    Scientific journal

  • [Molecular/neural mechanisms of fatigue].
    Yasuyoshi Watanabe
    Jun. 2007, Nihon rinsho. Japanese journal of clinical medicine, 65(6) (6), 972 - 4, Japanese, Domestic magazine
    Scientific journal

  • [Estimation of fatigue state in patient with CFS using actigraph and R-R interval power spectrum analysis].
    Seiki Tajima, Hirohiko Kuratsune, Kouzi Yamaguti, Ayumi Takahashi, Shoko Takashima, Yasuyoshi Watanabe, Yoshiki Nishizawa
    OBJECTIVES: In this study, we try to estimate the fatigue state using actigraphy and R-R interval power spectrum analysis. RESULTS: Actigraphy analysis showed that mean awake activity was decreased and duration of sleep was prolonged in patients with chronic fatigue syndrome (CFS), significantly (p < 0.001). Both of sleep episodes in wake period and wake episodes in sleep period were significantly increased in CFS patients in comparison with healthy volunteers (p < 0.001) In autonomic nerve analysis, sleep/awake ratio of high frequency component was significantly decreased in patients with CFS (p < 0.05). CONCLUSION: The quality of sleep in patients with CFS was decreased because of increase of wake episodes in sleep period. Also the lack of parasympathetic activation during sleep period might be associated with the deterioration of sleep quality in patients with CFS.
    Jun. 2007, Nihon rinsho. Japanese journal of clinical medicine, 65(6) (6), 1057 - 64, Japanese, Domestic magazine
    Scientific journal

  • Yasuhisa Tamura, Yosky Kataoka, Yilong Cui, Yasuharu Takamori, Yasuyoshi Watanabe, Hisao Yamada
    In the adult mammalian brain, multipotent stem or progenitor cells involved in reproduction of neurons and glial cells have been well investigated only in very restricted regions; the subventricular zone of the lateral ventricle and the dentate gyrus in the hippocampal formation. In the neocortex, a series of in vitro studies has suggested the possible existence of neural progenitor cells possessing neurogenic and/or gliogenic potential in adult mammals. However, the cellular properties of the cortical progenitor cells in vivo have not been fully elucidated. Using 5 '-bromodeoxyuridine labeling and immunohistochemical analysis of cell differentiation markers, we found that a subpopulation of NG2-immunopositive cells co-expressing doublecortin (DCX), an immature neuron marker, ubiquitously reside in the adult rat neocortex. Furthermore, these cells are the major population of proliferating cells in the region. The DCX(+)/NG2(+) cells reproduced the same daughter cells, or differentiated into DCX(+)/NG2(-) (approximately 1%) or DCX(-)/NG2(+) (approximately 10%) cells within 2 weeks after cell division. The DCX(+)/NG2(-) cells were also immunopositive for TUC-4, a neuronal linage marker, suggesting that these cells were committed to neuronal cell differentiation, whereas the DCX(-)/NG2(+) cells showed faint immunoreactivity for glutathione S-transferase (GST)-pi, an oligodendrocyte lineage marker, in the cytoplasm, suggesting glial cell lineage, and thereafter the cells differentiated into NG2(-)/GST-pi(+) mature oligodendrocytes after a further 2 weeks. These findings indicate that DCX(+)/NG2(+) cells ubiquitously exist as 'multipotent progenitor cells' in the neocortex of adult rats.
    BLACKWELL PUBLISHING, Jun. 2007, EUROPEAN JOURNAL OF NEUROSCIENCE, 25(12) (12), 3489 - 3498, English, International magazine
    [Refereed]
    Scientific journal

  • Effects of Applephenon and ascorbic acid on physical fatigue.
    Suzuka Ataka, Masaaki Tanaka, Satoshi Nozaki, Hiroshi Mizuma, Kei Mizuno, Tsuyoshi Tahara, Tomohiro Sugino, Tomoko Shirai, Yoshitaka Kajimoto, Hirohiko Kuratsune, Osami Kajimoto, Yasuyoshi Watanabe
    OBJECTIVE: We examined the effects of Applephenon and ascorbic acid administration on physical fatigue. METHODS: In a double-blinded, placebo-controlled, three-way crossover design, 18 healthy volunteers were randomized to oral Applephenon (1200 mg/d), ascorbic acid (1000 mg/d), or placebo for 8 d. The fatigue-inducing physical task consisted of workload trials on a bicycle ergometer at fixed workloads for 2 h on two occasions. During the test, subjects performed non-workload trials with maximum velocity for 10 s at 30 min (30-min trial) after the start of the test and 30 min before the end of the test (210-min trial). RESULTS: The change in maximum velocity between the 30- and 210-min trials was higher in the group given Applephenon than in the group given placebo; ascorbic acid had no effect. CONCLUSION: These results suggest that Applephenon attenuates physical fatigue, whereas ascorbic acid does not.
    May 2007, Nutrition (Burbank, Los Angeles County, Calif.), 23(5) (5), 419 - 23, English, International magazine
    Scientific journal

  • [Molecular imaging for drug development].
    Yasuyoshi Watanabe
    In vivo molecular imaging has become a key technology for drug development and pathophysiological science. We are mostly utilizing PET (positron emission tomography) as a first-choice modality, because of its ultra-high sensitivity for molecules, adequate temporal and spatial resolution, and especially broad spectrum of target molecules. The present status for development of PET molecular probes, instrumentations including microPET, and the methods for quantitative analyses will be introduced with some examples. In vivo molecular imaging could bring the high-quality information about: (1) Molecular diagnosis for living patients with symptoms (2) Closer approach for etiology and differential diagnosis (3) Direct follow-up of key molecules as disease markers (4) Pharmacokinetics/Pharmacodynamics in primates/human (5) Dose finding information for individuals, corresponding to SNP (6) Direct evidence for accumulation in non-target organs: Related to adverse effects (7) Drug effects with surrogate markers (8) Early decision of dropout substances (drug candidates). In 2005, RIKEN and National Institute of Radiological Science were selected as the key centers for development of All-Japan research network to further promote mutual international and multi-disciplinary collaboration on in vivo molecular imaging. On this occasion, the concept and project themes will also be introduced.
    Mar. 2007, Brain and nerve = Shinkei kenkyu no shinpo, 59(3) (3), 209 - 14, Japanese, Domestic magazine
    Scientific journal

  • Decrease of hepatic delta-aminolevulinate dehydratase activity in an animal model of fatigue.
    Tsuyoshi Tahara, Masaaki Tanaka, Satoshi Nozaki, Guanghua Jin, Hirotaka Onoe, Yasuyoshi Watanabe
    Fatigue can be defined physiologically as inability to maintain the expected power output. At present, no standard of fatigue are yet available. In order to find biomarkers of fatigue, we investigated the level of delta-aminolevulinic acid (ALA), the first intermediate metabolite in the heme biosynthetic pathway, in the plasma and urine of an animal model of fatigue. To prepare fatigued animals, we kept rats for 5 days in a cage filled with water to a height of 1.5 cm. As a result, the plasma and urinary ALA levels were increased in the fatigued animals as compared with those in the control animals. One day after the rats had been returned to their normal cages, these increased levels were restored to the control ones. We also examined the activity of the enzyme ALA dehydratase (ALAD), which is the second enzyme in the heme biosynthetic pathway, and ALAD gene expression during the fatigue and its recovery sessions. The ALAD activity, as well as its gene expression, in the liver of the fatigued animals was decreased as compared with those of the control animals. Both activity and gene expression of ALAD were recovered to their respective control levels after the rats had been allowed to rest in their normal cages for 1 day. Furthermore, the activity of ALA synthase (ALAS), the rate-limiting enzyme in the heme biosynthesis, in the liver was increased after the fatigue session for 5 days. Although this level of increase in the plasma concentration of ALA may not induce fatigue, increase in plasma and urinary ALA levels can be biomarkers of fatigue.
    Feb. 2007, Biochemical and biophysical research communications, 353(4) (4), 1068 - 73, English, International magazine
    Scientific journal

  • [Molecular/neural mechanisms of fatigue and the way to overcome fatigue].
    Yasuyoshi Watanabe
    Feb. 2007, Nihon yakurigaku zasshi. Folia pharmacologica Japonica, 129(2) (2), 94 - 8, Japanese, Domestic magazine
    Scientific journal

  • [Molecular imaging for drug development].
    Yasuyoshi Watanabe
    In vivo molecular imaging has become a key technology for pathophysiological science and drug development. We are mostly utilizing PET(positron emission tomography) as a first-choice modality, because of its ultra-high sensitivity for molecules, adequate temporal and spatial resolution, and especially broad spectrum of target molecules. In vivo molecular imaging could bring the high-quality information about: 1. Molecular diagnosis for living patients with symptoms 2. Closer approach for etiology and differential diagnosis 3. Direct follow-up of key molecules as disease markers 4. Pharmacokinetics/Pharmacodynamics in primates/human 5. Dose finding information for individuals, corresponding to SNPs 6. Direct evidence for accumulation in non-target organs related to adverse effects 7. Drug effects with surrogate markers 8. Early decision of dropout substances (drug candidates) Here, the examples are shown as beta-amyloid imaging for Alzheimer's and mild cognitive impairment, serotonin transporter imaging for chronic fatigue, and dopaminergic components imaging for evaluation of drug for autistic spectrum disorder. In 2005, RIKEN and National Institute of Radiological Science were selected as the key centers for development of All-Japan research network to further promote mutual international and multi -disciplinary collaboration on in vivo molecular imaging.
    Feb. 2007, Nihon rinsho. Japanese journal of clinical medicine, 65(2) (2), 357 - 62, Japanese, Domestic magazine
    Scientific journal

  • Increase in [11C]vorozole binding to aromatase in the hypothalamus in rats treated with anabolic androgenic steroids.
    Kayo Takahashi, Mathias Hallberg, Kristina Magnusson, Fred Nyberg, Yasuyoshi Watanabe, Bengt Långström, Mats Bergström
    In the present study, we investigated the alteration of aromatase expression in the brain by anabolic androgenic steroid treatment in male rats. The rats were given nandrolone decanoate (15 mg/kg/day) for 14 days, and the brains were used for autoradiography with [C]vorozole, which has been developed as a positron emission tomography tracer for aromatase by our group. The results indicated a significant increase of [C]vorozole binding by anabolic androgenic steroids in the bed nucleus of the stria terminalis and preoptic area. In contrast, no significant change of [C]vorozole binding was observed in the medial amygdala. Our results suggest that aromatase is significantly upregulated in the bed nucleus of the stria terminalis and preoptic area by anabolic androgenic steroids and also suggest that androgens regulate aromatase differently in these structures compared with the medial amygdala.
    Jan. 2007, Neuroreport, 18(2) (2), 171 - 4, English, International magazine
    Scientific journal

  • Comparison of dynamic FDG-microPET study in a rabbit turpentine-induced inflammatory model and in a rabbit VX2 tumor model.
    Yoshimasa Hamazawa, Koichi Koyama, Terue Okamura, Yasuhiro Wada, Tomoko Wakasa, Tomohisa Okuma, Yasuyoshi Watanabe, Yuichi Inoue
    PURPOSE: We investigated the optimum time for the differentiation tumor from inflammation using dynamic FDG-microPET scans obtained by a MicroPET P4 scanner in animal models. MATERIALS AND METHODS: Forty-six rabbits with 92 inflammatory lesions that were induced 2, 5, 7, 14, 30 and 60 days after 0.2 ml (Group 1) or 1.0 ml (Group 2) of turpentine oil injection were used as inflammatory models. Five rabbits with 10 VX2 tumors were used as the tumor model. Helical CT scans were performed before the PET studies. In the PET study, after 4 hours fasting, and following transmission scans and dynamic emission data acquisitions were performed until 2 hours after intravenous FDG injection. Images were reconstructed every 10 minutes using a filtered-back projection method. PET images were analyzed visually referring to CT images. For quantitative analysis, the inflammation-to-muscle (I/M) ratio and tumor-to-muscle (T/M) ratio were calculated after regions of interest were set in tumors and muscles referring to CT images and the time-I/M ratio and time-T/M ratio curves (TRCs) were prepared to show the change over time in these ratios. The histological appearance of both inflammatory lesions and tumor lesions were examined and compared with the CT and FDG-microPET images. RESULTS: In visual and quantitative analysis, All the I/M ratios and the T/M ratios increased over time except that Day 60 of Group 1 showed an almost flat curve. The TRC of the T/M ratio showed a linear increasing curve over time, while that of the I/M ratios showed a parabolic increasing over time at the most. FDG uptake in the inflammatory lesions reflected the histological findings. For differentiating tumors from inflammatory lesions with the early image acquired at 40 min for dual-time imaging, the delayed image must be acquired 30 min after the early image, while imaging at 90 min or later after intravenous FDG injection was necessary in single-time-point imaging. CONCLUSION: Our results suggest the possibility of shortening the overall testing time in clinical practice by adopting dual-time-point imaging rather than single-time-point imaging.
    Jan. 2007, Annals of nuclear medicine, 21(1) (1), 47 - 55, English, Domestic magazine
    Scientific journal

  • Nojima J, Sakudo A, Hakariya Y, Kuratsune H, Watanabe Y, Kanakura Y, Ikuta K
    The purpose of this study was to investigate whether visible and near-infrared (Vis-NIR) spectroscopy can be used for diagnoses of anti-phospholipid syndrome (APS). Vis-NIR spectra from 90 plasma samples [anti-phospholipid antibodies (aPLs)-positive group, n=48; aPLs-negative group, n=42] were subjected to principal component analysis (PCA) and soft independent modeling of class analogy (SIMCA) to develop multivariate models to discriminate between aPLs-positive and aPLs-negative. Both PCA and SIMCA models were further assessed by the prediction of 84 masked other determinations. The PCA model predicted successful discrimination of the masked samples with respect to aPLs-positive and aPLs-negative. The SIMCA model predicted 42 of 48 (87.5%) aPLs-positive patients and 33 of 36 (91.7%) aPLs-negative patients of Vis-NIR spectra from masked samples correctly. These results suggest that Vis-NIR spectroscopy combined with multivariate analysis could provide a promising tool to objectively diagnose APS.
    2007, Biochem Biophys Res Commun., 362(2) (2), 522 - 524, Japanese, International magazine
    [Refereed]
    Scientific journal

  • Yilong Cui, Hiroyuki Takamatsu, Takeharu Kakiuchi, Hiroyuki Ohba, Yosky Kataoka, Chihiro Yokoyama, Hirotaka Onoe, Yumiko Watanabe, Takamitsu Hosoya, Masaaki Suzuki, Ryoji Noyori, Hideo Tsukada, Yasuyoshi Watanabe
    Background and Purpose-Recently, we found that a novel subtype of prostacyclin (PGI(2)) receptor clearly distinct from the peripheral subtype in terms of ligand specificity is expressed in the central nervous system (CNS). (15R)-16-m-tolyl-17,18,19,20-tetranorisocarbacyclin (15R-TIC) was synthesized and demonstrated to be a specific ligand for this CNS-type PGI(2) receptor. Previously, we demonstrated 15R-TIC to be neuroprotective in vivo during transient forebrain ischemia in gerbils and permanent middle cerebral artery occlusion (MCAO) in rats. Furthermore, this compound was shown to exert an anti-apoptotic effect on primary cultured hippocampal neurons, indicating its neuroprotective effect against ischemic insults occurs via direct action on CNS-type PGI(2) receptor.Methods-Local cerebral hemodynamics and oxygen metabolism were measured simultaneously by using positron emission tomography with the O-15 steady-state method, before and up to 18 hours after 3-hour transient MCAO reperfusion in cynomolgus monkeys. Methyl ester of 15R-TIC (50 mu g/kg, n=4) or its vehicle (10% Intralipos, n=4) was injected intravenously within 5 minutes after onset of MCAO and continuously infused for 5 hours (50 mu g/kg per hour).Results-Neuropathology showed that 15R-TIC significantly reduced cortical damage after 3-hour MCAO. Positron emission tomography results showed 15R-TIC significantly reduced the volume of "infarct" region of interest and attenuated the decrease in cerebral metabolic rate of oxygen and oxygen extraction fraction, and these protective effects were not attributable to improvement of cerebral circulation.Conclusions-These results suggest that 15R-TIC has a potent neuroprotective effect against focal cerebral ischemia in a monkey MCAO via its direct action on CNS-type PGI(2) receptors.
    LIPPINCOTT WILLIAMS & WILKINS, Nov. 2006, STROKE, 37(11) (11), 2830 - 2836, English, International magazine
    [Refereed]
    Scientific journal

  • 18F-FDG small-animal PET for monitoring the therapeutic effect of CT-guided radiofrequency ablation on implanted VX2 lung tumors in rabbits.
    Tomohisa Okuma, Toshiyuki Matsuoka, Terue Okamura, Yasuhiro Wada, Akira Yamamoto, Yoshimasa Oyama, Koichi Koyama, Kenji Nakamura, Yasuyoshi Watanabe, Yuichi Inoue
    UNLABELLED: The primary goals of this study were to investigate the behavior of normal lung tissues after radiofrequency ablation (RFA) and to determine the suitability of 18F-FDG PET, using a dedicated small-animal scanner, for monitoring the early therapeutic effects of RFA on VX2 lung tumors (VX2s) in rabbits. METHODS: Fourteen Japanese white rabbits with normal lungs underwent RFA, followed by 18F-FDG PET at 1 d and at 1, 2, 4, and 8 wk. In addition, 7 rabbits with untreated VX2s underwent 18F-FDG PET, and 13 rabbits with RFA-treated VX2s underwent 18F-FDG PET at 1 d (n = 7) or 1 wk (n = 6) after the treatment. RESULTS: After RFA of normal lungs, ring-shaped accumulations of 18F-FDG, which coincided with inflammation caused by ablation, were observed. The mean early- (40-60 min after injection) and delayed (100-120 min)-phase ablated lesion-to-muscle ratios were, respectively, 2.9 +/- 1.0 and 3.3 +/- 0.8 (1 d), 4.1 +/- 0.6 and 5.2 +/- 0.9 (1 wk), 4.1 +/- 1.0 and 5.3 +/- 1.5 (2 wk), 3.1 +/- 0.5 and 3.6 +/- 1.1 (4 wk), and 1.8 +/- 0.1 and 2.3 +/- 0.1 (8 wk). At 4 and 8 wk, the uptake was less than that at 1 and 2 wk (P < 0.05). VX2s showed mean tumor-to-muscle ratios of 6.6 +/- 2.1 and 8.6 +/- 3.3 at the early and delayed phases, respectively. For ablated tumors, the respective ratios were 0.8 +/- 0.4 and 1.1 +/- 0.7 (1 d) and 1.2 +/- 0.5 and 1.5 +/- 0.7 (1 wk). These values were significantly lower than those for nonablated tumors (P < 0.001). Histopathologic examination confirmed the absence of viable tumors. 18F-FDG accumulation around ablated tumors reflected thermally damaged normal tissues and was significantly lower than that of control VX2s (P < 0.01). CONCLUSION: Our data suggest that 18F-FDG PET is promising for evaluating the therapeutic response of lung malignancies to RFA: Accumulation of 18F-FDG in surrounding normal tissues appears to be time dependent, and the data suggest that, clinically, 18F-FDG PET should be performed 4 wk or more after RFA. Delayed-phase images seem to better distinguish tumor from inflammation than do early-phase images.
    Aug. 2006, Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 47(8) (8), 1351 - 8, English, International magazine
    Scientific journal

  • Spectroscopic diagnosis of chronic fatigue syndrome by visible and near-infrared spectroscopy in serum samples.
    Akikazu Sakudo, Hirohiko Kuratsune, Takanori Kobayashi, Seiki Tajima, Yasuyoshi Watanabe, Kazuyoshi Ikuta
    To investigate visible and near-infrared (Vis-NIR) spectroscopy enabling chronic fatigue syndrome (CFS) diagnosis, we subjected sera from CFS patients as well as healthy donors to Vis-NIR spectroscopy. Vis-NIR spectra in the 600-1100 nm region for sera from 77 CFS patients and 71 healthy donors were subjected to principal component analysis (PCA) and soft independent modeling of class analogy (SIMCA) to develop multivariate models to discriminate between CFS patients and healthy donors. The model was further assessed by the prediction of 99 masked other determinations (54 in the healthy group and 45 in the CFS patient group). The PCA model predicted successful discrimination of the masked samples. The SIMCA model predicted 54 of 54 (100%) healthy donors and 42 of 45 (93.3%) CFS patients of Vis-NIR spectra from masked serum samples correctly. These results suggest that Vis-NIR spectroscopy for sera combined with chemometrics analysis could provide a promising tool to objectively diagnose CFS.
    Jul. 2006, Biochemical and biophysical research communications, 345(4) (4), 1513 - 6, English, International magazine
    Scientific journal

  • Imaging of aromatase distribution in rat and rhesus monkey brains with [11C]vorozole.
    Kayo Takahashi, Mats Bergström, Pernilla Frändberg, Eva-Lotta Vesström, Yasuyoshi Watanabe, Bengt Långström
    Aromatase is an enzyme that converts androgens to estrogens and may play a role in mood and mental status. The aim of this study was to demonstrate that brain aromatase distribution could be evaluated with a novel positron emission tomography (PET) tracer [(11)C]vorozole. Vorozole is a nonsteroidal aromatase inhibitor that reversibly binds to the heme domain of aromatase. In vitro experiments in rat brain, using frozen section autoradiography, illustrated specific binding in the medial amygdala (MA), the bed nucleus of stria terminalis (BST) and the preoptic area (POA) of male rat brain. Specific binding in female rat brain was found in the MA and the BST; however, the signals were lower than those of males. The K(d) of [(11)C]vorozole binding to aromatase in MA was determined to be 0.60+/-0.06 nM by Scatchard plot analysis using homogenates. An in vivo PET study in female rhesus monkey brain demonstrated the uptake of [(11)C]vorozole in the amygdala, where the uptake was blocked by the presence of excess amounts of unlabeled vorozole. Thus, this tracer has a high affinity for brain aromatase and could have a potential for in vivo aromatase imaging. This technique might enable the investigation of human brain aromatase in healthy and diseased persons.
    Jul. 2006, Nuclear medicine and biology, 33(5) (5), 599 - 605, English, International magazine
    Scientific journal

  • K Imamura, S Tanaka, J Ribot, M Kobayashi, M Yamamoto, K Nakadate, Y Watanabe
    We investigated how neural function is preserved or matured in the visual cortex of cats, following the induction of hydrocephalus by kaolin injection. In vivo optical imaging of intrinsic signals in 11-17-week-old hydrocephalic cats revealed orientation maps showing the orderly arrangement of preferred orientations when stimulated by grating stimuli at a low spatial frequency, whereas stimulus-evoked intrinsic signals in response to gratings at a high spatial frequency were often too weak to construct orientation maps. Furthermore, in two of the three hydrocephalic cats, initially deteriorated orientation maps became almost regular maps in the second imaging experiments conducted 8 and 11 weeks, respectively, after the first imaging. This indicates that, despite large structural deformation of the hydrocephalic brain, orientation maps are elaborated sufficiently after the age of 5-6 months, by which time the orientation map formation is usually completed in normal cats. Single unit recording from the decompressed visual cortex revealed that many neurons showed normal orientation selectivity, whereas the binocularity of these neurons was found to be reduced. These results suggested that the deformed visual cortex of hydrocephalic cats exhibits a high plasticity, retaining its functional organization.
    BLACKWELL PUBLISHING, Apr. 2006, EUROPEAN JOURNAL OF NEUROSCIENCE, 23(8) (8), 2087 - 2098, English, International magazine
    [Refereed]
    Scientific journal

  • Development of real-time bioradiographic system for functional and metabolic imaging in living brain tissue.
    Toru Sasaki, Akinori Iwamoto, Hisashi Tsuboi, Yasuyoshi Watanabe
    We have developed a novel imaging system "real-time bioradiography", which is able to estimate the dynamic changes of physiological function and metabolism in living tissues using positron emitter-labeled tracers and chemiluminescence probes. The apparatus is comprised of a photon-counting camera, image-controller, culturing chamber, reflexible solid scintillator and temperature-controlled imaging chamber. The image distribution of radioactivity and chemiluminescence was acquirable with the reflexible solid scintillator and without, respectively. The reflexible solid scintillator is effective to exclude the affect of intra-objective different light reflectivity on radiation detection and to improve the efficiency of radiation detection. To test and to demonstrate the efficacy of this system, we examined the glucose metabolism and superoxide formation during hypoxia-reoxygenation in living brain tissues using 2-[18F]fluoro-2-deoxy-D-glucose (FDG) and Lucigenin, respectively. FDG uptake and chemiluminescence images were obtained at time frames of every 15 min. Glucose metabolism was enhanced during the hypoxic treatment, but the superoxide formation was enhanced during reoxygenation. The enhanced glucose metabolism during hypoxia might cause the increase in superoxide formation during reoxygenation. Thus, this new method would open up possibilities to approach simultaneous biological monitoring of a variety of biochemical events with various combinations of positron emitter-labeled tracers and chemiluminescence probes in living tissues.
    Mar. 2006, Brain research, 1077(1) (1), 161 - 9, English, International magazine
    Scientific journal

  • Administration of secretin for autism alters dopamine metabolism in the central nervous system.
    Yoshihiro Toda, Kenji Mori, Toshiaki Hashimoto, Masahito Miyazaki, Satoshi Nozaki, Yasuyoshi Watanabe, Yasuhiro Kuroda, Shoji Kagami
    We evaluated the clinical effects of intravenously administered secretin in 12 children with autism (age range: 4-6 years, median age: 9 years, boy:girl=8:4). In addition, we investigated the association between improvement in symptoms and changes in the cerebrospinal fluid (CSF) homovanillic acid (HVA),5-hydroxyindole-3-acetic acid (5-HIAA), and 6R-5,6,7,8-tetrahydro-L-biopterin (BH(4)) levels after administration. After administration of secretin, the Autism Diagnostic Interview-Revised (ADI-R) score improved in 7 of the 12 children. However, the score deteriorated in 2 of the 12 children (in the item of 'restricted and repetitive, stereotyped interests and behaviors'). The HVA and BH(4) levels in CSF were increased in all children with improvement in the ADI-R score. In contrast, no patient without the elevation of the BH(4) level showed improvement in the score. These findings suggest that secretin activated metabolic turnover of dopamine in the central nervous system via BH(4), improving symptoms.
    Mar. 2006, Brain & development, 28(2) (2), 99 - 103, English, International magazine
    Scientific journal

  • Reduced responsiveness is an essential feature of chronic fatigue syndrome: a fMRI study.
    Masaaki Tanaka, Norihiro Sadato, Tomohisa Okada, Kei Mizuno, Tetsuya Sasabe, Hiroki C Tanabe, Daisuke N Saito, Hirotaka Onoe, Hirohiko Kuratsune, Yasuyoshi Watanabe
    BACKGROUND: Although the neural mechanism of chronic fatigue syndrome has been investigated by a number of researchers, it remains poorly understood. METHODS: Using functional magnetic resonance imaging, we studied brain responsiveness in 6 male chronic fatigue syndrome patients and in 7 age-matched male healthy volunteers. Responsiveness of auditory cortices to transient, short-lived, noise reduction was measured while subjects performed a fatigue-inducing continual visual search task. RESULTS: Responsiveness of the task-dependent brain regions was decreased after the fatigue-inducing task in the normal and chronic fatigue syndrome subjects and the decrement of the responsiveness was equivalent between the 2 groups. In contrast, during the fatigue-inducing period, although responsiveness of auditory cortices remained constant in the normal subjects, it was attenuated in the chronic fatigue syndrome patients. In addition, the rate of this attenuation was positively correlated with the subjective sensation of fatigue as measured using a fatigue visual analogue scale, immediately before the magnetic resonance imaging session. CONCLUSION: Chronic fatigue syndrome may be characterised by attenuation of the responsiveness to stimuli not directly related to the fatigue-inducing task.
    Feb. 2006, BMC neurology, 6, 9 - 9, English, International magazine
    Scientific journal

  • Usefulness of FDG-microPET for early evaluation of therapeutic effects on VX2 rabbit carcinoma.
    Kentaro Ishii, Masako N Hosono, Yasuhiro Wada, Mitsuyo Maeda, Satoko Kondo, Yoshie Takada, Takuhito Tada, Terue Okamura, Yasuyoshi Watanabe, Yuichi Inoue
    PURPOSE: The aim of this study was to determine the potential use of high-resolution FDG-microPET for predicting the primary effects of radiotherapy and/or hyperthermia on tumor-bearing rabbits. METHODS: Twenty-eight VX2 xenografts in the thighs of rabbits were divided into the following 5 treatment groups: radiotherapy at a single dose of 10, 20 or 30 Gy, hyperthermia (43 degrees Celsius, 1 hour), and the combination of radiotherapy and hyperthermia (10 Gy + 43 degrees Celsius, 1 hour). FDG-microPET images were obtained by using a microPET P4 system at pretreatment and at 24 hours and 7 days after treatment. For the evaluation by FDG-microPET, tumor/muscle (T/M) ratios, retention index [RI = (T/M ratio at 120 min - T/M ratio at 60 min) / T/M ratio at 60 min], and time activity curve (TAC) were acquired. RESULTS: We divided the xenografts into a responder group (partial response + stable disease, n=14) and a non-responder group (progressive disease, n = 14). The T/M ratio at 24 hours after the treatment in the responder group was decreased remarkably with that at pre-treatment (p < 0.05), while in the non-responder group it showed no significant change between the time points. The RI and TAC patterns were comparable to T/M ratios in each treatment group. T/M ratios, RI, and TAC indicated marked changes at the time point of 24 hours in the responder group, although the tumors did not show any significant hange in volume at that time. Photomicrographs of sections showed that the number of viable tumor cells in the responder group decreased at 24 hours after treatment and that inflammatory cell infiltration was marked and almost all viable tumor cells had disappeared by day 7 after treatment. CONCLUSION: These results suggest that early evaluation by FDG-microPET, especially 24 hours after treatment, is useful to predict the primary effects of the treatment. Histological analysis showed that inflammatory cell infiltration at 7 days after treatment was considered to be a cause of accumulation of FDG in the tumors that showed a significant decrease in tumor cell number. This false-positive should be noted when predicting tumor response by FDG accumulation.
    Feb. 2006, Annals of nuclear medicine, 20(2) (2), 123 - 30, English, Domestic magazine
    Scientific journal

  • K Imamura, H Morii, K Nakadate, T Yamada, N Mataga, Y Watanabe, N Mori
    Neuronal growth-associated proteins, including superior cervical ganglia clone 10 (SCG10) family molecules, play roles in neurite outgrowth and network formation as well as structural and functional plasticity. The present ontogenetic study revealed that the expression of neuronal growth-associated proteins in the visual cortex (VC) exhibited a sharp peak in the early postnatal period when growing lateral geniculate nucleus (LGN) axon terminals segregate into the ocular dominance columns depending on retinal activity. We then hypothesized that SCG10 family molecules, known for catastrophic factors of microtubules, play important roles in the formation of ocular dominance columns. To test this hypothesis, we studied whether: (i) monocular blockade of retinal activity changed the SCG10 expression in LGN and VC and (ii) brain-derived neurotrophic factor (BDNF) cortical infusion modified the expression of SCG10 family molecules and the number of excitatory/inhibitory cortical synapses. Using northern blot and in situ hybridization, we revealed that: (i) silencing retinal activity with tetrodotoxin eye injections dynamically reduced the expression of SCG10 mRNA and (ii) it was enhanced by BDNF in VC and LGN of kittens but not adult cats. These findings suggest that cortical infusion of BDNF and retinal activity up-regulate the expression of SCG10 in the LGN and VC and that up-regulated SCG10 in turn initiates marked reorganization of the microtuble network, eventually resulting in increase in synapse formation in the VC.
    BLACKWELL PUBLISHING, Feb. 2006, EUROPEAN JOURNAL OF NEUROSCIENCE, 23(3) (3), 637 - 648, English, International magazine
    [Refereed]
    Scientific journal

  • Two subtypes of NG2(+) cells in the perineuronal territory of the adult rat neocortex
    Yasuhisa Tamura, Yosky Kataoka, Yilong Cui, Yasuharu Takamori, Yasuyoshi Watanabe, Hisao Yamada
    ELSEVIER IRELAND LTD, 2006, NEUROSCIENCE RESEARCH, 55, S146 - S146, English

  • K. Nakadate, K. Imamura, Y. Watanabe
    Noradrenaline is thought to play modulatory roles in a number of physiological, behavioral, and cellular processes. Although many of these modulatory effects are mediated through alpha-1 adrenoceptors, basic knowledge of the cellular and subcellular distributions of these receptors is limited. We investigated the laminar distribution pattern of alpha-1 adrenoceptors in rat visual cortex, using immunohistochemistry at both light and electron microscopic levels. Affinity-purified anti-alpha-1 antibody was confirmed to react only with a single band of about 70-80 kDa in total proteins prepared from rat visual cortex. Alpha-1 adrenoceptors were widely distributed though all cortical layers, but relatively high in density in layers I, II/III, and V. Immunoreactivity was observed in both neuronal perikarya and processes including apical dendrites. In double-labeling experiments with anti-microtubule-associated protein 2, anti-neurofilament, anti-glial fibrillary acidic protein, anti-glutamic acid decarboxylase 65/67, anti-2-3-cyclic nucleotide 3-phosphodiesterase, and anti-tyrosine hydroxylase antibodies, alpha-1 adrenoceptors were found mainly in dendrites and somata of microtubule-associated protein 2-immunopositive neurons. About 20% of alpha-1 adrenoceptors were in GABAergic neurons. A small number of alpha-1 adrenoceptors were also distributed in axons of excitatory neurons, astrocytes, oligodendrocytes and noradrenergic fibers. Using an immunoelectron microscopic technique, numerous regions of alpha-1 adrenoceptor immunoreactivity were found in cell somata, on membranes of dendrites, and in postsynaptic regions. Moreover, a small number of immunoreaction products were also detected in axons and presynaptic sites. These findings provide the first quantitative evidence regarding the cellular and subcellular localization of alpha-1 adrenoceptor immunoreactivity in visual cortex. Moreover, the ultrastructural distribution of alpha-1 adrenoceptor immunoreactivity suggests that alpha-1 adrenoceptors are transported mainly into dendrites and that they exert effects at postsynaptic sites of neurons. © 2006 IBRO.
    2006, Neuroscience, 141(4) (4), 1783 - 1792, English
    [Refereed]
    Scientific journal

  • Altered expression of neprilysin family members in the pituitary gland of sleep-disturbed rats, an animal model of severe fatigue.
    Tokiko Ogawa, Sumiko Kiryu-Seo, Masaaki Tanaka, Hiroyuki Konishi, Nobuhisa Iwata, Takaomi Saido, Yasuyoshi Watanabe, Hiroshi Kiyama
    Alterations of the expression of some peptidases in the pituitary gland of a fatigued rat model were identified. Rats were kept in a cage filled with water to a height of 1.5 cm to disturb deep sleep. After 24-h sleep disturbance, expression of neutral endopeptidase 24.11 (neprilysin) mRNA was increased in the intermediate lobe of the pituitary gland, whereas the mRNA expression of another family member, damage-induced neuronal endopeptidase, which is normally expressed in a subgroup of anterior pituitary cells, was significantly suppressed. These alterations were demonstrated by RT-PCR, northern blotting and in situ hybridization. Other family members, such as neprilysin 2 and endothelin converting enzyme-1, did not show any change in mRNA expression. An increase of neprilysin mRNA expression was not seen in any other tissues of the sleep-disturbed rats. The enzymatic activity of neprilysin was also increased in the pituitary. The augmentation of neprilysin expression and activity was prolonged as long as the sleep disturbance continued (up to 5 days), and returned to the basal level when rats were allowed to sleep freely. These results suggest that peptide processing and degradation in the pituitary may be an influential factor in fatigued states such as sleep disturbance.
    Nov. 2005, Journal of neurochemistry, 95(4) (4), 1156 - 66, English, International magazine
    Scientific journal

  • Tetrahydrobiopterin in the treatment of children with autistic disorder: a double-blind placebo-controlled crossover study.
    Torsten Danfors, Anne-Liis von Knorring, Per Hartvig, Bengt Langstrom, Robert Moulder, Bo Stromberg, Richard Torstenson, Ulrika Wester, Yasuyoshi Watanabe, Orvar Eeg-Olofsson
    Twelve children, all boys, aged 4 to 7 years, with a diagnosis of autistic disorder and low concentrations of spinal 6R-l-erythro-5,6,7,8-tetrahydrobiopterin (tetrahydrobiopterin) were selected to participate in a double-blind, randomized, placebo-controlled, crossover study. The children received a daily dose of 3 mg tetrahydrobiopterin per kilogram during 6 months alternating with placebo. Treatment-induced effects were assessed with the Childhood Autism Rating Scale every third month. The results showed small nonsignificant changes in the total scores of Childhood Autism Rating Scale after 3- and 6-month treatment. Post hoc analysis looking at the 3 core symptoms of autism, that is, social interaction, communication, and stereotyped behaviors, revealed a significant improvement of the social interaction score after 6 months of active treatment. In addition, a high positive correlation was found between response of the social interaction score and IQ. The results indicate a possible effect of tetrahydrobiopterin treatment.
    Oct. 2005, Journal of clinical psychopharmacology, 25(5) (5), 485 - 9, English, International magazine
    Scientific journal

  • A dynamic shift of neural network activity before and after learning-set formation.
    Chihiro Yokoyama, Hideo Tsukada, Yasuyoshi Watanabe, Hirotaka Onoe
    Learning-set (LS) is a property of insight and hypothesis testing characterized by the ability to solve novel problems based on previous experiences with problem solving. However, the neural organization and mechanisms underlying LS remain unclear. To further characterize this process, positron emission tomography (PET) studies with [15O]H2O were performed to measure regional cerebral blood flow (rCBF) during the learning phase of the two-choice visual discrimination task under the LS paradigm in rhesus monkeys. When comparing studies before and after LS formation, the orbitofrontal and lateral prefrontal cortices were differentially activated, and functional connections between these structures and the striatum, which contributes to habit learning, were altered. We conclude that changes in the lateral prefrontal cortex during problem solving may contribute to the executive function of working memory and also inhibit control of a primitive learning system, thereby promoting LS formation.
    Jun. 2005, Cerebral cortex (New York, N.Y. : 1991), 15(6) (6), 796 - 801, English, International magazine
    Scientific journal

  • MicroPET detection of enhanced 18F-FDG utilization by PKA inhibitor in awake rat brain.
    Rie Hosoi, Akira Matsumura, Shigekazu Mizokawa, Masaaki Tanaka, Fusao Nakamura, Kaoru Kobayashi, Yasuyoshi Watanabe, Osamu Inoue
    To obtain PET imaging of glucose metabolism in the brains of conscious rats, a method of rat head fixation was developed. PET measurement with microPET was performed for 60 min after 18F-FDG injection. Significant enhancement of glucose utilization in the right striatum was observed with infusion of Rp-adenosine-3,5-cyclic phosphorothioate triethylamine (Rp-cAMPS). FDG uptake increments were also seen in the ipsilateral frontal cortex and thalamus. As initial FDG uptake in the brain was not significantly altered by Rp-cAMPS, increased glucose metabolism might be due to an increase in the phosphorylation rate by hexokinase rather than the delivery process from plasma to the brain. In contrast to awake rats, the effect of Rp-cAMPS was abolished by anesthesia using chloral hydrate, indicating that neuronal activity has an important role in short term regulation of hexokinase activity through the cAMP/PKA system in the brain. These results strongly demonstrated the value of measuring glucose utilization in the brains of conscious rats.
    Mar. 2005, Brain research, 1039(1-2) (1-2), 199 - 202, English, International magazine
    Scientific journal

  • Directed differentiation of telencephalic precursors from embryonic stem cells.
    Kiichi Watanabe, Daisuke Kamiya, Ayaka Nishiyama, Tomoko Katayama, Satoshi Nozaki, Hiroshi Kawasaki, Yasuyoshi Watanabe, Kenji Mizuseki, Yoshiki Sasai
    We demonstrate directed differentiation of telencephalic precursors from mouse embryonic stem (ES) cells using optimized serum-free suspension culture (SFEB culture). Treatment with Wnt and Nodal antagonists (Dkk1 and LeftyA) during the first 5 d of SFEB culture causes nearly selective neural differentiation in ES cells ( approximately 90%). In the presence of Dkk1, with or without LeftyA, SFEB induces efficient generation ( approximately 35%) of cells expressing telencephalic marker Bf1. Wnt3a treatment during the late culture period increases the pallial telencephalic population (Pax6(+) cells yield up to 75% of Bf1(+) cells), whereas Shh promotes basal telencephalic differentiation (into Nkx2.1(+) and/or Islet1/2(+) cells) at the cost of pallial telencephalic differentiation. Thus, in the absence of caudalizing signals, floating aggregates of ES cells generate naive telencephalic precursors that acquire subregional identities by responding to extracellular patterning signals.
    Mar. 2005, Nature neuroscience, 8(3) (3), 288 - 96, English, International magazine
    Scientific journal

  • Prevention and/or recovery effects by green odor(s) on fatigue and green-odor-responsible brain regions as revealed by PET.
    Yasuyoshi Watanabe, Tetsuya Sasabe, Kouzi Yamaguti, Masayuki Kobayashi, Shigeyuki Yamamoto, Hirohiko Kuratsune, Kouta Sano, Akikazu Hatanaka, Hideo Tsukada, Hirotaka Onoe
    Jan. 2005, Chemical senses, 30 Suppl 1, i268-9, English, International magazine
    Scientific journal

  • Reduction of serotonin transporters of patients with chronic fatigue syndrome.
    Shigeyuki Yamamoto, Yasuomi Ouchi, Hirotaka Onoe, Etsuji Yoshikawa, Hideo Tsukada, Hidetoshi Takahashi, Masao Iwase, Kouzi Yamaguti, Hirohiko Kuratsune, Yasuyoshi Watanabe
    To assess the involvement of serotonin in the symptoms of chronic fatigue syndrome, we investigated the serotonergic neurotransmitter system of chronic fatigue syndrome patients by the positron emission tomography (PET). Here we show that the density of serotonin transporters (5-HTTs) in the brain, as determined by using a radiotracer, [C](+)McN5652, was significantly reduced in the rostral subdivision of the anterior cingulate as compared with that in normal volunteers. This subdivision is different from that in the dorsal anterior cingulate in which binding potential values of individual patient showed a weak negative correlation with self-reported pain score of the patients. Therefore, an alteration of serotonergic system in the rostral anterior cingulate plays a key role in pathophysiology of chronic fatigue syndrome.
    Dec. 2004, Neuroreport, 15(17) (17), 2571 - 4, English, International magazine
    Scientific journal

  • Functional imaging of gustatory perception and imagery: "top-down" processing of gustatory signals.
    Masayuki Kobayashi, Masaki Takeda, Noriaki Hattori, Masaki Fukunaga, Tetsuya Sasabe, Noriko Inoue, Yasuo Nagai, Tohru Sawada, Norihiro Sadato, Yasuyoshi Watanabe
    By recalling gustatory memories, it is possible to generate vivid gustatory perceptions in the absence of gustatory inputs. This gustatory image influences our gustatory processing. However, the mechanism of the "top-down" modulation of gustatory perception in the human is still unclear. Our findings propose a new perspective on the neural basis of gustatory processing. Although gustatory imagery and gustatory perception shared common parts of neural substrates, there was an asymmetrical topography of activation in the insula: the left insula was predominantly activated by gustatory imagery tasks. In addition, the middle and superior frontal gyri were not activated by gustatory perception but they participated in the generation of gustatory hallucinations. These regions in the frontal cortex may mediate the "top-down" control of retrieving gustatory information from the storage of long-term memories.
    Dec. 2004, NeuroImage, 23(4) (4), 1271 - 82, English, International magazine
    Scientific journal

  • Mechanisms underlying fatigue: a voxel-based morphometric study of chronic fatigue syndrome.
    Tomohisa Okada, Masaaki Tanaka, Hirohiko Kuratsune, Yasuyoshi Watanabe, Norihiro Sadato
    BACKGROUND: Fatigue is a crucial sensation that triggers rest, yet its underlying neuronal mechanisms remain unclear. Intense long-term fatigue is a symptom of chronic fatigue syndrome, which is used as a model to study the mechanisms underlying fatigue. METHODS: Using magnetic resonance imaging, we conducted voxel-based morphometry of 16 patients and 49 age-matched healthy control subjects. RESULTS: We found that patients with chronic fatigue syndrome had reduced gray-matter volume in the bilateral prefrontal cortex. Within these areas, the volume reduction in the right prefrontal cortex paralleled the severity of the fatigue of the subjects. CONCLUSION: These results are consistent with previous reports of an abnormal distribution of acetyl-L-carnitine uptake, which is one of the biochemical markers of chronic fatigue syndrome, in the prefrontal cortex. Thus, the prefrontal cortex might be an important element of the neural system that regulates sensations of fatigue.
    Oct. 2004, BMC neurology, 4(1) (1), 14 - 14, English, International magazine
    Scientific journal

  • Yasuhiro Wada, Akira Matsumura, Fusao Nakamura, Masaaki Tanaka, Hiroshi Mizuma, Kei Mizuno, Satoshi Nozaki, Hideki Nakajima, Satoko Kondo, Kentaro Ishii, Koichi Koyama, Yoshimasa Hamazawa, Tomohisa Okuma, Terue Okamura, Yuichi Inoue, Yasuyoshi Watanabe
    MicroPET P4 is a Positron Emission Tomography (PET) scanner designed for small animal study with a 22-cm animal port and a 7.8-cm axial field of view (FOV). The scanner consists of 168 detector modules, each with an 8×8 array of 2.2×2.2×10 mm3 lutetium oxyorthosilicate (LSO) crystals, arranged as 32 crystal rings with an inner diameter of 26 cm. The system operates in 3D mode and data acquisition is done in list mode. The object animals and target regions for ongoing microPET studies in this site were rat and monkey brains and rabbit lungs. The purpose of this study is to determine the attenuation effects of these objects. Three cylindrical phantoms with outer diameters of 3, 7 and 9 cm and simulated rat and monkey heads and rabbit thorax, respectively, were used for investigating the attenuation effects. The attenuation effects can be divided into “factor changing” (FC) and “increasing nonuniformity” (NU). The NU values were 10.2%, 31.8% and 42.5% in 3-, 7- and 9-cm phantoms, respectively. The FC values were −26.6%, −49.2% and −59.3% in 3-, 7- and 9-cm phantoms, respectively. © 2004, Elsevier B.V.
    Aug. 2004, International Congress Series, 1265(C) (C), 69 - 73, English
    [Refereed]
    Scientific journal

  • [Designed molecular probes in brain research: molecular imaging of IP2 receptor in the human brain].
    Masaaki Suzuki, Hisashi Doi, Koichi Kato, Takamitsu Hosoya, Yumiko Watanabe, Yasuyoshi Watanabe
    The study of the role of prostaglandins in living human brain requires a highly designed non-invasive molecular probe with a specific function in the central nervous system and high stability in an in vivo system in addition to the ability of blood-brain-barrier penetration. We succeeded in designing 15R-TIC, which binds with a novel prostacyclin receptor subtype (IP2) expressed specifically in the central nervous system. 15R-TIC exhibited a distinct nerve-protecting effect in both high oxygen and in vivo ischemic conditions. In addition, a rapid C-methylation reaction, developed in order to incorporate a short-lived 11C-positron nuclide into the molecule, realized the synthesis of 15R-[11C]TIC methyl ester with the radioactivity of 2.5 GBq. The molecular imaging was established for both monkey and human brains by intravenous injection of this positron emission tomography (PET) probe.
    Aug. 2004, Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology, 24(4) (4), 221 - 9, Japanese, Domestic magazine
    Scientific journal

  • 脳内セロトニン神経系は片頭痛病態(Spreading depression)に影響する(Brain serotonergic nervous system modulates spreading depression: A pathophysiology of migraine)
    崔 翼龍, 片岡 洋祐, 田村 泰久, 李 慶華, 野崎 聡, 水間 広, 渡辺 恭良, 山田 久夫
    日本神経化学会, Aug. 2004, 神経化学, 43(2-3) (2-3), 358 - 358, English

  • Increase in reaction time for solving problems during learning-set formation.
    Chihiro Yokoyama, Hirotaka Onoe, Yasuyoshi Watanabe
    Six rhesus monkeys were tested for a change in reaction time for problem-solving during a learning-set task, in which they showed progressive improvement in the rate of learning successive problems of visual discrimination. To evaluate the processing time for cognitive processes in problem-solving, the differences in release latency and movement time between the visual discrimination task and the visuomotor control task were defined. In their first experience, the monkeys required several hundreds of trials for solving the problem, and the Deltarelease latency was constant throughout the learning. With increasing experience, they solved problems within fewer trials than with the first problem. At this stage, the Deltarelease latency was high at the beginning and then decreased. The rise in the Deltarelease latency within the learning acquisition period increased depending on the amount of experience with problems they had solved, whereas the Deltamovement time within that period was not significantly affected by the experience with problems. The present findings suggest that the number of problem-solving experiences could promote profound cognitive processing, which may be related to a conceptual representation that actualizes the flexibility of learning, namely, the learning set.
    Jul. 2004, Behavioural brain research, 152(2) (2), 221 - 9, English, International magazine
    Scientific journal

  • Use of FDG-microPET for detection of small nodules in a rabbit model of pulmonary metastatic cancer.
    Satoko Kondo, Masako N Hosono, Yasuhiro Wada, Kentaro Ishii, Akira Matsumura, Yoshie Takada, Mari Tashiro, Terue Okamura, Haruyuki Fukuda, Ryusaku Yamada, Yasuyoshi Watanabe, Yuichi Inoue
    OBJECTIVE: The performance of microPET using 18F-FDG was evaluated in a rabbit model of hematogenous pulmonary metastatic cancer. METHODS: A total of 15 Japanese white rabbits and VX-2 carcinoma were used in this study. In the microPET study, tumor-bearing rabbits were administered intravenously 74 MBq of 18F-FDG, and 30 min later, the emission data were acquired for 60 min. The transmission scans were performed with a 68Ge/68Ga external point source. To augment the anatomical information, we performed multi-detector row computed tomography (MDCT) in the combination with MDCT and microPET on 10 rabbits. The other 5 rabbits were followed once a week for 5 weeks only by microPET. Tumor/muscle (T/M) ratios were used for quantitative evaluation in this study. RESULTS: Multiple pulmonary nodules were detected by MDCT and microPET starting 14 days after the tumor injection. The high-uptake lesions in the lung detected by microPET corresponded well to the tumors detected by MDCT. The smallest nodule detected by microPET was ca. 1.5 mm in diameter. Overall, 87 nodules were detected by MDCT and the ratios of lesions detected by microPET to those by MDCT were 35.3%, 77.5%, and 90% for tumors equal to or smaller than 2 mm, 2-4 mm, and 4-6 mm in diameter, respectively. The respective T/M ratios were 2.41 +/- 0.41, 2.93 +/- 0.55, and 3.34 +/- 0.71. The T/M ratio increased with tumor size, but it was similar in each tumor size category. In the 35-day follow-up protocol, it was possible to follow sequentially the same tumor by the microPET. CONCLUSIONS: By FDG-microPET, it is possible to evaluate tumors larger than 2 mm in diameter and to follow the growth of individual tumors. Our results also suggest that the rabbit model of VX-2 pulmonary metastasis is a stable experimental model for evaluation using FDG. Monitoring of the therapeutic effects of anticancer drugs and radiation therapy could be tried by using this model and microPET.
    Feb. 2004, Annals of nuclear medicine, 18(1) (1), 51 - 7, English, Domestic magazine
    Scientific journal

  • Cui Yilong, Kataoka Yosky, Li Qing-Hua, Nozaki Satoshi, Mizuma Hiroshi, Watanabe Yasuyoshi, Yamada Hisao
    Inhibition periods (less than 10 times/min) for dozens of minutes were often observed in a long-term (24 hours) intracranial self-stimulation (ICSS; 50-60 times/min) in rats; electrical stimulations were applied to the hemi-lateral medial forebrain bundle of rats when the rats pressed a lever. The inhibition was not induced by thermal effect on neural function or by muscular fatigue, since the animals in the inhibition period started ICSS again when more intensive stimulations to the ipsi-lateral medial forebrain bundle or stimulations to the contra-lateral medial forebrain bundle were applied to the animals. In such a long-term ICSS, the inhibition period was significantly decreased in the animals pharmacologically treated with 5,7-dihydroxy-tryptamine just after their birth for inducing degeneration of serotonergic neurons in the dorsal raphe nucleus, although the treatment did not affect ICSS in short duration. These observations indicate that the serotonergic nervous system facilitates or modulates the inhibition of the long-term ICSS and would be involved in weariness or fatigue sensation. [Jpn J Physiol 54 Suppl:S209 (2004)]
    PHYSIOLOGICAL SOCIETY OF JAPAN, 2004, Proceedings of Annual Meeting of the Physiological Society of Japan, 2004, S209 - S209

  • Role of lactate in the brain energy metabolism: revealed by Bioradiography.
    Masaaki Tanaka, Fusao Nakamura, Shigekazu Mizokawa, Akira Matsumura, Kiyoshi Matsumura, Tetsuhito Murata, Makoto Shigematsu, Katsuhiro Kageyama, Hironobu Ochi, Yasuyoshi Watanabe
    To elucidate the role of lactate in the brain, we used a novel method, 'Bioradiography', in which the dynamic process could be followed in living slices by use of positron-emitter-labeled compounds and imaging plates. We studied the incorporation of 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) into rat brain slices incubated in oxygenated Krebs-Ringer solution. Under the glucose-free condition, [18F]FDG uptake rate in the cerebral cortex decreased with time and plateaued within 350 min but the addition of 5 mM lactate made the [18F]FDG uptake linear. When an inhibitor of the lactate transporter, 0.5 mM alpha-cyano-4-hydroxycinnamate (4-CIN) was applied to the glucose-free solution, the uptake rate decreased. Under the normal glucose condition, [18F]FDG uptake linearly increased for 6 h, but when 10 mM lactate was applied, the uptake rate decreased. In contrast, when 0.5 mM 4-CIN was applied to the normal glucose solution, [18F]FDG uptake rate increased. These results suggest that exogenous and endogenous lactate can substitute for glucose in the brain.
    Jan. 2004, Neuroscience research, 48(1) (1), 13 - 20, English, International magazine
    Scientific journal

  • QH Li, K Nakadate, S Tanaka-Nakadate, D Nakatsuka, YL Cui, Y Watanabe
    Serotonin (5-HT) is recognized as a potential regulatory factor in neuronal development. Two subtypes of receptors for it, 5-HT2A and 5-HT2C, are distributed broadly in the rat brain, suggesting their role in a variety of brain functions. Here, we investigated the expression patterns of these 5-HT2 receptors in the rat brain during postnatal development by using Western blot and immunohistochemical analyses. By Western blot analysis, the expression of the 5-HT2A receptor was at a low level at postnatal day 3 (P3) and increased greatly during the first 3 postnatal weeks; whereas the 5-HT2C receptor was already expressed at a high level at P3, and its expression increased only slightly during postnatal development. Immunohistochemical analysis showed the different expression patterns of 5-HT2A and 5-HT2C receptor subtypes during postnatal development: the transient expression of the 5-HT2C receptor was observed in layer IV of the somatosensory, visual, and auditory cortices from P10 to P28, and in the thalamus, mainly in the ventral posterolateral and ventral posteromedial nuclei, from P7 to P21; however, the immunoreactivity of the 5-HT2A receptor was detectable slightly at P3, but thereafter the intensity of immunolabeling increased with postnatal development and at P21 reached the adult level and pattern. These results suggest that 5-HT2 receptors have potential significance in brain development, with a functional difference between 5-HT2A and 5-HT2C receptor subtypes.
    WILEY-LISS, Jan. 2004, JOURNAL OF COMPARATIVE NEUROLOGY, 469(1) (1), 128 - 140, English, International magazine
    [Refereed]
    Scientific journal

  • Recovery from fatigue: changes in local brain 2-[18F]fluoro-2-deoxy-D-glucose utilization measured by autoradiography and in brain monoamine levels of rat.
    Shigekazu Mizokawa, Masaaki Tanaka, Akira Matsumura, Satoshi Nozaki, Yasuyoshi Watanabe
    We recently established an animal model of fatigue in which rats were kept in a cage filled with water to a height of 1.5 cm for 5 days. In this way, after the fatigue session, they were returned to their home cage. Rats resting for 15 min or 2 h showed reduced 2-[18F]fluoro-2-deoxy-D-glucose uptake in their brain. Rats resting for 1 h showed a significantly increased ratio of 5-hydroxyindoleacetic acid/5-hydroxytryptamine, an index of serotonin turnover, in the frontal cortex, hippocampus, and cerebellum, and the ratio of [3,4-dihydroxyphenylacetic acid+homovanillic acid]/dopamine, an index of dopamine turnover, tended to be increased as compared with the control. These data suggest that improvement of glucose uptake and increased serotonergic and dopaminergic neuronal activities are associated with recovery from central fatigue.
    Dec. 2003, Neuroscience letters, 353(3) (3), 169 - 72, English, International magazine
    Scientific journal

  • Establishment and assessment of a rat model of fatigue.
    Masaaki Tanaka, Fusao Nakamura, Shigekazu Mizokawa, Akira Matsumura, Satoshi Nozaki, Yasuyoshi Watanabe
    To establish an animal model of fatigue, we kept rats in a cage filled with water to a height of 1.5 cm. We selected a weight-loaded forced swimming test for evaluation of the extent of fatigue. Animals kept in the wet cage for 5 days showed a reduction in 2-[18F]fluoro-2-deoxy-D-glucose uptake into their brain. The session for 1 day showed significantly increased 5-hydroxyindoleacetic acid (5-HIAA)/5-hydroxytryptamine (5-HT) and [3,4-dihydroxyphenyl-acetic acid (DOPAC)+homovanillic acid (HVA)]/dopamine (DA) ratios in all brain regions, but the session for 5 days showed the restoration of the 5-HIAA/5-HT ratio in the hippocampus and hypothalamus and in the (DOPAC+HVA)/DA ratio in the striatum and hypothalamus. Our data suggest that decreased glucose uptake and insufficient serotonin and dopamine turnover introduced by deprivation of rest were correlated with central fatigue.
    Dec. 2003, Neuroscience letters, 352(3) (3), 159 - 62, English, International magazine
    Scientific journal

  • Assessment of microPET performance in analyzing the rat brain under different types of anesthesia: comparison between quantitative data obtained with microPET and ex vivo autoradiography.
    Akira Matsumura, Shigekazu Mizokawa, Masaaki Tanaka, Yasuhiro Wada, Satoshi Nozaki, Fusao Nakamura, Susumu Shiomi, Hironobu Ochi, Yasuyoshi Watanabe
    MicroPET (positron emission tomography) has been implemented for use in experiments with small animals. However, the quantification and optimal conditions for scanning are not established yet. The aim of this study was to compare the results obtained by microPET with those by ex vivo autoradiography of rat brain slices, based on the 2-[18F]fluoro-2-deoxy-D-glucose (FDG) method, and to establish the optimal conditions for scanning. As an example, we examined glucose metabolism in the rat brain under 6 types of anesthesia and in the conscious state. The scanning conditions for the rat brain were (1) use of a 4-mm-thick leaden jacket, (2) an energy window of 350-650 keV, and (3) a coincidence time window of 6 ns. Under these conditions, the quantitative ROI data from microPET showed a good correlation with the corresponding ROI data from FDG autoradiography in the animal study (r2=0.81). With our protocol, when anesthesia was started 40 min after the FDG injection, the glucose metabolism was almost the same as that in the conscious rat brain.
    Dec. 2003, NeuroImage, 20(4) (4), 2040 - 50, English, International magazine
    Scientific journal

  • Association between serotonin transporter gene polymorphism and chronic fatigue syndrome.
    Masaaki Narita, Naoko Nishigami, Naoko Narita, Kouzi Yamaguti, Nobuo Okado, Yasuyoshi Watanabe, Hirohiko Kuratsune
    Interaction between the hypothalamo-pituitary-adrenal axis and the serotonergic system is thought to be disrupted in chronic fatigue syndrome (CFS) patients. We examined a serotonin transporter (5-HTT) gene promoter polymorphism, which affects the transcriptional efficiency of 5-HTT, in 78 CFS patients using PCR amplification of the blood genomic DNA. A significant increase of longer (L and XL) alleic variants was found in the CFS patients compared to the controls both by the genotype-wise and the allele-wise analyses (both p<0.05, by chi(2) test and Fisher's exact test). Attenuated concentration of extracellular serotonin due to longer variants may cause higher susceptibility to CFS.
    Nov. 2003, Biochemical and biophysical research communications, 311(2) (2), 264 - 6, English, International magazine
    Scientific journal

  • Diagnostic evaluation of 2', 5'-oligoadenylate synthetase activities and antibodies against Epstein-Barr virus and Coxiella burnetii in patients with chronic fatigue syndrome in Japan.
    Kazufumi Ikuta, Takeshi Yamada, Tokio Shimomura, Hirohiko Kuratsune, Ryuzo Kawahara, Shiro Ikawa, Eiko Ohnishi, Yoshihiro Sokawa, Hideto Fukushi, Katsuya Hirai, Yasuyoshi Watanabe, Takeshi Kurata, Teruo Kitani, Takeshi Sairenji
    To investigate the association of viral infections with chronic fatigue syndrome (CFS), we assayed 2', 5'-oligoadenylate synthetase (2-5AS) activities in peripheral blood mononuclear cells from CFS patients in Japan. These patients were diagnosed in two hospitals, H1 and H2, located in different areas of the country. The activities were detected in 19 (86%) and 7 (32%) of each of the 22 patients in H1 and H2, respectively, while they were detected in only four (11%) out of the 38 healthy controls. IFN-alpha was similarly detected in a few CFS patients and healthy controls. We also assayed the antibody titers against Epstein-Barr virus (EBV) and Coxiella burnetii in these patients. The EBV anti-EA-IgG antibodies were detected in two (9%) and seven (32%) of each of the 22 patients in H1 and H2, respectively. Anti-C. burnetii IgG antibodies were detected in six (27%) out of 22 patients in H1 but not in 22 patients in H2, while they were detected in one (11%) of the nine healthy controls. Some CFS patients may be associated with EBV or C. burnetii infection. There were some statistical correlations between the 2-5AS activities and antibody titers of EA-IgG (P < 0.05, Student's t-test) but not to the antibody titers of C. burnetii. The up-regulation of 2-5AS activities suggests immunological dysfunctions with some virus infections in the CFS patients. Our results indicate that 2-5AS activities are useful for a diagnostic marker of CFS and for exploring the complicated pathogenesis of CFS.
    Oct. 2003, Microbes and infection, 5(12) (12), 1096 - 102, English, International magazine
    Scientific journal

  • Activation of the anterior cingulate gyrus by 'Green Odor': a positron emission tomography study in the monkey.
    Tetsuya Sasabe, Masayuki Kobayashi, Yusuke Kondo, Hirotaka Onoe, So Matsubara, Shigeyuki Yamamoto, Hideo Tsukada, Kayo Onoe, Hiroshi Watabe, Hidehiro Iida, Mikihiko Kogo, Kohta Sano, Akikazu Hatanaka, Tohru Sawada, Yasuyoshi Watanabe
    The equivalent mixture of cis-3-hexenol and trans-2-hexenal (hexenol/hexenal), 'green odor', is known to have a healing effect on the psychological damage caused by stress. Behavioral studies in humans and monkeys have revealed that hexenol/hexenal prevents the prolongation of reaction time caused by fatigue. In the present study, we investigated which brain regions are activated by the odor of hexenol/hexenal using positron emission tomography with alert monkeys. Regional cerebral blood flow (rCBF) in the prepyriform area (the primary olfactory cortex) was commonly increased by the passive application of odor: acetic acid, isoamylacetate or hexenol/hexenal. We observed rCBF increases in the orbitofrontal cortex (the secondary olfactory cortex) by these olfactory stimuli in two of three monkeys, and found no predominance of laterality of the activated hemisphere. Furthermore, rCBF increase in the cerebellum was observed in two of three monkeys, and the odor of acetic acid increased rCBF in the substantia innominata in all monkeys. In addition to these olfactory related regions, the anterior cingulate gyrus was activated by the odor of hexenol/hexenal. These findings suggest that the increase of rCBF in the anterior cingulate gyrus by the odor of hexenol/hexenal may contribute the healing effects of this mixture observed in the monkey.
    Sep. 2003, Chemical senses, 28(7) (7), 565 - 72, English, International magazine
    Scientific journal

  • Role of acetyl-L-carnitine in the brain: revealed by Bioradiography.
    Masaaki Tanaka, Fusao Nakamura, Shigekazu Mizokawa, Akira Matsumura, Kiyoshi Matsumura, Yasuyoshi Watanabe
    To elucidate the role of acetyl-L-carnitine in the brain, we used a novel method, 'Bioradiography,' in which the dynamic process could be followed in living slices by use of positron-emitter labeled compounds and imaging plates. We studied the incorporation of 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) into rat brain slices incubated in oxygenated Krebs-Ringer solution. Under the glucose-free condition, [18F]FDG uptake rate decreased with time and plateaued within 350 min in the cerebral cortex and cerebellum, and the addition of 1 or 5mM acetyl-L-carnitine did not alter the [18F]FDG uptake rate. When a glutaminase inhibitor, 0.5mM 6-diazo-5-oxo-L-norleucine (DON), was added under the normal glucose condition, [18F]FDG uptake rate decreased. Acetyl-L-carnitine (1mM), which decreased [18F]FDG uptake rate, reversed this DON-induced decrease in [18F]FDG uptake rate in the cerebral cortex. These results suggest that acetyl-L-carnitine can be used for the production of releasable glutamate rather than as an energy source in the brain.
    Jul. 2003, Biochemical and biophysical research communications, 306(4) (4), 1064 - 9, English, International magazine
    Scientific journal

  • Role of heme oxygenase-1 protein in the neuroprotective effects of cyclopentenone prostaglandin derivatives under oxidative stress.
    Takumi Satoh, Megumi Baba, Daisaku Nakatsuka, Yasuyuki Ishikawa, Hiroyuki Aburatani, Kyoji Furuta, Toshihisa Ishikawa, Hiroshi Hatanaka, Masaaki Suzuki, Yasuyoshi Watanabe
    Previously we found that some cyclopenteone prostaglandin derivatives (PGs), referred to as neurite outgrowth-promoting PGs (NEPPs), have dual biological activities of promoting neurite outgrowth and preventing neuronal death [Satoh et al. (2000) J. Neurochem., 75, 1092-1102; Satoh et al. (2001) J. Neurochem., 77, 50-62; Satoh et al. (2002) In Kikuchi, II. (ed.), Strategenic Medical Science Against Brain Attack. Springer-Verlag, Tokyo, pp. 78-93]. To investigate possible cellular mechanisms of the neuroprotective effects, we performed oligo hybridization-based DNA array analysis with mRNA isolated from HT22, a cell line that originated from a mouse hippocampal neuron. Several transcripts up-regulated by NEPP11 were identified. Because heme oxygenase 1 (HO-1) mRNA was the most prominently induced and was earlier reported to protect neuronal and non-neuronal cells against oxidative stress, we focused on it as a possible candidate responsible for the neuroprotective effects. We found NEPP11 to induce HO-1 protein (32 kDa) in HT22 cells in both the presence and the absence of glutamate, whereas non-neuroprotective prostaglandins (PGs) Delta12-PGJ2 or PGA2 did not. Overexpression of HO-1-green fluorescence protein (GFP) fusion protein significantly protected HT22 cells against oxidative glutamate toxicity, whereas that of GFP alone did not. Furthermore, biliverdin and bilirubin, products of HO-1 enzymatic activity on heme, protected HT22 cells from oxidative glutamate toxicity. These results, together with our previous results, suggest that NEPP11 activates the expression of HO-1 and that HO-1 produces biliverdin and bilirubin, which result in the inhibition of neuronal death induced by oxidative stress. NEPP11 is the first molecular probe reported to have a neuroprotective action through induction of HO-1 in neuronal cells.
    Jun. 2003, The European journal of neuroscience, 17(11) (11), 2249 - 55, English, International magazine
    Scientific journal

  • [Neural and molecular mechanisms of fatigue and recovery from fatigue].
    Yasuyoshi Watanabe
    Fatigue is an indispensable biosignal for maintaining life. However, the neural/molecular mechanisms of fatigue are still unclear. Here, the recent progress in this field is introduced, mostly through our project research under the control of the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japanese Government. The sensing mechanisms of fatigue in the brain might be related to the orbitofrontal-dorsoprefrontal-cingulate triangle circuits. We hypothesized the neural circuits for fatigue sensation through our PET study on chronic fatigue patients and healthy volunteers. The serotonergic system might be involved in the sensation in the prefrontal cortex, although the hyperserotonin hypothesis might be wrong. The fatigue sensation is somehow related to hypofunction of the glutamatergic system through reduced uptake of acetyl-carnitine in the discrete brain regions. For creation of new methods and drugs overcoming fatigue, different types of animal models of fatigue were developed. By using such animal models, the green leaf odor, ascorbic acid, acetyl-carnitine, and tetrahydrobiopterin have been found to be effective.
    Jun. 2003, Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology, 23(3) (3), 149 - 53, Japanese, Domestic magazine
    Scientific journal

  • Improvement by repeated administration of 6R-tetrahydrobiopterin of 5,7-dihydroxytryptamine-induced abnormal behaviors in immature rats.
    Hiroshi Mizuma, Mika Mizutani, Satoshi Nozaki, Hirohito Iizuka, Hideo Tohyama, Nobuhiro Nishimura, Yasuyoshi Watanabe, Ryuichiro Kohashi
    To clarify the therapeutic effects of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (6R-BH(4)) on the abnormal behaviors induced by neonatal 5,7-dihydroxytryptamine (5,7-DHT, 100 microg; i.c.v.) treatment in immature rats, 6R-BH(4) (10-40 mg/kg) was administered intraperitoneally from 22nd to 28th days or only once on the 28th day. The locomotion activities decreased dramatically in 5,7-DHT-treated rats (p<0.01; as compared to controls) on the 28th day. The reduced locomotion was recovered dose-dependently by repeated administration of 6R-BH(4), whereas it was not altered after a single injection of 6R-BH(4). In addition, repeated administration of 6R-BH(4) significantly facilitated 5-HT turnover ratio (5-HIAA/5-HT) in the striatum, cerebral cortex, and cerebellum. These findings suggest that the behavioral restoration by 6R-BH(4) might be due to the enhancement of 5-HT turnover by accumulated but not a single dose of 6R-BH(4).
    Feb. 2003, Biochemical and biophysical research communications, 302(1) (1), 156 - 61, English, International magazine
    Scientific journal

  • [Non-human primate behaviors as models for development of higher cognitive functions].
    Chihiro Yokoyama, Hirotaka Onoe, Kayo Onoe, Hideo Tsukada, Yasuyoshi Watanabe, Kenji Fukui
    Non-human primate behaviors have a special value for the neurobiological study of the development of higher cognitive functions of humans, because of the near evolutional relation between two species. We surveyed results and futures of neurobiological studies of a retrieval task, a learning-set and a self-injurious behavior expressed by non-human primates. On the retrieval task that is related to the development of inhibitory control, it was revealed a hierarchical ordering of inhibitory control processes in which the distinct neuronal circuits were involved. On the learning-set that is related to the development of abstract thinking, neural circuits for the individual learning dramatically changed from an automatic process to a cognitive process depending on the learning-set formation. The self-injurious behavior is expressed during early normal development in humans, and no other animals but non-human primates express it without administration of drugs. For that behavior, probable change in interactions of multiple monoaminergic systems was suggested as its underlying causes. Further studies on development of higher cognitive functions using non-human primates could be required for understanding the nature of human cognition.
    Feb. 2003, Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology, 23(1) (1), 1 - 9, Japanese, Domestic magazine
    Scientific journal

  • Y Cui, Y Kataoka, QH Li, C Yokoyama, A Yamagata, N Mochizuki-Oda, J Watanabe, H Yamada, Y Watanabe
    Spreading depression (SD) has been linked to several neurological disorders as epilepsy, migraine aura, trauma, and cerebral ischemia, which were also influenced by disorderliness of the brain redox homeostasis. To investigate whether local tissue oxidation directly induces SD, we oxidized a restricted local area of the rat cerebral cortex using photo-dynamic tissue oxidation (PDTO) technique and examined the cerebral blood flow (CBF) and direct current (DC) potential in and around the oxidized area. Intensive PDTO induced prolonged depolarization only in the photo-oxidized area, which led to global changes of CBF and DC potential: synchronous negative shifts of DC potential (with an amplitude of approximately 20 mV) and hyperperfusion of CBF occurred. The changes in DC potential and CBF spread at a rate of around 3 mm/min beyond the oxidized area to the whole hemisphere of the cerebral cortex, indicating that intensive local oxidation induces SD in the rat brain. (C) 2002 Elsevier Science (USA). All rights reserved.
    ACADEMIC PRESS INC ELSEVIER SCIENCE, Jan. 2003, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 300(3) (3), 631 - 636, English, International magazine
    [Refereed]
    Scientific journal

  • Attenuated fever in pregnant rats is associated with blunted syntheses of brain cyclooxygenase-2 and PGE2.
    Kyoko Imai-Matsumura, Kiyoshi Matsumura, Akira Terao, Yasuyoshi Watanabe
    Attenuation of fever occurs in pregnant animals. This study examined a hypothesis that brain production of PGE(2), the final mediator of fever, is suppressed in pregnant animals. Near-term pregnant rats and age-matched nonpregnant female rats were injected with lipopolysaccharide (100 microg/kg) intraperitoneally. Four hours later, colonic temperature was measured, their cerebrospinal fluid (CSF) was sampled for PGE(2) assay, and their brains were processed for immunohistochemistry of cyclooxygenase-2, an enzyme involved in PGE(2) biosynthesis. In the pregnant rats, lipopolysaccharide injection resulted in significantly smaller elevations in both colonic temperature and CSF-PGE(2) level than in nonpregnant rats. In the pregnant rats, lipopolysaccharide-induced cyclooxygenase-2 expression was blunted in terms of the number of positive cells. There was a significant correlation between PGE(2) level in CSF and the number of cyclooxygenase-2-positive endothelial cells. These results suggest that suppressed PGE(2) production in the brain is one cause for the attenuated fever response at near-term pregnancy and that this suppressed PGE(2) production is due to the suppressed induction of cyclooxygenase-2 in brain endothelial cells.
    Dec. 2002, American journal of physiology. Regulatory, integrative and comparative physiology, 283(6) (6), R1346-53, English, International magazine
    Scientific journal

  • [Cyclopentenone prostaglandin derivatives as neuroprotective compounds].
    Takumi Satoh, Yasuyoshi Watanabe
    Dec. 2002, Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme, 47(15) (15), 2032 - 6, Japanese, Domestic magazine
    Scientific journal

  • Neuropilin-2 is overexpressed in the rat brain after limbic seizures.
    Shuichi Shimakawa, Shuhei Suzuki, Ryohei Miyamoto, Kimitaka Takitani, Katsuji Tanaka, Takuya Tanabe, Eiji Wakamiya, Fusao Nakamura, Miyuki Kuno, Shushi Matsuura, Yasuyoshi Watanabe, Hiroshi Tamai
    Structural rearrangement and synaptic reorganization are known to occur in the brain after seizures. If neuronal rearrangement after seizures always results in abnormal hyperexcitability, it would provide an accurate pathway to the appropriate target and as a result, it may be the mechanism of epileptogenesis. This study examined the mechanism of axon guidance in the mature rat brain after seizures by evaluating the expression of the axonal guidance molecule, neuropilin-2. We assessed the expression of neuropilin-2 by northern blotting and immunohistochemistry in rat with seizures created by kindling stimulation and kainate injection.The neuropilin-2 mRNA level was increased in the whole brain of the rats at 24 h after either type of seizure. Neuropilin-2 mRNA was not increased at 2 weeks after the last stimulation. Immunohistochemistry demonstrated that neuropilin-2 protein was increased in the dentate gyrus and the entorhinal cortex in the both seizure models. These findings suggested that there was overexpression of neuropilin-2 in the brains of mature rats with different types of seizure. Accordingly, neuropilin-2 might regulate remodeling after seizures as it does during the development of the hippocampal formation. Our findings suggest that axons may not project and outgrow 'aberrantly' after seizures, but may be regulated by the chemorepellent effect through neuropilin-2.
    Nov. 2002, Brain research, 956(1) (1), 67 - 73, English, International magazine
    Scientific journal

  • Brain regions involved in fatigue sensation: reduced acetylcarnitine uptake into the brain.
    Hirohiko Kuratsune, Kouzi Yamaguti, Gudrun Lindh, Birgitta Evengård, Gisela Hagberg, Kiyoshi Matsumura, Masao Iwase, Hirotaka Onoe, Mamoru Takahashi, Takashi Machii, Yuzuru Kanakura, Teruo Kitani, Bengt Långström, Yasuyoshi Watanabe
    Fatigue is an indispensable sense for ordering rest. However, the neuronal and molecular mechanisms of fatigue remain unclear. Chronic fatigue syndrome (CFS) with long-lasting fatigue sensation seems to be a good model for studying these mechanisms underlying fatigue sensation. Recently, we found that most patients with CFS showed a low level of serum acetylcarnitine, which well correlated with the rating score of fatigue, and that a considerable amount of acetyl moiety of serum acetylcarnitine is taken up into the brain. Here we show by metabolite analysis of the mouse brain that an acetyl moiety taken up into the brain through acetylcarnitine is mainly utilized for the biosynthesis of glutamate. When we studied the cerebral uptake of acetylcarnitine by using [2-(11)C]acetyl-L-carnitine in 8 patients with CFS and in 8 normal age- and sex-matched controls, a significant decrease was found in several regions of the brains of the patient group, namely, in the prefrontal (Brodmann's area 9/46d) and temporal (BA21 and 41) cortices, anterior cingulate (BA24 and 33), and cerebellum. These findings suggest that the levels of biosynthesis of neurotransmitters through acetylcarnitine might be reduced in some brain regions of chronic fatigue patients and that this abnormality might be one of the keys to unveiling the mechanisms of the chronic fatigue sensation.
    Nov. 2002, NeuroImage, 17(3) (3), 1256 - 65, English, International magazine
    Scientific journal

  • Neural substrates of human facial expression of pleasant emotion induced by comic films: a PET Study.
    Masao Iwase, Yasuomi Ouchi, Hiroyuki Okada, Chihiro Yokoyama, Shuji Nobezawa, Etsuji Yoshikawa, Hideo Tsukada, Masaki Takeda, Ko Yamashita, Masatoshi Takeda, Kouzi Yamaguti, Hirohiko Kuratsune, Akira Shimizu, Yasuyoshi Watanabe
    Laughter or smile is one of the emotional expressions of pleasantness with characteristic contraction of the facial muscles, of which the neural substrate remains to be explored. This currently described study is the first to investigate the generation of human facial expression of pleasant emotion using positron emission tomography and H(2)(15)O. Regional cerebral blood flow (rCBF) during laughter/smile induced by visual comics and the magnitude of laughter/smile indicated significant correlation in the bilateral supplementary motor area (SMA) and left putamen (P < 0.05, corrected), but no correlation in the primary motor area (M1). In the voluntary facial movement, significant correlation between rCBF and the magnitude of EMG was found in the face area of bilateral M1 and the SMA (P < 0.001, uncorrected). Laughter/smile, as opposed to voluntary movement, activated the visual association areas, left anterior temporal cortex, left uncus, and orbitofrontal and medial prefrontal cortices (P < 0.05, corrected), whereas voluntary facial movement generated by mimicking a laughing/smiling face activated the face area of the left M1 and bilateral SMA, compared with laughter/smile (P < 0.05, corrected). We demonstrated distinct neural substrates of emotional and volitional facial expression and defined cognitive and experiential processes of a pleasant emotion, laughter/smile.
    Oct. 2002, NeuroImage, 17(2) (2), 758 - 68, English, International magazine
    Scientific journal

  • Functional anatomy of chemical senses in the alert monkey revealed by positron emission tomography.
    Masayuki Kobayashi, Tetsuya Sasabe, Masaki Takeda, Yusuke Kondo, Shin-Ichi Yoshikubo, Kazuyuki Imamura, Hirotaka Onoe, Tohru Sawada, Yasuyoshi Watanabe
    Functional imaging technique using positron emission tomography (PET) has made it possible to localize functional brain regions in the human brain by detecting changes in regional cerebral blood flow (rCBF). Performing PET studies in the monkey will aid in integrating monkey electrophysiological research with human PET studies. We examined changes in rCBF during olfactory or combined olfactory and gustatory (flavour) stimulation using PET in the alert rhesus monkey. Olfactory or flavour stimulation with acetic acid or apple increased rCBF in the prepyriform area, substantia innominata and amygdala. Besides these areas, flavour stimulation increased rCBF in the anterior insula and frontal operculum, orbitofrontal cortex, inferior frontal gyrus and cerebellum. Apple odour or flavour stimuli increased rCBF in the inferior occipital gyrus in addition to the above areas. These findings suggest that the increases of rCBF in response to neural activities in the primary olfactory and gustatory cortices are detectable by the use of PET. In addition, regions activated by apple stimuli suggest that higher brain function might be detected with PET in the alert monkey.
    Sep. 2002, The European journal of neuroscience, 16(5) (5), 975 - 80, English, International magazine
    Scientific journal

  • In vitro autoradiographic localization of (125)i-secretin receptor binding sites in rat brain.
    Satoshi Nozaki, Rika Nakata, Hiroshi Mizuma, Nobuhiro Nishimura, Yumiko Watanabe, Ryuichiro Kohashi, Yasuyoshi Watanabe
    Although the existence of the receptor for secretin in the brain was suggested, the localization of secretin receptor and the neuronal function of secretin have not been clarified yet. In the present study, the localization of secretin receptor was investigated in the rat brain by using an in vitro autoradiography technique. Frozen section autoradiography with (125)I-secretin showed intense binding in the nucleus of solitary tract, laterodorsal thalamic nucleus, and accumbens nucleus; moderate binding in the hippocampus, caudate/putamen, cerebellum, cingulate and orbital cortices. Scatchard plot analysis gave the Kd value of 125 pM with Bmax of 134 fmol/mg tissue in the hippocampus. The binding specificity was confirmed with secretin and its analogs, VIP, PACAP, and glucagon. These results indicate the secretin receptor system might have some neural functions in the brain, which could give the basis for therapeutic use of secretin in autistic children.
    Mar. 2002, Biochemical and biophysical research communications, 292(1) (1), 133 - 7, English, International magazine
    Scientific journal

  • A positron-emitter labeled glycine(B) site antagonist, [(11)C]L-703,717, preferentially binds to a cerebellar NMDA receptor subtype consisting of GluR epsilon3 subunit in vivo, but not in vitro.
    Terushi Haradahira, Takashi Okauchi, Jun Maeda, Ming-Rong Zhang, Takayo Kida, Kouichi Kawabe, Masayoshi Mishina, Yasuyoshi Watanabe, Kazutoshi Suzuki, Tetsuya Suhara
    In previous studies, we have found that [(11)C]L-703,717, a positron-emitter labeled antagonist for the glycine-binding site of NMDA receptors, only localizes in rodent cerebellum under in vivo conditions. In order to understand the unusual cerebellar localization, we have examined the binding of [(11)C]L-703,717 to a cerebellar-specific NMDA receptor subtype consisting of GLuRepsilon3 subunit, by comparing its autoradiographic distributions between GluRepsilon3-deficient and wild-type mice. Ex vivo [(11)C]L-703,717 binding to wild-type mice showed a highly specific localization of radioactivity in the cerebellum, whereas that to the GluRepsilon3-deficient mice showed no specific localization of radioactivity in any of the brain regions. In contrast to the ex vivo binding, in vitro [(11)C]L-703,717 binding displayed a similar binding characteristic between GluRepsilon3-deficient and wild-type mice with highly specific localizations in the hippocampus and cerebral cortex. Therefore, the present study clearly demonstrated that [(11)C]L-703,717 preferentially binds to a cerebellar NMDA receptor subtype consisting of GluRepsilon3 subunit in vivo, but not in vitro.
    Feb. 2002, Synapse (New York, N.Y.), 43(2) (2), 131 - 3, English, International magazine
    Scientific journal

  • Yumiko Watanabe, Kiyoshi Matsumura, Hajime Takechi, Koichi Kato, Hiroshi Morii, Margareta Björkman, Bengt Langstrom, Ryoji Noyori, Masaaki Suzuki, Yasuyoshi Watanabe
    Wiley, Jan. 2002, Journal of Neurochemistry, 72(6) (6), 2583 - 2592
    [Refereed]
    Scientific journal

  • Y Takeuchi, N Mochizuki-Oda, H Yamada, K Kurokawa, Y Watanabe
    A change in the intracellular Ca2+ ([Ca2+](i)) level induced by hypoxia was detected in rat adrenal slices by use of fura-2/AM. After hypoxic stress, an increase in [Ca2+](i) was observed only in the adrenal medulla. This increase was inhibited by nifedipine, but not modified by the cholinergic receptor blockers. The hypoxia-induced increase in [Ca2+](i) was observed in all postnatal developmental stages to a similar extent, whereas the nicotine and high K+ sensitivities increased along with postnatal development. A 10 nM ryanodine enhanced the hypoxia-induced [Ca2+](i) increase in adult but not in neonatal rat slices. These results suggest the existence of an oxygen-sensing mechanism in adult rat adrenals even after sympathetic innervation. Hypoxic responses seemed to be similar both in neonate and in adult rat adrenals and were triggered by the influx of Ca2+ via L-type voltage-sensitive Ca2+ channels. However, the sustained [Ca2+](i) increase caused by hypoxia might depend on postnatal development and be triggered by Ca2+-induced Ca2+ release (CICR). (C) 2001 Academic Press.
    ACADEMIC PRESS INC, Nov. 2001, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 289(1) (1), 51 - 56, English
    [Refereed]
    Scientific journal

  • Increase of interstitial glycerol reflects the degree of ischaemic brain damage: a PET and microdialysis study in a middle cerebral artery occlusion-reperfusion primate model
    P Frykholm, L Hillered, B Langstrom, L Persson, J Valtysson, Y Watanabe, P Enblad
    Objective-To evaluate interstitial glycerol as a marker of ischaemia by studying the changes in glycerol in direct relation to changes in regional cerebral metabolic rate of oxygen (CMRO2), the lactate/ pyruvate ratio (LP ratio), and glutamate. Methods-Transorbital 2 hour middle cerebral artery occlusion (MCAO) was performed in eight monkeys, which were studied with continuous microdialysis for 24 hours. Interstitial fluids were collected by microdialysis and analysed for glycerol, lactate, pyruvate, and glutamate with an enzymatic assay and high performance liquid chromatography. Sequential PET studies of cerebral blood flow (CBF), CMRO2, oxygen extraction ratio (OER), and cerebral blood volume (CBV) were performed. The microdialysis probe regions were classified as severe ischaemia or penumbra, depending on whether the mean CMRO2 side to side ratio was below or above 60%, respectively. Results-A nine-fold, sustained increase in glycerol was registered after MCAO in severe ischaemia regions. In penumbra regions, the increase in glycerol was five-fold, but the glycerol concentration returned to baseline within 8 hours of clip removal. The difference between severe ischaemia and penumbra glycerol values was statistically significant. As expected from previous studies, the interstitial LP ratio and glutamate increased markedly in severe ischaemia, with a less pronounced change in penumbra regions. There was a time lag between the biochemical changes in severe ischaemia regions, with the LP ratio preceding glutamate, followed by glycerol. Conclusions-A marked, sustained increase in interstitial glycerol is indicative of severe ischaemia in this stroke model. A transient, diminutive increase in interstitial glycerol may reflect a penumbra situation. Interstitial glycerol in combination with other biochemical markers such as the LP ratio and glutamate may be useful for clinical monitoring of the ischaemic brain, reflecting a sequence of secondary pathophysiological events.
    BMJ PUBLISHING GROUP, Oct. 2001, JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, 71(4) (4), 455 - 461, English
    [Refereed]
    Scientific journal

  • 生後発達に伴うセロトニン受容体2Aと2Cの発現パターンの変化
    李 慶華, 中舘 和彦, 田中 佐和子[中舘], 中塚 大策, 野崎 聡, 崔 翼龍, 渡辺 恭良
    日本神経化学会, Sep. 2001, 神経化学, 40(2-3) (2-3), 302 - 302, Japanese

  • 中枢神経組織酸化モデルにおける組織抗酸化能力及びモノアミン動態の変化
    崔 翼龍, 片岡 洋祐, 野崎 聡, 田村 泰久, 林 要人, 宇都宮 一泰, 植田 勇人, 三山 吉夫, 山田 久夫, 渡辺 恭良
    日本神経化学会, Sep. 2001, 神経化学, 40(2-3) (2-3), 399 - 399, Japanese

  • 培養中枢ニューロンの静止膜電位及び膜抵抗に対する近赤外レーザー光の作用
    田村 泰久, 片岡 洋祐, 小田 紀子[望月], 崔 翼龍, 渡辺 恭良, 山田 久夫
    日本神経化学会, Sep. 2001, 神経化学, 40(2-3) (2-3), 400 - 400, Japanese

  • 中舘 和彦, 田中 佐和子[中舘], 今村 一之, Hirayama Kei, Kapatos Gregory, 渡辺 恭良
    ラットを用い,生後1日目から8週齢迄の脳全域におけるGTPシクロヒドロラーゼI(GTP-CH)の分布を免疫組織化学法で検討した.その結果,いずれの週齢においてもモノアミン系合成産生細胞に強い発現が認められた.又,5-HT産生細胞だけでなくnNOS産生細胞にも共発現しているのが観察され,GTP-CH単独で発現している細胞の存在も示唆された
    (株)ライフ・サイエンス, Aug. 2001, Progress in Medicine, 21(8) (8), 1949 - 1954, Japanese

  • Y Kataoka, YL Cui, A Yamagata, M Niigaki, T Hirohata, N Oishi, Y Watanabe
    Living organisms have been known to spontaneously emit ultraweak photons in vivo and in vitro. Origin of the photon emission remains unclear, especially in the nervous system. The spontaneous ultraweak photon emission was detected here from cultured rat cerebellar granule neurons using a photomultiplier tube which was highly sensitive to visible light. The photon emission was facilitated by the membrane depolarization of neurons by a high concentration of K(+) and was attenuated by application of tetrodotoxin or removal of extracellular Ca(2+), indicating the photon emission depending on the neuronal activity and likely on the cellular metabolism. Furthermore, almost all the photon emission was arrested by 2,4-dinitrophenylhydrazine, indicating that the photon emission would be derived from oxidized molecules. Detection of the spontaneous ultraweak photon emission will realize noninvasive and real-time monitoring of the redox state of neural tissue corresponding to the neuronal activity and metabolism. (C) 2001 Academic Press.
    ACADEMIC PRESS INC ELSEVIER SCIENCE, Jul. 2001, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 285(4) (4), 1007 - 1011, English
    [Refereed]
    Scientific journal

  • Margareta Björkman, Hisashi Doi, Bahram Resul, Masaaki Suzuki, Ryoji Noyori, Yasuyoshi Watanabe, Bengt L{\aa}ngström
    Wiley, Dec. 2000, Journal of Labelled Compounds and Radiopharmaceuticals, 43(14) (14), 1327 - 1334, English
    Scientific journal

  • Designed prostaglandins with neurotrophic activities
    K Furuta, K Tomokiyo, T Satoh, Y Watanabe, M Suzuki
    WILEY-V C H VERLAG GMBH, Nov. 2000, CHEMBIOCHEM, 1(4) (4), 283 - 286, English
    [Refereed]
    Scientific journal

  • Masaaki Suzuki, Hisashi Doi, Koichi Kato, Margareta Björkman, Bengt Långström, Yasuyoshi Watanabe, Ryoji Noyori
    A rapid method for Pd-promoted cross-coupling of methyl iodide and tributyltin derivatives of tolylisocarbacyclins was developed with the objective of applying to the PET study on the IP2 receptor in a living human brain. The high efficiency is obtainable for both of the one-pot operation using a large excess of CuCl and the stepwise operation consisting of the initial preparation of a methylpalladium complex followed by mixing with the remaining requisite materials for the cross-coupling. The latter protocol allowed for the highly reproducible synthesis of an actual PET tracer with total radioactivity of several GBq. Several stannanes could be employed as precursors of PET tracers in this rapid cross-coupling reaction. (C) 2000 Elsevier Science Ltd.
    Oct. 2000, Tetrahedron, 56(42) (42), 8263 - 8273
    Scientific journal

  • Designed cyclopentenone prostaglandin derivatives as neurite outgrowth-promoting compounds for CAD cells, a rat catecholaminergic neuronal cell line of the central nervous system
    T Satoh, K Furuta, K Tomokiyo, M Suzuki, Y Watanabe
    Here we reported the effects of neurite outgrowth-promoting prostaglandins (NEPP's) on neurons of the central nervous system (CNS). Serum deprivation promoted neurite outgrowth from CAD cells, a CNS-derived cathecholaminergic neuronal cell line. NEPP's (0.05-0.2 mu M) accelerated the neurite outgrowth from CAD cells in serum-free medium but didn't in serum-containing medium. Through the study of structure-function relationship with the NEPP's 1-10, NEPP 10 (13,14-dihydro-15-epi-Delta(7)-prostaglandin A(1) (methyl ester) revealed the best compound, exhibiting potent neurite outgrowth-promoting activity with minimal cytotoxicity, suggesting that it is the best compound for drug development. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.
    ELSEVIER SCI IRELAND LTD, Sep. 2000, NEUROSCIENCE LETTERS, 291(3) (3), 167 - 170, English
    [Refereed]
    Scientific journal

  • Neovascularization with blood-brain barrier breakdown in delayed neuronal death.
    Y Kataoka, Y Cui, H Yamada, K Utsunomiya, H Niiya, H Yanase, Y Nakamura, A Mitani, K Kataoka, Y Watanabe
    Various kinds of acute pathological events in the central nervous system, such as ischemia, hemorrhage, and trauma, often cause brain edema. The edema may advance for days or weeks while inducing extensive damage in neural function, regardless of the extent of the original damage, and often results in death. Delayed edema is thought to be vasogenic; however, the mechanism underlying edema induction remains unknown. We found delayed vascular cell proliferation with a blood-brain barrier breakdown in and around the gerbil CA1 hippocampus, a region known to be involved in delayed apoptotic neuronal death 2-6 days after transient ischemia. Vascular cell proliferation, assessed by (3)H-thymidine incorporation, was most prominent 4-6 days after ischemia, and extravasation of exogenously applied dye or endogenous serum albumin from blood vessels was observed concomitantly. We propose neovascularization in delayed neuronal death as a cause of brain edema advancing days after neurological events.
    Jul. 2000, Biochemical and biophysical research communications, 273(2) (2), 637 - 41, English, International magazine
    Scientific journal

  • Masaaki Suzuki, Ryoji Noyori, Bengt Långström, Yasuyoshi Watanabe
    Molecular design to develop a stable biochemical probe for a study of the role of prostacyclin (PGI2) in the brain led to the discovery of (15R)- 16-m-tolyl-17,18,19,20-tetranorisocarbacylin (referred to as 15R-TIC), that selectively bind to a novel PGI2 receptor, IP2, expressed in the central nervous system (CNS). This artificial prostaglandin with the 15R configuration exhibits high binding affinity for the IP2 receptor in the thalamus (IC50 = 32 nM) and weak affinity for the peripheral-type PGI2 receptor, IP1, in the NTS (IC50 = 1.2 μM). The length of the ω side- chain and the position of the methyl substituent on the aromatic ring strongly influence the binding characteristics. The features of the IP2 receptor were elucidated by quantitative mapping, specificity studies, and Scatchard analysis, as well as by a study using knockout mice with a tritium- labeled 15R-TIC and related radioligands. In order to conduct in vivo PET studies, a rapid methylation reaction using methyl iodide and an excess amount of an aryltributylstannane has been developed. This has successfully been applied to the synthesis of short-lived 11C-incorporated PET tracers, 15R-[11C]TIC and its methyl ester. The PET experiments accomplished the imaging of the IP2 receptor in the brain of living rhesus monkeys through intravenous administration. The elimination of the C(15) chirality results in 15-deoxy-TIC with ten-fold higher affinity and selectivity for the IP2 receptor than original 15R-TIC. Neither 15R-TIC nor 15-deoxy-TIC inhibit platelets aggregation, up to 400 nM, while PGI2 derivatives which bind with the IP1 receptor show a very potent inhibitory effect at a several nM level. Notably, these artificial CNS-specific PGI2 ligands, like the unstable natural PGI2 itself, prevent the apoptotic cell death of hippocampal neurons induced under high (50%) oxygen atmosphere and by xanthine and xanthine oxidase or serum deprivation. The difference in the binding potency between 15R-TIC and 15-deoxy-TIC for the IP2 receptor correlates well with the extent of the prevention of the neuronal cell death (IC50 values of 300 and 30 nM, respectively, under high oxygen atmosphere). 15R-TIC protects CA1 pyramidal neurons against ischemic damage in gerbils. Thus the designed TICs have neuronal survival-promoting activity both in vitro and in vivo, providing the possibility as a new type of chemotherapeutic agents for applications in neurodegeneration.
    May 2000, Bulletin of the Chemical Society of Japan, 73(5) (5), 1053 - 1070
    Scientific journal

  • 渡辺 恭良, 田中 佐和子[中舘], 中舘 和彦, 今村 一之
    (公社)日本ビタミン学会, Dec. 1999, ビタミン, 73(12) (12), 754 - 754, Japanese

  • Protective effect of prostaglandin I-2 analogs on ischemic delayed neuronal damage in gerbils
    YL Cui, Y Kataoka, T Satoh, A Yamagata, N Shirakawa, Y Watanabe, M Suzuki, H Yanase, K Kataoka, Y Watanabe
    We found a novel subtype of prostaglandin (PG) I-2 receptor (IP2) expressed in the central nervous system. Recently we have demonstrated that (15R)-16-m-tolyl-17,18,19,20-tetranorisocarbacyclin (15R-TIC) and 15-deoxy-16-m-tolyl-17,18,19,20-tetranorisocarbacyclin (15-deoxy-TIC), IP2-specific ligands, significantly prevented high (50%) oxygen-induced apoptotic neuronal death in cultured hippocampal neurons, We report here a potent neuroprotective effect of such analogs on delayed neuronal death of hippocampal CA1 neurons following transient ischemia for 3 min in gerbils, (15S)-16-m-tolyl-17,18,19,20-tetranorisocarbacyclin (15S-TIC), which nonselectively acts both on the PGI(2) receptor expressed in the peripheral tissue (IP1) and on IP2, also showed a neuroprotective effect on such an ischemic model at higher doses than those for 15R-TIC and 15-deoxy-TIC. These PGI(2) analogs did not affect brain temperature, indicating that the agents showed the neuroprotective effect not by a hypothermic effect, but rather by the direct action on neurons, (C) 1999 Academic Press.
    ACADEMIC PRESS INC ELSEVIER SCIENCE, Nov. 1999, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 265(2) (2), 301 - 304, English
    [Refereed]
    Scientific journal

  • Effects of monocular enucleation on parvalbumin in rat visual system during postnatal development
    Yoritsugu Hada, Yuko Yamada, Kazuyuki Imamura, Nobuko Mataga, Yasuyoshi Watanabe, Misao Yamamoto
    Purpose. To re-evaluate the hypothesis that the expression of the calcium-binding protein parvalbumin (PV) in a subpopulation of γ- aminobutyric acid (GABA)ergic neurons is an appropriate molecular marker for the effect on ocular dominance plasticity of monocular deprivation during the postnatal sensitive period. Methods. Long-Evans rats underwent monocular enucleation immediately before eye opening (postnatal day [P] 14). Immunohistochemical analysis using anti-PV antibody was performed on the superior colliculus (SC) and lateral geniculate nucleus (LGN) at P45. In the visual cortex (VC) developmental changes in immunoreactivity were also examined at the ages of P17, P20, P27, and P45. Northern blot analysis for PV mRNA was also performed at P45. Changes in PV expression in the visual system of these rats were evaluated by use of a computer-based quantitative technique. Results. PV-immunoreactive neurons were present in the SC and VC, whereas only a few were found in the LGN. The monocular enucleation at the onset of the sensitive period markedly reduced PV immunoreactivity in the neuropil of the SC, contralateral to the enucleated eye when examined one month later. No consistent and significant change in PV immunoreactivity was found in either the LGN or the VC. The number of PV-immunoreactive neurons in the VC rapidly decreased to the adult level during the middle of the sensitive period. The expression of PV mRNA in these central visual structures was not affected by early monocular enucleation. Conclusions. Expression of PV is developmentally regulated, and marked changes in its protein expression in the SC can be induced by monocular enucleation. Contrary to the original hypothesis, monocular enucleation did not consistently affect the expression of PV in the rat VC. The expression of PV is probably regulated by multiple factors, not merely by binocular competition.
    Oct. 1999, Investigative Ophthalmology and Visual Science, 40(11) (11), 2535 - 2545, English
    Scientific journal

  • CNS-specific prostacyclin ligands as neuronal survival-promoting factors in the brain
    T Satoh, Y Ishikawa, Y Kataoka, YL Cui, H Yanase, K Kato, Y Watanabe, K Nakadate, K Matsumura, H Hatanaka, K Kataoka, R Noyori, M Suzuki, Y Watanabe
    Prostacyclin (PGI(2)) is a critical regulator of the cardiovascular system, via dilatation of vascular smooth muscle and inhibition of platelet aggregation (Moncada, S., 1982, Br. J. Pharmacol., 76, 3). Our previous studies demonstrated that a novel subtype of PGI(2) receptor, which is clearly distinct from a peripheral subtype in terms of ligand specificity, is expressed in the rostral region of the brain, e.g. cerebral cortex, hippocampus, thalamus and striatum, and that (15R)-16-m-17,18,19,20-tetranorisocarbacyclin (15R-TIC) and 15-deoxy-16-m-17,18,19,20-tetranorisocarbacyclin (15-deoxy-TIC) specifically bind to the central nervous system (CNS)-specific PGI(2) receptor. Here, we report that these CNS-specific PGI(2) receptor ligands, including PGI(2) itself, prevented the neuronal death. They prevented apoptotic cell death of hippocampal neurons induced by high (50%) oxygen atmosphere, xanthine + xanthine oxidase, and serum deprivation. IC(50)s for neuronal death were similar to 30 and 300 nM for 15-deoxy-TIC and 15R-TIC, respectively, which well correlated with the binding potency for the CNS-specific PGI(2) receptor. 6-Keto-PGF(1 alpha) (a stable metabolite of PGI(2)), peripheral nervous system-specific PGI(2) ligands and other prostaglandins (PGs) than PGI(2) did not show such neuroprotective effects. In vivo, 15R-TIC protected CA1 pyramidal neurons against ischaemic damage in gerbils. These results indicate that CNS-specific PGI(2) ligands have neuronal survival-promoting activity both in vitro and in vivo, and may represent a new type of therapeutic drug for neurodegeneration.
    WILEY-BLACKWELL, Sep. 1999, EUROPEAN JOURNAL OF NEUROSCIENCE, 11(9) (9), 3115 - 3124, English
    [Refereed]
    Scientific journal

  • M. Kobayashi, K. Imamura, P. A. Kaub, K. Nakadate, Y. Watanabe
    The effects of N-methyl-D-aspartate and noradrenaline on intracellular Ca2+ concentration in slices of rat visual cortex were studied using a fluorescent indicator, Fura-2. Bath application of N-methyl-D-aspartate (1- 100 μM) increased intracellular Ca2+ concentration in a dose-dependent manner, especially in layers II/III. Noradrenaline (1-100 μM) also increased intracellular Ca2+ concentration in a dose-dependent manner, especially in layers I and IV. However, the maximum increase in intracellular Ca2+ concentration after 100 μM noradrenaline application was less than half of that after 100 μM N-methyl-D-aspartate application in slices obtained from animals in the sensitive period. The effect of noradrenaline was most prominent in slices of the sensitive period, whereas the N-methyl-D- aspartate-induced intracellular Ca2+ concentration response decreased with age. Additive effects from application of both N-methyl-D-aspartate and noradrenaline on intracellular Ca2+ concentration were found only in the neonatal stage. Pharmacological experiments showed that α1-adrenergic receptors play a major role in the noradrenaline-induced intracellular Ca2+ concentration response, although both α2- and β-adrenergic receptors were also partially involved. The release of Ca2+ from intracellular storage underlay the early phase of the noradrenaline-induced intracellular Ca2+ concentration response, while extracellular Ca2+ influxes contributed to the sustained phase. Experiments using a gliotoxin, fluorocitric acid, suggested that the function of glial cells is involved in the noradrenaline- induced increase of intracellular Ca2+ concentration. The larger intracellular Ca2+ concentration response to noradrenaline during the sensitive period may modulate the increase in intracellular Ca2+ concentration by N-methyl-D-aspartate to maintain a higher level of cortical plasticity during this period.
    Jun. 1999, Neuroscience, 92(4) (4), 1309 - 1322, English
    [Refereed]
    Scientific journal

  • Prostaglandin J(2) and its metabolites promote neurite outgrowth induced by nerve growth factor in PC12 cells
    T Satoh, K Furuta, M Suzuki, Y Watanabe
    Although A- and J-type prostaglandins (PG's) arrest the cell cycle at the G(1) phase in vitro and suppress tumor growth in vivo, their effects on neuronal cells have not so far been clarified. Here, we found promotion of neurite outgrowth as a novel biological function of PGJ's, In PC12h cells, PGJ's (PGJ(2), Delta(12)-PGJ(2) and 15-deoxy-Delta(12,14)-PGJ(2)) promoted neurite outgrowth in the presence of nerve growth factor (NGF), whereas they themselves did not show such a promotion, The potency of promoting neurite outgrowth was PGJ(2) < Delta(12)-PGJ(2) < 15-deoxy-Delta(12,14)PGJ(2). However, troglitazone, an activator of peroxisome proliferator-activated receptor gamma (PPAR gamma), and other PG's including PGA(1), PGA(2) and PGD(2) did not promote neurite outgrowth. These results suggest that PGJ's promote neurite outgrowth independently of PPAR gamma activation. (C) 1999 Academic Press.
    ACADEMIC PRESS INC, Apr. 1999, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 258(1) (1), 50 - 53, English
    [Refereed]
    Scientific journal

  • Masaaki Suzuki, Koichi Kato, Yumiko Watanabe, Takumi Satoh, Kiyoshi Matsumura, Yasuyoshi Watanabe, Ryoji Noyori
    Biologically remarkable 15-deoxy-TIC has been realised by the removal of the C(15) chiral centre in 15R-TIC, a stable ligand for a CNS-type prostacyclin receptor (IP2); this deoxy derivative exhibits ten-fold higher affinity and selectivity than 15R-TIC for the IP2 receptor in correlation with the anti-apoptotic activity for neuronal cells.
    Feb. 1999, Chemical Communications, (4) (4), 307 - 308
    Scientific journal

  • Differential expression of immediate-early genes, c-fos and zif268, in the visual cortex of young rats: Effects of a noradrenergic neurotoxin on their expression
    Y Yamada, Y Hada, K Imamura, N Mataga, Y Watanabe, M Yamamoto
    We investigated the expression pattern of two immediate-early genes, zif268 and c-fos, under various visual conditions using immunohistochemical and northern blot analysis in the visual cortex of young rats. The basal expression of c-fos was low and was further reduced by dark; rearing that lasted for one week. A marked and transient increase was induced upon visual stimulation applied immediately after dark rearing. Zif268 showed a relatively high basal level. Its expression was reduced by dark rearing of the animals, but returned rapidly to the basal expression level following the introduction of light. Administration of N-(2-chloroethyl) -N-ethyl-2-bromobenzylamine, a selective noradrenergic neurotoxin, suppressed the basal expression of c-fos messenger RNA. The response of c-fos to photo-stimulation was also significantly lower in the visual cortex of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine-treated young rats. In contrast, no significant change in zif268 expression was detected between normal and N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine-treated animals. These findings suggest that differential expression of these immediate-early genes is involved in the activity-dependent regulation of cortical function. One possibility is that the noradrenergic system controls cortical function, including plasticity, by modifying the expression of c-fos. (C) 1999 IBRO. Published by Elsevier Science Ltd.
    PERGAMON-ELSEVIER SCIENCE LTD, 1999, NEUROSCIENCE, 92(2) (2), 473 - 484, English
    [Refereed]
    Scientific journal

  • 発達異常視覚野におけるc-FOSタンパクの発現様式
    今村 一之, 中舘 和彦, 小林 真之, Kaub Peter A., 渡辺 恭良
    日本神経化学会, Sep. 1998, 神経化学, 37(3) (3), 527 - 527, Japanese

  • 嗅覚研究の最前線 PET・fMRIを用いた嗅覚系の解析
    渡辺 恭良, 今村 一之, 小林 真之, 片岡 洋祐, 尾上 浩隆, 中舘 和彦, 駒井 章治, 吉久保 真一, 服部 慶明, 永井 康雄
    (一社)日本鼻科学会, Aug. 1998, 日本鼻科学会会誌, 37(3) (3), 170 - 170, Japanese

  • Margarete Björkman, Yvonne Andersson, Hisashi Doi, Koichi Kato, Masaaki Suzuki, Ryoji Noyori, Yasuyoshi Watanabe, Bengt Långström
    A one-pot synthesis of (15R)-16-(3-[11C]methylphenyl)-17,18,19,20-tetranoriso-carbacyclin methyl ester was performed using a palladium-promoted reaction of [11C]methyl iodide with (15R)-16-(3-tri-n-butylstannylphenyl)-17,18,19,20-tetranorísocarbacyclin methyl ester. The C-15 epimer (15S)-16-(3-[11C]methylphenyl)-17,18,19,20-tetranorisocarbacyclin methyl ester was synthesised in the same way starting from (15S)-16-(3-tributylstannylphenyl)-17,18,19,20-tetranorisocarbacyclin methyl ester. The decay-corrected radiochemical yields were 33-45% based on [11C]methyl iodide produced, and the radiochemical purity of the product was >95%. The total synthesis time was 35 min, counted from end of radionuclide production to product ready for administration. The 11C-labelled prostacyclin methyl esters were easily hydrolysed using sodium hydroxide affording the 11C-labelled prostacyclin acids in quantitative yields. The stereoisomers (15A)-16-(3-methylphenyl)-17,18,19,20-tetranorisocarbacyclin [11C]methyl ester and (15S)-16-(3-methylphenyl)-17,18,19,20-tetranorisocarbacyclin [11C]-methyl ester were synthesised by esterification using [11C] methyl iodide and the tetrabutylammonium salts of (15R)-16-(3-methylphenyl)-17,18,19,20-tetranorisocarbacyclin acid and (15S)-16-(3-methylphenyl)-17,18,19,20-tetranorisocarbacyclin acid, respectively. The decay-corrected radiochemical yields were in the range of 55% counting from [11C]methyl iodide produced, and the radiochemical purity of the product was >95%. The total synthesis time was 35 min, counting from end of radionuclide production to product ready for administration. Both of these labelling methods can be used for labelling with 13C when (13C)methyl iodide is used. The methods described herein have already proved important since they enable the in vivo use of PET to study the action of prostacyclins in the brain. © Acta Chemica Scandinavica 1998.
    May 1998, Acta Chemica Scandinavica, 52(5) (5), 635 - 640
    Scientific journal

  • Chunyu Cao, Kiyoshi Matsumura, Kanato Yamagata, Yasuyoshi Watanabe
    Cyclooxygenase-2 (COX-2) is an inducible type of enzyme that is involved in prostaglandin biosynthesis. In the present study, we examined whether or not COX-2 is involved in fever that is induced by tumor necrosis factor-alpha (TNF-α) and, if so, where in the brain COX-2 is induced by this factor. Intraperitoneal (i.p.) injection of TNF-α into rats evoked a fever that started 1 h after the TNF injection, peaked 3 h after the injection, and then gradually declined. The fever was suppressed by pretreatment with a COX-2-specific inhibitor. With a time course similar to that of fever, COX-2 mRNA was induced in brain blood vessels. On the other hand, in some of the telencephalic neurons, COX-2 mRNA was constitutively expressed under the normal condition but its level gradually decreased during the course of fever. Fever was also evoked by an intracerebroventricular (i.c.v.) injection of TNF-α. This febrile response was also suppressed by a COX-2 specific inhibitor and was associated with the induction of COX-2 mRNA in the brain blood vessels. On the other hand, the telencephalic neurons did not show consistent change in COX-2 mRNA level after i.c.v. injection of TNF-α or saline. COX-2-like immunoreactivity was found in some cells of the brain blood vessels 3 h after the TNF-α injection by either i.p. or i.c.v. route. Most of the COX-2-like immunoreactive cells were endothelial cells since COX-2-like immunoreactivity was colocalized with von Willebrand factor, an endothelial cell marker, in the same cells. These results suggest that the brain blood vessels are the major sites where TNF-α enhances PG biosynthesis after peripheral as well as after central injection, and provides further evidence supporting the hypothesis that COX-2 induced in the brain blood vessels is involved in fever.
    May 1998, Molecular Brain Research, 56(1-2) (1-2), 45 - 56, English
    [Refereed]
    Scientific journal

  • Hirohiko Kuratsune, Kouzi Yamaguti, Gudrun Lindh, Birgitta Evengård, Mamoru Takahashi, Takashi Machii, Kiyoshi Matsumura, Joh Takaishi, Sumio Kawata, Bengt Långström, Yuzuru Kanakura, Teruo Kitani, Yasuyoshi Watanabe
    Recently, we found a serum acylcarnitine (ACR) deficiency in Japanese pf.'dents with chronic fatigue syndrome (CFS). To clarify whether this ACR abnormality is a characteristic of CFS or not, we also studied the levels of serum carnitine in Swedish subjects. Both serum ACR and free carnitine (FCR) levels in normal healthy subjects were quite different between Japanese (n=131) and Swedish people (n=46) (p< 0.001). However, it is confirmed that Swedish patients with CFS (n=57) also had serum ACR deficiency (p< 0.001). When we studied the levels of serum ACR and FCR in Japanese patients with various kinds of diseases (CFS, hematological malignancies, chronic pancreatitis, hypertension, diabetes mellitus, chronic hepatitis type C, psychiatric diseases), a significant decrease in the levels of serum ACR was only found in patients with CFS and chronic hepatitis type C (p< 0.001). Therefore, we concluded that ACR deficiency in serum might be a characteristic abnormality in only certain types of diseases.
    Spandidos Publications, 1998, International Journal of Molecular Medicine, 2(1) (1), 51 - 56, English
    Scientific journal

  • Role of brain endothelial cyclooxygenase-2 in the transmission of immune signal to the central nervous system
    K Matsumura, CY Cao, K Nakadate, H Morii, Y Watanabe
    KARGER, 1998, BRAIN AND BIODEFENCE, 21, 99 - 109, English
    [Refereed]
    International conference proceedings

  • Masaaki Suzuki, Hisashi Doi, Margareta Björkman, Yvonne Andersson, Bengt Långström, Yasuyoshi Watanabe, Ryoji Noyori
    The reaction of methyl iodide and (excess) aryltributylstannane to give a methylarene has been studied with the focus on the realization of rapid coupling for incorporation of short-lived radionuclides into bioactive organic compounds. The coupling of methyl iodide with tributylphenylstannane (40 equiv) is accomplished in >90% yield within 5 min at 60°C with a tri-o-tolylphosphine-bound, coordinatively unsaturated Pd(o) complex together with a Cu(I) salt and K2CO3 in DMF. This protocol is applicable to a variety of homo- and heteroaromatic tin compounds, to give the corresponding methylated derivatives. The effects of the tri-o-tolylphosphine ligand, a Cu(I) salt, and DMF are discussed. This new protocol provides a firm chemical basis for the synthesis of 11CH3-incorporated PET tracers.
    Dec. 1997, Chemistry - A European Journal, 3(12) (12), 2039 - 2042
    Scientific journal

  • A postsynaptic excitatory amino acid transporter with chloride conductance functionally regulated by neuronal activity in cerebellar Purkinje cells
    Y Kataoka, H Morii, Y Watanabe, H Ohmori
    Excitatory amino acid (EAA) neurotransmitters induce postsynaptic depolarization by activating receptor-mediated cation conductances, a process known to underlie changes in synaptic efficacy. Using a patch-clamp method, we demonstrate here an EAA-dependent postsynaptic anion conductance mediated by EAA transporters present on cerebellar Purkinje cell bodies and dendrites in culture. This transporter-mediated current was modulated by neuronal activity: it exhibited facilitation for >20 min after transient depolarization accompanied by Ca2+ influx. Evidence is presented suggesting that the transporter facilitation is mediated by arachidonate release after Ca2+-dependent activation of phospholipase A(2), which exists in Purkinje cells. This postsynaptic reuptake system may represent a novel modulatory mechanism of synaptic transmission as well as prevent neuronal excitotoxicity.
    SOC NEUROSCIENCE, Sep. 1997, JOURNAL OF NEUROSCIENCE, 17(18) (18), 7017 - 7024, English
    [Refereed]
    Scientific journal

  • Keiko Muguruma, Kiyoshi Matsumura, Yumiko Watanabe, Tsuyoshi Shiomitsu, Kazuyuki Imamura, Yasuyoshi Watanabe
    To examine visual activity-dependent regulation of the central noradrenergic (NAergic) system, we carried out in vitro autoradiography for α2-, β-adrenergic and NMDA, non-NMDA glutamatergic receptors together with immunohistochemical analysis for dopamine β-hydroxylase in the major central visual structures, including the lateral geniculate nucleus, superior colliculus (SC), and visual cortex of pigmented rats, that had received monocular enucleation. β-Adrenergic receptor (β-AR) binding in the SC contralateral to the enucleated eye was significantly decreased (82%, P < 0.01) following monocular deprivation started at P12 and continued for 2 or 11 weeks. No significant change in β-AR binding was found in other structures examined. The number of varicosities in NAergic fibers was significantly increased following longer enucleation, i.e. for 11 weeks, in the contralateral SC (197%, P < 0.001), whereas that in the ipsilateral SC was reduced (75%, P < 0.001). Changes in α2-adrenergic NMDA, and non-NMDA glutamatergic receptor binding were small in these animals. Changes in neither β-AR binding nor innervation pattern of NAergic fibers were found in one-year-old rats that had received a comparable period of monocular enucleation. Furthermore, neither unilateral ablation of the visual cortex to reduce a different set of major afferents nor neonatal enucleation, which induced anatomical reorganization of the afferents, was found to be effective. These findings suggest that β-AR binding and innervation pattern of NAergic fibers in the SC are modified only when massive imbalance of retinal afferent activity is imposed during a limited period in early postnatal life (i.e. the sensitive period).
    Aug. 1997, Neuroscience Research, 28(4) (4), 311 - 324, English
    Scientific journal

  • Involvement of cyclooxygenase-2 in LPS-induced fever and regulation of its mRNA by LPS in the rat brain
    CY Cao, K Matsumura, K Yamagata, Y Watanabe
    We previously showed that a febrile dose of lipopolysaccharide (LPS in rats resulted in induction of cyclooxygenase-2 (COX-2) mRNA in brain blood vessels/leptomeninges and telencephalic neurons. To elucidate the causal link between fever and LPS-induced COX-2 mRNA, we experimentally modified one or the other of these parameters and examined their relation. 1) LPS-induced fever was suppressed by pretreatment with a COX-2-specific inhibitor. 2) Levels of COX-2 mRNA in the neurons and blood vessels 2.5 h after LPS administration were even higher in the inhibitor pretreated rats (afebrile) than in vehicle-pretreated ones (febrile). 3) After repeated administration of LPS, rats became tolerant to LPS, in which state LPS induced neither fever nor COX-2 mRNA in blood vessels/ leptomeninges. When rats had not completely established LPS tolerance. they showed various degrees of fever that were closely correlated with the level of COX-2 mRNA in blood vessels but not with that in neurons. 4) Urethan anesthesia reduced basal as well as LPS-induced COX-2 mRNA in telencephalic neurons, but the rats still responded to LPS with fever and induction of COX-2 mRNA in the blood vessels/leptomeninges. These results suggest that COX-2 induced in brain blood vessels/leptomeninges is involved in the molecular mechanism of LPS-induced fever.
    AMER PHYSIOLOGICAL SOC, Jun. 1997, AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, 272(6) (6), R1712 - R1725, English
    [Refereed]
    Scientific journal

  • Noriko Mochizuki-Oda, Yuko Takeuchi, Kiyoshi Matsumura, Yoshio Oosawa, Yasuyoshi Watanabe
    Hypoxia (5% O2) enhanced catecholamine release in cultured rat adrenal chromaffin cells. Also, the intracellular free Ca2+ concentration ([Ca2+](i)) increased within 3 min in ~50% of the chromaffin cells under hypoxic stimulation. The increase depended on the presence of extracellular Ca2+. Nifedipine and ω-conotoxin decreased the population of the cells that showed the hypoxia-induced [Ca2+](i) increase, showing that the Ca2+ influx was attributable to L- and N-type voltage-dependent Ca2+ channels. The membrane potential was depolarized during the perfusion with the hypoxic solution and returned to the basal level following the change to the normoxic solution (20% O2). Membrane resistance increased twofold under the hypoxic condition. The current-voltage relationship showed a hypoxia-induced decrease in the outward K+ current. Among the K+ channel openers tested, cromakalim and levcromakalim, both of which interact with ATP-sensitive K+ channels, inhibited the hypoxia-induced [Ca2+](i) increase and catecholamine release. The inhibitory effects of cromakalim and levcromakalim were reversed by glibenclamide and tolbutamide, potent blockers of ATP-sensitive K+ channels. These results suggest that some fractions of adrenal chromaffin cells are reactive to hypoxia and that K+ channels sensitive to cromakalim and glibenclamide might have a crucial role in hypoxia-induced responses. Adrenal chromaffin cells could thus be a useful model for the study of oxygen- sensing mechanisms.
    Blackwell Publishing Ltd, 1997, Journal of Neurochemistry, 69(1) (1), 377 - 387, English
    Scientific journal

  • Possible role of cyclooxygenase-2 in the brain vasculature in febrile response
    K Matsumura, CY Cao, Y Watanabe
    NEW YORK ACAD SCIENCES, 1997, THERMOREGULATION, 813, 302 - 306, English
    [Refereed]
    Scientific journal

  • Enhancement of mRNA expression of tissue-type plasminogen activator by L-threo-3,4-dihydroxyphenylserine in association with ocular dominance plasticity
    N Mataga, K Imamura, T Shiomitsu, Y Yoshimura, F Fukamauchi, Y Watanabe
    Tissue-type plasminogen activator (tPA) plays important roles in the regulation of synaptic plasticity in the hippocampus and cerebellum. We found that the expression of tPA mRNA in the visual cortex was increased significantly by the peripheral administration of L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS; 100 mg/kg, i.p.), which we had previously shown to have a promotive effect on ocular dominance (OD) plasticity. When plasminogen activator inhibitor-1 (PAI-I; 100 mu M in an osmotic minipump) was infused into the kitten visual cortex, OD plasticity was suppressed; i.e. a significantly large number of binocular cells was recorded in the PAI-1-infused cortex following monocular deprivation. These results, therefore, suggest that the PA system is involved in the promotive effect of L-threo-DOPS in OD plasticity.
    ELSEVIER SCI IRELAND LTD, Nov. 1996, NEUROSCIENCE LETTERS, 218(3) (3), 149 - 152, English
    [Refereed]
    Scientific journal

  • Down-regulation of beta-adrenergic receptor following long-term monocular deprivation in cat visual cortex
    K Muguruma, K Imamura, H Morii, Y Watanabe
    To examine how adrenergic receptor binding is modified by experimental manipulation of sensory afferent, we carried out binding experiments (membrane fraction and in vitro autoradiography) for both alpha(2)- and beta-adrenergic receptors in the brain of cats which had been deprived of vision in one eye. In the cerebral cortex of control animals, beta-adrenergic receptor (beta-AR) binding was found to be higher in the occipital regions than in other regions, while alpha(2)-AR binding was relatively uniform. Monocular deprivation throughout the postnatal sensitive period (1-7 month of age) significantly decreased beta-AR binding in the visual cortex and lateral geniculate nucleus. Scatchard plot analysis in the visual cortex showed ca. 50% reduction in B-max and little change in K-d. No significant difference was found in alpha(2)-AR binding following monocular deprivation. Similar extent of down-regulation in -AR binding was confirmed in all layers of visual cortex using autoradiography.
    ELSEVIER SCIENCE BV, Nov. 1996, BRAIN RESEARCH, 740(1-2) (1-2), 131 - 140, English
    [Refereed]
    Scientific journal

  • Repeated peripheral administration of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin alters the binding activities of 5-HT1A and 5-HT2 receptors in rat brain
    K Muguruma, K Imamura, Y Watanabe
    Repeated peripheral administration of 6R-L-erythro-5,6,7.8-tetrahydrobiopterin (R-THBP) induced significant changes in the binding activities of serotonergic receptors in the rat brain. The increase in the hippocampus and the decrease in the visual cortex of [H-3]8-hydroxy-N,N-dipropyl-2-aminotetralin ([H-3]8-OH-DPAT) binding (5-HT1A binding site) were found to be significant following R-THBP administration (20 mg/kg, twice a day for 1 week). [H-3]Ketanserin binding (5-HT2 binding site) was increased in the striatum and hippocampus, whereas it was decreased in the cerebellum and visual cortex. Scatchard plot analysis showed ca. 20% reduction in the B-max of [H-3]8-OH-DPAT and [H-3]ketanserin binding in the visual cortex, and K-D values for [H-3]8-OH-DPAT and [H-3]ketanserin bindings in the hippocampus were significantly reduced 51% and 66%, respectively. These differential changes in 5-HT binding might be involved in the central action of R-THBP. (C) 1996 Academic Press, Inc.
    ACADEMIC PRESS INC ELSEVIER SCIENCE, Oct. 1996, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 227(3) (3), 794 - 799, English
    [Refereed]
    Scientific journal

  • Chunyu Cao, Kiyoshi Matsumura, Kanato Yamagata, Yasuyoshi Watanabe
    We previously showed that intraperitoneal injection of lipopolysaccharide induced cyclooxygenase-2 (COX-2) mRNA in as yet unidentified cells of blood vessels and leptomeninges in the rat brain and proposed a possible role of these cells as the source of prostaglandin E2 in the genesis of fever (Cao et al., Brain Res., 697 (1995) 187-196). In the present study, to proceed further with this line of research, we addressed the following two questions: first, does a pyrogenic dose of interleukin-1β (IL-1β), an endogenous pyrogen, induce COX-2 mRNA in the brain blood vessels and leptomeninges? Secondly, if it does, what type of cells are positive for COX-2 mRNA? Intraperitoneal injection of recombinant human IL-1β (30 μg/kg) induced fever in rats and an in situ hybridization study revealed that faint but significant COX-2 mRNA signals appeared in the blood vessels and leptomeninges at 1.5 h after the injection (the early rising phase of fever). The mRNA signals increased in number and intensity at 4 h (early plateau phase), decreased at 6.5 h (early recovery phase), and completely disappeared by 10 hr after the injection (late recovery phase). The COX-2 mRNA positive cells in the blood vessels were likely to be the endothelial cells since the corresponding cells in the adjacent mirror-imaged section also expressed mRNAs for intracellular adhesion molecule-1 and the type-I interleukin-1 receptor, although those in the leptomeninges still remained unidentified. These results imply that circulating IL-1β acts on its receptor on the endothelial cells of the brain vasculature to induce COX-2 mRNA, which is possibly responsible for the elevated level of PGE2 seen during fever.
    Elsevier B.V., Sep. 1996, Brain Research, 733(2) (2), 263 - 272, English
    [Refereed]
    Scientific journal

  • Kouzi Yamaguti, Hirohiko Kuratsune, Yasuyoshi Watanabe, Mamoru Takahashi, Ichiro Nakamoto, Takashi Machii, Gunilla Jacobsson, Hirotaka Onoe, Kiyoshi Matsumura, Sven Valind, Bengt Långström, Teruo Kitani
    Carnitine metabolism during starvation and just after refeeding was studied by the measurement of acylcarnitine (ACR) and total carnitine (TCR) concentration in the serum and liver of mice. Starvation caused marked increases in the concentration of serum ACR, and of acid-soluble ACR in the liver. The refeeding caused the quick decrement of serum ACR with a concomitant marked increase in the level of acid-soluble TCR in the liver. Through the use of positron emission tomography in a rhesus monkey, a marked increase in [2-11C]acetyl-L-carnitine uptake in the liver was observed after the administration of glucose accompanying the decrease of serum ACR. From this study, it is clear that the mammalian liver can salvage and conserve the unused ACR when the state of energy metabolism is improved.
    Academic Press Inc., Aug. 1996, Biochemical and Biophysical Research Communications, 225(3) (3), 740 - 746, English
    Scientific journal

  • Hajime Takechi, Kiyoshi Matsumura, Yumiko Watanabe, Koichi Kato, Ryoji Noyori, Masaaki Suzuki, Yasuyoshi Watanabe
    By use of several prostacyclin analogs and an in vitro autoradiographic technique, we have found a novel subtype of the prostacyclin receptor, one having different binding properties compared with those of the known prostacyclin receptor in the rat brain. Isocarbacyclin, which is a potent agonist for the known prostacyclin receptor, had high affinity for the novel subtype (dissociation constant (K(d)) of 7.8 nM). However, iloprost, which is usually used as a stable prostacyclin analog, showed low affinity binding (K(d) = 159 nM) for the subtype. Other prostaglandins showed no or little affinity for the subtype. [3H]Isocarbacyclin binding was high in the thalamus, lateral septal nucleus, hippocampus, cerebral cortex, striatum, and dorsal cochlear nucleus. Although the nucleus of the solitary tract and the spinal trigeminal nucleus showed a high density of [3H]isocarbacyclin binding, [3H]iloprost also had high affinity in these regions, and the binding specificity was similar to that for the known prostacyclin receptor. Hemilesion studies of striatal neurons lesioned by kainate or of dopaminergic afferents lesioned by 6-hydroxydopamine revealed that the binding sites of the novel subtype exist on neuronal cells in the striatum, but not on the presynaptic terminal of afferents or on glial cells. Electrophysiological studies carried out in the CA1 region of the hippocampus revealed that prostacyclin analogs have a facilitatory effect on the excitatory transmission through the novel prostacyclin receptor. The widespread expression of the prostacyclin receptor in the central nervous system suggests that prostacyclin has important roles in neuronal activity.
    Mar. 1996, Journal of Biological Chemistry, 271(10) (10), 5901 - 5906
    Scientific journal

  • Masaaki Suzuki, Koichi Kato, Ryoji Noyori, Yumiko Watanabe, Hajime Takechi, Kiyoshi Matsumura, Bengt Långström, Yasuyoshi Watanabe
    Wiley, Feb. 1996, Angewandte Chemie International Edition in English, 35(3) (3), 334 - 336
    [Refereed]
    Scientific journal

  • Suzuki Masaaki, Hosoya Takamitsu, Takeuchi Kyoko, Kato Koichi, Fukunaga Hirofumi, Noyori Ryoji, Watanabe Yumiko, Matsumura Kiyoshi, Takechi Hajime, Watanabe Yasuyoshi, Langstrom Bengt
    Recently, the role of prostaglandins (PGs) in brain function has attracted much attention. We succeeded in creating a stable ligand with high binding affinity and selectivity for a prostacyclin (1, PGI_2) receptor expressed in the central nervous system (CNS). The ligand, (15R)-16-m-tolyl-17,18,19,20-tetranorisocarbacyclin (3, 15R-TIC), was prepared starting from the Horner-Emmons reaction of aldehyde 4 and β-keto phosphonate 5 followed by 1,2-reduction of the enone, separation of the resulting C(15)-epimers, and hydrolysis of the methyl ester. The binding assay was conducted by the [^3H]isocarbacyclin displacement study using the rat frozen tissue sections containing the thalamus or NTS (nucleus tractus solitarius) as representative of the CNS or peripheral nervous system. Consequently, 3 exhibited high binding affinity sufficient for a receptor in the thalamus (IP_2) but showed very weak binding for a receptor in the NTS (IP_1). In contrast, cicaprost (12), a stable PGI_2 agonist belonging to an iloprost family, showed high binding affinity and selectivity for IP_1. 15S-TIC (9), the C(15)-epimer of 3, and isocarbacyclin (2) bound strongly with both of the receptors. Electrophysiological studies carried out in the CA1 region of the rat hippocampus revealed that the PGI_2 analogs have a facilitatory effect on the excitatory transmission through IP_2. The widespread expression of IP_2 in the CNS suggests that PGI_2 has important roles in neuronal activity. In order to identify IP_2, we prepared an azido-functionalized isocarbacyclin derivative 14 as a photoaffinity probe, which showed strong binding affinity for IP_2.
    Symposium on the Chemistry of Natural Products Steering Committee, 1996, Symposium on the Chemistry of Natural Products, symposium papers, 38, 241 - 246, Japanese

  • Chunyu Cao, Kiyoshi Matsumura, Kanato Yamagata, Yasuyoshi Watanabe
    Cyclooxygenase 2 (COX-2) is a newly discovered isoform of cyclooxygenase that is inducible by lipopolysaccharide (LPS) or cytokines. This enzyme is considered to play a major role in inflammatory processes by catalyzing the production of prostaglandins. In the present study, induction of COX-2 mRNA in the rat brain by intraperitoneal injection of LPS was studied by the in situ hybridization technique with special attention paid to timing and sites of induction along with the time course of fever. In situ hybridization was carried out on sections of rat brain, 1 h (latent phase), 2.5 h (maximally febrile phase), 4 h (plateau phase), and 7 h (recovery phase) after the LPS injection, as well as on those from the brains of untreated and saline-injected rats. Injection of LPS induced COX-2 mRNA in the brain in two different constituents: neuronal cells and non-parenchymal cells of the blood vessels and leptomeninges. Induction in the neuronal cells was restricted to some telencephalic areas where the COX-2 mRNA signal was also detected in control animals. The signal was maximally enhanced by 50 to 80% over the basal level 1 h after LPS injection. The COX-2 mRNA signal was hardly detectable in neuronal and glial cells in other brain regions, including the preoptic area, either in control or LPS-injected rats. Strong COX-2 mRNA signals, however, appeared in the inner surface of blood vessels and the leptomeninges over the entire brain, including the preoptic area and its vicinity. The signals were not detectable in the brains of control rats and were most intense in the brains of rats treated with LPS for 2.5 h or 4 h. These results demonstrate that two major cell groups in the brain, neuronal cells and non-parenchymal cells, are responsible for the enhanced production of prostaglandins after systemic LPS treatment. Considering the site and timing of induction, we propose a possible role for blood vessels and leptomeninges as the source of prostaglandin E2 in the genesis of fever. © 1995 Elsevier Science B.V. All rights reserved.
    Oct. 1995, Brain Research, 697(1-2) (1-2), 187 - 196, English
    [Refereed]
    Scientific journal

  • PROSTAGLANDIN-E2 EXCITES NEURONS OF THE NUCLEUS-TRACTUS-SOLITARIUS BY ACTIVATING CATION CHANNELS
    K MATSUMURA, Y WATANABE, H ONOE, Y WATANABE, S TANAKA, T SHIRAKI, S KOBAYASHI
    Nucleus tractus solitarius (NTS) has a high density of prostaglandin E2 (PGE2)-binding sites. Action of PGE2 (10(-9)-10(-6) M) was tested on neurons in a NTS slice with patch-clamp recording under synaptic blockade. PGE2 raised the firing rate in approximately half of the neurons in cell-attached patch mode. In whole-cell current clamp, PGE2 depolarized membrane potential accompanied by an increase in firing rate. In whole-cell voltage clamp (-58 mV), PGE2 induced the inward current with an increase in conductance. The current was linearly related to voltage from -100 mV to -10 mV and suppressed between -10 mV and 20 mV. The current-voltage curve remained similar under low external Cl- or high internal Cl- conditions and after external Na+ was replaced by Cs+. It is concluded that PGE2 excites NTS neurons by activating cation conductance.
    ELSEVIER SCIENCE BV, Oct. 1993, BRAIN RESEARCH, 626(1-2) (1-2), 343 - 346, English
    [Refereed]

  • PG OSBORNE, N MATAGA, H ONOE, Y WATANABE
    The locomotor activity and grooming of conscious freely moving rats were recorded during a 60-min unilateral perfusion of the preoptic area with neuroactive compounds using the microdialysis technique. The GABA agonist, muscimol (I 0, 20 and 100 muM) induced a dose-dependent increase in locomotor activity and grooming which was attenuated by co-perfusion with the GABA antagonist, bicuculline (10 muM), and was blocked by systemic injection of haloperidol, a preferential dopamine D2 receptor antagonist (0.25 mg/kg). Muscimol-induced hyperactivity was associated with a simultaneous increase of striatal extracellular dopamine. These data suggest that the preoptic area is functionally linked with the extrapyramidal dopaminergic system possibly via GABAergic system.
    ELSEVIER SCI IRELAND LTD, Aug. 1993, NEUROSCIENCE LETTERS, 158(2) (2), 201 - 204, English
    [Refereed]
    Scientific journal

  • REGULATION OF PROSTAGLANDIN-D(2)-RECEPTOR AND PROSTAGLANDIN-E(2)-RECEPTOR BINDING IN THE CENTRAL-NERVOUS-SYSTEM
    H MORII, Y WATANABE
    Prostaglandin (PG) D2 and PGE2 receptor binding activities are regulated in various fashions. The protein phosphorylation by exogenous cAMP-dependent protein kinase or calmodulin-dependent protein kinase II significantly increased PGE2 binding activity through an increase in the apparent amount of the maximal binding, suggesting that the PGE2 receptor may be regulated through protein phosphorylation-dephosphorylation. Other possible regulatory mechanisms were found as the result of studies on functional modification of glycoconjugates. Pretreatment with glycoprotein-specific endoglycosidases (peptide N-glycohydrolase F, endo-alpha-N-acetylgalactosaminidase) decreased both PGD2 and PGE2 receptor binding activities and consequently these activities became nonspecific ones. In addition, these binding activities were increased by the addition of a ganglioside or cerebroside mixture, but not ceramide. The addition of separate purified glycolipids showed more specifically their effect on each PG binding. PGD2 binding activity was increased by GD1a and GQ1b and decreased by GM1 and GT1a, while PGE2 binding activity was increased by GQ1b and galactocerebroside. In such a way, PG receptors may require some specific microenvironment for their maximal binding activity.
    ELSEVIER SCIENCE BV, Mar. 1993, JOURNAL OF LIPID MEDIATORS, 6(1-3) (1-3), 445 - 451, English
    [Refereed]
    Scientific journal

  • GLIOTOXIN-INDUCED SUPPRESSION OF OCULAR DOMINANCE PLASTICITY IN KITTEN VISUAL-CORTEX
    K IMAMURA, N MATAGA, Y WATANABE
    We studied the role of astrocytes in the regulation of ocular dominance plasticity. A small quantity of 10 muM fluorocitrate (0.2 nmol in 20 mul) was pressure-injected into the visual cortex of 7-9-week-old kittens (subcortical depth: 0-5 mm, 20 mul/10 min). Immediately after injection, 1 eye contralateral to the injected cortex was closed for 3 days. Single-unit recordings revealed that the proportion of binocular cells was significantly higher in a region close (approximately 1 mm) to the fluorocitrate injection site than that in a remote region (> 4 mm) within the same hemisphere and that in the opposite hemisphere. The results suggest that reduction of glial functions by fluorocitrate retarded the usual process of shift in ocular dominance of visual cells following monocular deprivation.
    ELSEVIER SCI IRELAND LTD, Feb. 1993, NEUROSCIENCE RESEARCH, 16(2) (2), 117 - 124, English
    [Refereed]
    Scientific journal

  • L-THREO-3,4-DIHYDROXYPHENYLSERINE ENHANCED OCULAR DOMINANCE PLASTICITY IN ADULT CATS
    N MATAGA, K IMAMURA, Y WATANABE
    We studied whether ocular dominance plasticity can be restored to the aplastic visual cortex of the adult cat by peripheral administration of L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS), an exogenous precursor of L-noradrenaline (NA). We found that NA output in the visuocortical dialysate was significantly increased by a single administration of L-threo-DOPS (200 mg or 1 g, i.p.). Single unit recordings revealed a significant reduction of binocular cells (binocularity = 0.30) in juvenile cats (7-8 months of age) that had been monocularly deprived for one month in combination with L-threo-DOPS (200 mg/day, per os). These results suggest that peripheral administration of L-threo-DOPS enhances ocular dominance plasticity, presumably through activation of the central noradrenergic system.
    ELSEVIER SCI IRELAND LTD, Aug. 1992, NEUROSCIENCE LETTERS, 142(2) (2), 115 - 118, English
    [Refereed]
    Scientific journal

  • A NOVEL ROLE OF 6R-TETRAHYDROBIOPTERIN IN THE CENTRAL-NERVOUS-SYSTEM
    N MATAGA, K IMAMURA, Y WATANABE
    ELSEVIER SCIENCE PUBL B V, 1992, NEUROBIOLOGY OF INFANTILE AUTISM, 965, 333 - 334, English
    [Refereed]
    International conference proceedings

  • A NOVEL ROLE OF 6R-TETRAHYDROBIOPTERIN - MICRODIALYSIS AND ELECTROPHYSIOLOGICAL STUDIES
    N MATAGA, K IMAMURA, Y WATANABE
    ELSEVIER SCIENCE PUBL B V, 1992, FRONTIERS AND NEW HORIZONS IN AMINO ACID RESEARCH, 541 - 545, English
    [Refereed]
    International conference proceedings

  • A POSSIBLE ROLE OF CARBOHYDRATE MOIETIES IN PROSTAGLANDIN-D2 AND PROSTAGLANDIN-E2 RECEPTOR PROTEINS FROM THE PORCINE TEMPORAL CORTEX
    H MORII, Y WATANABE
    ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS, Jan. 1992, ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 292(1) (1), 121 - 127, English
    [Refereed]
    Scientific journal

  • REGULATION OF PROSTAGLANDIN-E2 RECEPTOR-BINDING ACTIVITY IN PORCINE TEMPORAL CORTEX BY PROTEIN-PHOSPHORYLATION
    H MORII, M TANEMURA, Y WATANABE
    Regulation of prostaglandin (PG) E2 receptors was investigated in a 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate-solubilized fraction from the synaptic membrane of porcine temporal cortex. The fraction was preincubated with exogenous protein kinases, and then the binding of PGE2 was measured. PGE2 binding was increased approximately twofold by pretreatment with the catalytic subunit of cyclic AMP-dependent protein kinase (A kinase) or calmodulin-dependent protein kinase II but not by that with protein kinase C. The increase was dependent on the ATP concentration, with ED50 values being close to the K(m) values of these protein kinases. Protein kinase inhibitors specific for A kinase and for calmodulin-dependent protein kinase II abolished the effect in a dose-dependent manner, with IC50 values being similar to those reported. Further study using the catalytic subunit of A kinase revealed that the maximal binding capacity apparently increased without affecting the affinity and the rate constants for association and dissociation. On the other hand, acid phosphatase treatment reduced the binding activity to the level of nonspecific binding. In addition, treatment by A kinase did not affect the binding of guanosine 5'-(3-thiotriphosphate) by the GTP-binding proteins and the activation of adenylate cyclase mediated by stimulatory guanine nucleotide-binding regulatory protein, and therefore the phosphorylation is believed to occur on the receptor protein. The results suggests that the PGE2 receptor can take active phosphorylated and inactive dephosphorylated forms, of which only the phosphorylated one can bind PGE2.
    LIPPINCOTT-RAVEN PUBL, Oct. 1991, JOURNAL OF NEUROCHEMISTRY, 57(4) (4), 1281 - 1287, English
    [Refereed]
    Scientific journal

  • 6R-TETRAHYDROBIOPTERIN PERFUSION ENHANCES DOPAMINE, SEROTONIN, AND GLUTAMATE OUTPUTS IN DIALYSATE FROM RAT STRIATUM AND FRONTAL-CORTEX
    N MATAGA, K IMAMURA, Y WATANABE
    The effect of 6R-tetrahydrobiopterin (R-THBP) on neurotransmitter release was investigated using in vivo brain microdialysis in urethane-anesthetized rats. Perfusion of 1.0 mM R-THBP enhanced the level of dopamine output in dialysates collected from the striatum and frontal cortex. R-THBP perfusion also increased serotonin (striatum) and glutamate outputs (striatum and frontal cortex). Dopaminergic terminals in the striatum were destroyed unilaterally by continuous infusion of 6-hydroxydopamine (6-OHDA) using an osmotic minipump system. The effect of R-THBP administration on glutamate level was found to be almost completely suppressed in the 6-OHDA-lesioned side of striatum, while in the intact side of striatum the glutamate level in the dialysates responded normally to R-THBP perfusion. These results suggest that R-THBP may play a role in the mechanisms of release of dopamine, serotonin, and glutamate. The functioning of the catecholaminergic system probably mediates the increase in glutamate output due to R-THBP perfusion.
    ELSEVIER SCIENCE BV, Jun. 1991, BRAIN RESEARCH, 551(1-2) (1-2), 64 - 71, English
    [Refereed]
    Scientific journal

  • SOLUBILIZATION OF PROSTAGLANDIN-D2 BINDING-PROTEIN FROM PORCINE TEMPORAL CORTEX
    H MORII, Y WATANABE
    ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS, Jan. 1991, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 174(1) (1), 364 - 371, English
    [Refereed]
    Scientific journal

■ MISC
  • カルシウム摂取不足が血中25-hydroxyvitamin D濃度に与える影響 横断的疫学調査による検討
    津川 尚子, 桑原 晶子, 浦 千尋, 小笠原 帆南, 田中 清, 水野 敬, 渡辺 恭良
    (公社)日本ビタミン学会, Apr. 2022, ビタミン, 96(4) (4), 204 - 204, Japanese

  • 擬似ウイルス感染モデルラットでの脳内炎症は倦怠感の惹起に関わる
    越智祐太, 新垣和貴子, 胡迪, 李丹渓, 重田美香, 林中恵美, 和田康弘, 土居久志, 渡辺恭良, 崔翼龍
    2022, 日本神経化学会大会抄録集(Web), 65th

  • 条件付け誘発性のプラセボ鎮痛はmedial prefrontal cortex-ventrolateral periaqueductal gray回路の活性化を介する
    根山広行, 武玉萍, 井上美智子, 清水朋子, 加藤成樹, 渡辺恭良, 小林和人, 崔翼龍
    2022, 日本神経化学会大会抄録集(Web), 65th

  • 慢性疲労症候群における筋力低下に伴う影響
    田中 邦彦, 福田 早苗, 山口 浩二, 渡辺 恭良, 倉恒 弘彦
    日本疲労学会, May 2019, 日本疲労学会誌, 15(1) (1), 69 - 69, Japanese

  • 慢性疲労症候群における筋力低下に伴う影響
    田中 邦彦, 福田 早苗, 山口 浩二, 渡辺 恭良, 倉恒 弘彦
    日本疲労学会, May 2019, 日本疲労学会誌, 15(1) (1), 69 - 69, Japanese

  • 半導体コンプトンカメラGREIによるNa+/K+の同時イメージング
    本村 信治, 喜井 勲, 羽場 宏光, 薬師寺 秀樹, 渡辺 恭良, 榎本 秀一
    日本分子イメージング学会, May 2019, JSMI Report, 12(2) (2), 170 - 170, Japanese

  • 慢性疲労症候群におけるフレイルの状況と日常生活への影響
    田中 邦彦, 福田 早苗, 雪野 皐月, 山口 浩二, 松本 美富士, 渡辺 恭良, 倉恒 弘彦
    日本疲労学会, May 2018, 日本疲労学会誌, 14(1) (1), 63 - 63, Japanese

  • 健常者を対象とした疲労感想起に関与する神経メカニズムの解明
    山野 恵美, 石井 聡, 田中 雅彰, 渡辺 恭良
    日本疲労学会, May 2018, 日本疲労学会誌, 14(1) (1), 56 - 56, Japanese
    [Refereed]

  • Hidefumi Mukai, Yasuyoshi Watanabe
    Positron emission tomography (PET) visualizes radiolabeled compounds in the living body with a high sensitivity, quantitative performance, and considerably high spatial and temporal resolution. This technique is useful for pharmacokinetic analysis and drug efficacy evaluation in preclinical and clinical studies. PET enables the investigation of drug concentrations in human tissues, which was impossible by conventional evaluation technologies. In addition, we can use PET probes to visualize the expression and function of disease-related molecules as surrogate endpoints in clinical trials. In this review, we will exemplify our collaborative preclinical and clinical studies on pharmacokinetics, DDS, and theranostics with a variety of academic and industrial collaboraters. First, we developed a series of PET probes to study transporters(organic anion transporting polypeptides, multidrug resistance-associated protein 2, etc.)such as[11C] Dehydropravastatin. Because substantial species differences in expression and function of transporters have been reported, these probes are especially useful to examine drug-drug interactions in human beings. Secondly, we established a PET-based system to visualize translocation of intranasally administered drugs and analyze pharmacokinetics on nasal drug absorption using 2 -deoxy-2 [18F] fluoroglucose in rats. As far as we know, this is the first study that demonstrated the visualization of nasal absorption process and detailed pharmacokinetic analysis. Thirdly, HER2 -positive breast cancer and its metastasis were successfully delineated in a64 Cu-trastuzumab clinical PET study, which indicates immuno-PET probes are potential companion diagnostics for molecular target medicines and will become alternatives to biopsy. PET imaging strongly connects drug efficacy with pharmacokinetics, which could accelerate drug development during overall process.
    Japan Society of Drug Delivery System, 2018, Drug Delivery System, 33(3) (3), 204 - 213, Japanese
    Book review

  • バイオイメージングの創薬、診断、治療への展開 がんと炎症の差別化イメージング
    野崎 聡, 笹野 有未, 山本 憲一郎, 馬渡 彩, 柴田 仁奈, 中谷 友香, 尾上 嘉代, 和田 康弘, 露口 尚弘, 土居 久志, 児玉 和也, 渡辺 恭良
    日本癌学会, Sep. 2017, 日本癌学会総会記事, 76回, S15 - 4, English

  • メンケス病モデルマウスにおける銅キレート剤ジスルフィラムを用いた銅の経口投与についての検討
    保科 隆男, 野崎 聡, 濱崎 考史, 山下 加奈子, 佐久間 悟, 瀬戸 俊之, 中谷 友香, 児玉 浩子, 渡辺 恭良, 新宅 治夫
    (一社)日本小児神経学会, May 2017, 脳と発達, 49(Suppl.) (Suppl.), S453 - S453, Japanese

  • 慢性疲労症候群の栄養摂取状況と疲労度との関連
    田中 邦彦, 福田 早苗, 雪野 皐月, 山口 浩二, 渡邊 恭良, 倉恒 弘彦
    日本疲労学会, May 2017, 日本疲労学会誌, 13(1) (1), 74 - 74, Japanese

  • 慢性疲労症候群における筋質評価の検討
    雪野 皐月, 福田 早苗, 田中 邦彦, 内山 朋香, 山口 浩二, 渡邊 恭良, 倉恒 弘彦
    日本疲労学会, May 2017, 日本疲労学会誌, 13(1) (1), 76 - 76, Japanese

  • ME/CFS患者における睡眠時身体活動と心拍変動の相互関連を通じた睡眠の質的評価の試み
    山口 浩二, 笹部 哲也, 中富 康仁, 田中 邦彦, 福田 早苗, 倉恒 弘彦, 稲葉 雅章, 渡邊 恭良
    日本疲労学会, May 2017, 日本疲労学会誌, 13(1) (1), 90 - 90, Japanese

  • メタボローム解析による慢性疲労症候群バイオマーカーの開発
    山野 恵美, 杉本 昌弘, 久米 慧嗣, 大和 正典, 田島 世貴, 山口 浩二, 倉恒 弘彦, 福田 早苗, 曽我 朋義, 渡邊 恭良, 片岡 洋祐
    日本疲労学会, May 2017, 日本疲労学会誌, 13(1) (1), 89 - 89, Japanese

  • [18F]AA-7 腫瘍特異的アミノ酸トランスポーターを標的とした新規PETトレーサーの開発
    野崎 聡, 笹野 有未, 山本 憲一郎, Hume WE, 和田 康弘, 石井 聡, 田中 雅彰, 塩見 進, 露口 尚弘, 児玉 和也, 渡辺 恭良
    (一社)日本核医学会, Oct. 2016, 核医学, 53(Suppl.) (Suppl.), S312 - S312, Japanese

  • [18F]AA-7 腫瘍特異的アミノ酸トランスポーターを標的とした新規PETトレーサーの開発
    野崎 聡, 大下 智子, 中谷 友香, 笹野 有未, 山本 憲一郎, 林中 恵美, 和田 康弘, 石井 聡, 田中 雅彰, 塩見 進, 露口 尚弘, 児玉 和也, 渡辺 恭良
    日本分子イメージング学会, Apr. 2016, JSMI Report, 9(2) (2), 97 - 97, Japanese

  • 慢性疲労症候群の生活習慣 筋肉量低下・筋力・身体能力低下と生活習慣との関連
    榊 弥香, 福田 早苗, 田中 邦彦, 山口 浩二, 山田 真介, 絵本 正憲, 松本 美富士, 渡辺 恭良, 倉恒 弘彦, 稲葉 雅章
    慢性疲労症候群(CFS)患者における筋肉量・筋力の低下、サルコペニア(S)・プレサルコペニア(PS)該当者の比率、活動量や睡眠・食生活、臨床的特徴などについて検討した。CFSの診断基準を満たす外来CFS患者30名(男7名、女23名、平均42.8歳)を対象に、体組成を測定し、アンケート調査を行った。その結果、筋肉量について同年代と比較した場合、女性CFS患者では有意に減少していた。筋肉量がPSに該当したのは18名(男5名、女性13名)、s備群に該当するのは10名(男3名、女7名)であった。握力のみがSに該当したのは女性10名で、握力と筋肉量PS双方に該当したのは5名であった。PSに該当するCFS患者と非該当患者を比較した場合、男性PS該当患者では、疲れ、筋肉痛、頭痛、重症度などがに多く、女性ではPS非該当患者の方が頭痛や意識混乱症状が多くみられた。栄養素に関しては、男性PS該当患者では、エネルギー摂取量、水分、タンパク質、亜鉛などの摂取量が少なく、女性PS該当患者ではビタミンDの摂取量が多かった。女性の握力低下CFS患者については、握力S非該当患者に比べ、平均活動量全区間の活動量が有意に低く、睡眠時間全区間における睡眠時間が有意に長かった。
    日本疲労学会, Mar. 2016, 日本疲労学会誌, 11(2) (2), 56 - 70, Japanese

  • CLINICAL EVALUATION OF OATPs AND MRP2 ACTIVITY USING POSITRON EMISSION TOMOGRAPHY (PET) WITH [C-11]DEHYDROPRAVASTATIN
    Tomotaka Shingaki, Masaaki Tanaka, Akira Ishii, Yumiko Katayama, Shusaku Tazawa, Yasuhiro Wada, Yilong Cui, Kazuya Maeda, Hiroyuki Kusuhara, Yuichi Sugiyama, Yasuyoshi Watanabe
    TAYLOR & FRANCIS LTD, Nov. 2015, DRUG METABOLISM REVIEWS, 47, 241 - 242, English
    Summary international conference

  • 11C-ケトプロフェンメチルエステルS体の生体内分布と被ばく線量評価
    大西 章仁, 千田 道雄, 赤松 剛, 相田 一樹, 佐々木 將博, 山本 泰司, 馬渡 彩, 宿里 充穂, 土居 久志, 渡辺 恭良, 尾上 浩隆
    (一社)日本核医学会, Sep. 2015, 核医学, 52(3) (3), 269 - 269, Japanese

  • Human biodistribution and dosimetry of S-enantiomer C-11-ketoprofen methyl ester, a potential PET probe of neuroinflammatory processes for Alzheimer's disease
    Akihito Ohnishi, Michio Senda, Go Akamatsu, Kazuki Aita, Masahiro Sasaki, Yasuji Yamamoto, Miho Shukuri, Hisashi Doi, Yasuyoshi Watanabe, Hirotaka Onoe
    SOC NUCLEAR MEDICINE INC, May 2015, JOURNAL OF NUCLEAR MEDICINE, 56(3) (3), English
    Summary international conference

  • 細胞膜透過ペプチド併用経鼻投与によるインスリン脳内デリバリー 64Cu-NODAGA標識インスリンを用いた脳内分布評価
    亀井 敬泰, 新垣 友隆, 金山 洋介, 蔵地 理代, 長谷川 功紀, 渡辺 恭良, 武田 真莉子
    (公社)日本薬学会, Mar. 2015, 日本薬学会年会要旨集, 135年会(4) (4), 73 - 73, Japanese

  • 次世代生命基盤技術を用いたB型肝炎制圧のための創薬研究 PET分子イメージングによる薬効評価・薬物動態研究
    渡辺恭良, 金山洋介, HUME William Ewan, 張周恩, 丹羽節, 落合秀紀, 隅田有人, 崔翼龍, 佐古健生
    2015, 次世代生命基盤技術を用いたB型肝炎制圧のための創薬研究 平成26年度 総括・分担研究報告書, 74‐77, Japanese

  • 分子イメージング技術の最前線とそのDDS研究・臨床へのインパクト 分子イメージング活用創薬とDDS開発
    渡辺 恭良, 向井 英史, 新垣 友隆
    日本DDS学会, Jul. 2014, 日本DDS学会学術集会プログラム予稿集, 30回, 118 - 118, Japanese

  • 腫瘍組織内抗癌タンパク産生B.choshinensisの作製と抗腫瘍効果
    向井 英史, 高橋 麻衣子, 渡辺 恭良
    日本DDS学会, Jul. 2014, 日本DDS学会学術集会プログラム予稿集, 30回, 176 - 176, Japanese

  • 疲労・睡眠への栄養教育プログラムの構築
    藤井 比佐子, 福田 早苗, 千須和 直美, 渡辺 恭良
    疲労・睡眠への栄養教育プログラムを構築し、有効性を検討した。栄養教育プログラムは4つの項目(管理栄養士による集団栄養教育、食生活日誌、管理栄養士による個別栄養指導、メール配信)で構成した。女性被験者32名を栄養教育プログラムを実施した栄養教育群16名、非実施の対照群16名に無作為に分けた。開始前は両群とも全体的に摂取基準値より摂取量が低く、個人別の栄養摂取基準値に対する栄養摂取量の割合1.0を下回っていたが、栄養教育群ではエネルギー、亜鉛、ビタミンK、ビタミンB2、B6、葉酸、ビタミンC、食物繊維において介入前より充足率が上昇し、摂取量基準値に近づいたが、対照群では大きな変化は見られなかった。食生活改善の10段階評価の度合いは平均値6.50であった。「朝ご飯の習慣ができた」、「昼をきっちり食べ体力ができた」、「間食は減った」、「規則正しい食事ができるようになった」など食生活の改善について意見を認めた。
    女性健康科学研究会, May 2014, 女性健康科学研究会受賞研究報告集, 3(1) (1), 38 - 42, Japanese

  • メタボローム解析による慢性疲労症候群診断バイオマーカーの検討
    山野 恵美, 久米 慧嗣, 大和 正典, 田島 世貴, 福田 早苗, 倉恒 弘彦, 渡辺 恭良, 片岡 洋祐
    日本疲労学会, May 2014, 日本疲労学会誌, 10(1) (1), 69 - 69, Japanese

  • 職域集団における疲労とメタボリック症候群との関連について(中間解析結果より)
    藤井 比佐子, 福田 早苗, 小山 英則, 長見 まき子, 倉恒 弘彦, 渡辺 恭良
    日本疲労学会, May 2014, 日本疲労学会誌, 10(1) (1), 78 - 78, Japanese

  • 新しいPET分子プローブ(11C-セトロゾール)を用いた難治性てんかんの病態解明へのアプローチ
    露口 尚弘, 高橋 佳代, 和田 康弘, 渡辺 恭良
    (一社)日本てんかん学会, Sep. 2013, てんかん研究, 31(2) (2), 382 - 382, Japanese

  • 改善方法と有用性 栄養教育による睡眠と疲労改善効果
    藤井 比佐子, 福田 早苗, 渡辺 恭良
    日本疲労学会, Jun. 2013, 日本疲労学会誌, 9(1) (1), 81 - 81, Japanese

  • 機能と評価方法 脳磁図計を用いた精神的ストレスに対する生体反応の個人差に関する検討
    山野 恵美, 田中 雅彰, 石井 聡, 渡辺 恭良
    日本疲労学会, Jun. 2013, 日本疲労学会誌, 9(1) (1), 87 - 87, Japanese

  • 遺伝子・核酸デリバリーシステム 核酸医薬・DDS開発におけるPETイメージング
    向井 英史, 渡辺 恭良
    日本DDS学会, Jun. 2013, 日本DDS学会学術集会プログラム予稿集, 29回, 100 - 100, Japanese

  • 小動物用PETイメージングによるメンケス病モデルマウスを用いた新規治療法の開発と評価
    野村 志保, 野崎 聡, 濱崎 考史, 二宮 英一, 林中 恵美, 和田 康弘, 渡辺 恭良, 新宅 治夫
    (一社)日本周産期・新生児医学会, Jun. 2013, 日本周産期・新生児医学会雑誌, 49(2) (2), 631 - 631, Japanese

  • 疲労、睡眠の質、自律神経機能と血中Brain-derived neurotrophic factorの相互関係
    神崎 暁慶, 角谷 学, 蔵城 雅文, 庄司 拓仁, 白石 順, 角田 千尋, 森脇 優司, 山本 徹也, 福田 早苗, 渡辺 恭良, 小山 英則
    日本疲労学会, Jun. 2013, 日本疲労学会誌, 9(1) (1), 59 - 59, Japanese

  • Realization of [C-11]CH3-incorporated thiamine and fursultiamin for PET molecular imaging of vitamin B-1
    Hisashi Doi, Aya Mawatari, Masakatsu Kanazawa, Satoshi Nozaki, Yukihiro Nomura, Kouji Akimoto, Shinji Ninomiya, Masaaki Suzuki, Yasuyoshi Watanabe
    WILEY-BLACKWELL, May 2013, JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS, 56, S98 - S98, English
    Summary international conference

  • 慢性疲労症候群及び一般住民集団における疲労の重症度評価質問票とパフォーマンスステイタス評価の比較
    福田 早苗, 谷畑 健生, 山口 浩二, 中富 康仁, 渡辺 恭良, 倉恒 弘彦
    慢性疲労症候群(CFS)患者と一般住民集団における重症度評価質問票(FP scale)とパフォーマンスステイタス(PS)評価の関係について検討した。その結果、患者が専門医師評価より高くPS評価をつける割合は10〜50%程度で、各PS評価において患者評価が専門医師評価と一致しない割合は30〜77%であり、約55%において患者評価と専門医師の評価で乖離が認められた。また患者と専門医師それぞれにおけるFP scaleから算出したFP Indexの平均値は大きく異なり、各PS評価における平均得点は専門医師評価のPS評価毎のFP index得点において特に顕著な差を示し、患者評価のPS評価ではPS評価があがればFP indexが増加する傾向であった。次に一般住民を対象としてFP indexを算出しPS評価との関連について検討したところ、PS2の評価を行う対象でのFP indexの平均得点が高く中等度以上のPS評価でFP indexの平均得点が高いことが認められた。
    日本疲労学会, Mar. 2013, 日本疲労学会誌, 8(2) (2), 53 - 59, Japanese

  • 次世代生命基盤技術を用いたB型肝炎制圧のための創薬研究 有効・安全性評価に関する研究 PET分子イメージングによる薬効評価・薬物動態研究
    渡辺恭良, EWAN Hume William, 金山洋介, 八塩桂司, 崔翼龍
    2013, 次世代生命基盤技術を用いたB型肝炎制圧のための創薬研究 平成24年度総括・分担研究報告書

  • Yasuyoshi Watanabe, Hirohiko Kuratsune, Osami Kajimoto
    01 Dec. 2012, The Handbook of Operator Fatigue, 209 - 224

  • げっ歯類および霊長類サルを用いた[11C]Ketoprofen-methyl esterの特性評価
    宿里 充穂, 高島 忠之, 馬渡 彩, 山中 創, 片山 由美子, 千田 道雄, 佐々木 將博, 土居 久志, 鈴木 正昭, 渡辺 恭良, 尾上 浩隆
    (一社)日本核医学会, Aug. 2012, 核医学, 49(3) (3), S249 - S249, Japanese

  • 日本におけるCFS 最近の知見 慢性疲労症候群の実態調査
    福田 早苗, 中富 康仁, 山口 浩二, 渡辺 恭良, 倉恒 弘彦
    日本疲労学会, Jun. 2012, 日本疲労学会誌, 8(1) (1), 23 - 23, Japanese

  • 大学生における疲労と生活習慣に関する研究
    藤井 比佐子, 福田 早苗, 倉恒 弘彦, 渡辺 恭良
    日本疲労学会, Jun. 2012, 日本疲労学会誌, 8(1) (1), 34 - 34, Japanese

  • 抗テネイシンCペプチドアプタマーPETプローブの高感度化に関する検討
    向井 英史, 松村 一史, 川上 茂, 高橋 麻衣子, 造田 真希, 林中 恵美, 山下 富義, 橋田 充, 和田 康弘, 渡辺 恭良
    日本DDS学会, Jun. 2012, 日本DDS学会学術集会プログラム予稿集, 28回, 156 - 156, Japanese

  • 64Cu標識CetuximabのEGFR発現がん組織への特異的集積評価
    金山 洋介, 角田 ちぬよ, 田沢 周作, 蔵地 理代, 森本 陽子, 長谷川 功紀, 林中 恵美, 和田 康弘, 高橋 和弘, 渡辺 恭良
    日本分子イメージング学会, May 2012, JSMI Report, 5(2) (2), 121 - 121, Japanese

  • 健常人における慢性疲労症候群関連症状38項目による疲労質問票の因子構造と妥当性の検討
    田島 世貴, 中富 康仁, 山口 浩二, 福田 早苗, 小泉 淳一, 稲葉 雅章, 渡辺 恭良, 倉恒 弘彦
    健常人における慢性疲労症候群関連症状38項目による疲労質問票の因子構造と妥当性について検討した。まず929名(男753名、女176名、19〜65歳)を対象として疲労関連症状38項目について5件法で回答を求め因子分析を行い、更に二元配置分散分析を行ったところ、膠原病・自律神経失調因子得点、不安・抑うつ因子得点、前頭葉機能抑制因子得点、皮膚因子得点、過労因子得点で有意な性別効果を認め、膠原病・自律神経失調因子得点、過眠因子得点で有意に年齢効果が認められた。次に慢性疲労症候群患者106名を対象としてチャルダー疲労スケジュール、CES-Dへの回答を求め、平均反応時間計測、身体活動量計測による睡眠覚醒リズム評価を行い、チャルダー疲労スケール得点、CES-D得点、X-CPT変法平均反応時間、七つの睡眠関連指標との相関について検討した。その結果、不安・抑うつ因子得点とCES-D得点、慢性疲労因子得点とチャルダー疲労スケール得点は高い正相関を認め、前頭葉機能抑制因子得点とX-CPT平均反応時間は有意な正相関、過眠因子得点は日中平均活動量と負相関、中途覚醒回数と正相関、不眠因子得点は睡眠効率と負相関、中途覚醒回数と正相関を示した。
    日本疲労学会, Mar. 2012, 日本疲労学会誌, 7(2) (2), 88 - 96, Japanese

  • 抗疲労臨床評価ガイドライン 日常生活により問題となる疲労に対する抗疲労製品の効果に関する臨床評価ガイドライン
    渡辺 恭良, 橋本 信也, 倉恒 弘彦, 近藤 一博, 川原 貴, 久保 千春, 下光 輝一, 西澤 良記, 伴 信太郎, 三池 輝久, 松本 美富士, 木谷 照夫, 平山 佳伸, 山口 浩二, 田中 雅彰, 水野 敬, 中富 康仁, 福田 早苗, 日本疲労学会分科会臨床評価ガイドライン委員会
    日本疲労学会, Mar. 2012, 日本疲労学会誌, 7(2) (2), 1 - 13, Japanese

  • 小動物用PETを用いたメンケス病モデルマウスでの銅キレート剤投与効果に関する研究
    野村 志保, 野崎 聡, 武田 泰輔, 二宮 英一, 濱崎 考史, 藤岡 弘季, 林中 恵美, 和田 康弘, 渡辺 恭良, 新宅 治夫
    (公社)日本小児科学会, Feb. 2012, 日本小児科学会雑誌, 116(2) (2), 455 - 455, Japanese

  • Sanae Fukuda, Hirohiko Kuratsune, Osami Kajimoto, Yasuyoshi Watanabe
    Chronic fatigue syndrome (CFS) is a disorder diagnosed following at least 6 months of disabling, unexplained mental and physical fatigue accompanied by other physical and psychological symptoms. Fibromyalgia (FM) is a chronic pain syndrome of unknown etiology characterized by diffuse pain and tender points, which must be present for more than 3 months. These patients have the path similarity in psycho-neuro-endocrino-immunological system. In this paper, we introduce quantitative methods for assessment of fatigue developed by us. We then briefly summarize abnormalities found in CFS and FM, and show the neural and molecular mechanisms and introduce potential common biomarkers for CFS and FM. © 2012-IOS Press and the authors. All rights reserved.
    2012, Advances in Neuroimmune Biology, 3(3-4) (3-4), 361 - 366, English

  • 渡辺 恭良, 田中 雅彰, 鴫原 良仁, 石井 聡, 水野 敬, 山野 恵美
    公益社団法人 日本ビタミン学会, 2012, ビタミン, 86(5) (5), 345 - 346, Japanese

  • Development of Early Diagnostic Techniques for Rheumatoid Arthritis Using Carbone Eleven Labeled PK11195 and Carbone Eleven Labeled Ketoprofen
    Satoshi Nozaki, Sinobu Suzuki, Naoko Ozaki, Jeffrey Encinas, Hisashi Doi, Yasuhiro Wada, Masaaki Suzuki, Yasuyoshi Watanabe
    WILEY-BLACKWELL, Oct. 2011, ARTHRITIS AND RHEUMATISM, 63(10) (10), S74 - S75, English
    Summary international conference

  • 慢性疲労up to date 慢性疲労症候群の病態及び実情について
    福田 早苗, 中富 康仁, 山口 浩二, 稲葉 雅章, 渡辺 恭良, 倉恒 弘彦
    日本疲労学会, May 2011, 日本疲労学会誌, 7(1) (1), 39 - 39, Japanese

  • 慢性疲労症候群患者と健常者におけるGTP cyclohydrolase I遺伝子多型の解析
    堀口 美恵子, 福田 早苗, 一瀬 宏, 中富 康仁, 山口 浩二, 倉恒 弘彦, 渡辺 恭良
    日本疲労学会, May 2011, 日本疲労学会誌, 7(1) (1), 73 - 73, Japanese

  • 慢性疲労症候群における脳内ミクログリア活性化 PET研究
    中富 康仁, 水野 敬, 石井 聡, 和田 康弘, 田中 雅彰, 田沢 周作, 尾上 嘉代, 福田 早苗, 河邉 譲治, 高橋 和弘, 片岡 洋祐, 塩見 進, 山口 浩二, 稲葉 雅章, 倉恒 弘彦, 渡邊 恭良
    日本疲労学会, May 2011, 日本疲労学会誌, 7(1) (1), 66 - 66, Japanese

  • 理研CMISにおける64Cu-DOTA-Trastuzumab注射液の治験薬GMP製造への取り組み
    田沢 周作, 長谷川 功紀, 金山 洋介, 蔵地 理代, 森本 陽子, 林 和孝, 立花 晃子, 高橋 和弘, 矢野 恒夫, 渡辺 恭良
    日本分子イメージング学会, May 2011, JSMI Report, 4(2) (2), 116 - 116, Japanese

  • 病態モデル動物のライブイメージング 64Cu標識P-セレクチン抗体を用いたLDLレセプター欠損マウスの動脈硬化病変の検出
    中村 郁子, 長谷川 功紀, 和田 康弘, 片岡 洋祐, 大和 正典, 蔵地 理代, 林中 恵美, 平瀬 徹明, 野出 孝一, 渡辺 恭良
    日本分子イメージング学会, May 2011, JSMI Report, 4(2) (2), 33 - 33, Japanese

  • 64Cu-DOTA-Trastuzumabの合成法と評価法の確立 A431およびC6腫瘍担持マウスでのPET研究
    長谷川 功紀, 金山 洋介, 角田 ちぬよ, 松本 恭子, 田沢 周作, 蔵地 理代, 森本 陽子, 林中 恵美, 高橋 和弘, 和田 康弘, 渡辺 恭良
    日本分子イメージング学会, May 2011, JSMI Report, 4(2) (2), 114 - 114, Japanese

  • Trastuzumabのフラグメント化によるがんイメージングへの影響 担がんマウスを用いたPET研究
    金山 洋介, 長谷川 功紀, 角田 ちぬよ, 林中 恵美, 和田 康弘, 榎本 秀一, 渡辺 恭良
    日本分子イメージング学会, May 2011, JSMI Report, 4(2) (2), 115 - 115, Japanese

  • 無麻酔下コモンマーモセットPETを用いた抗精神病薬ルラシドンとオランザピンのドパミンD2受容体占有率の評価
    中澤 俊介, 西村 直浩, 横山 ちひろ, 川崎 章弘, 倉井 佐知, 土居 久志, 矢野 恒夫, 渡辺 恭良, 尾上 浩隆
    日本分子イメージング学会, May 2011, JSMI Report, 4(2) (2), 125 - 125, Japanese

  • 六君子湯の作用解析を目的とした放射性標識グレリンの合成と基礎的検討
    西村 三恵, 長谷川 功紀, 佐古 健生, 中村 郁子, 林中 恵美, 和田 康弘, 渡辺 恭良
    (公社)日本薬学会, Mar. 2011, 日本薬学会年会要旨集, 131年会(4) (4), 151 - 151, Japanese

  • 堀口 美恵子, 福田 早苗, 一瀬 宏, 中富 康仁, 山口 浩二, 倉恒 弘彦, 渡辺 恭良
    公益社団法人 日本ビタミン学会, 2011, ビタミン, 85(11) (11), 616 - 616, Japanese

  • 渡辺 恭良, 片岡 洋祐, 金 光華, 山野 恵美, 倉恒 弘彦, 山口 浩二, 中富 康仁
    公益社団法人 日本ビタミン学会, 2011, ビタミン, 85(3) (3), 152 - 153, Japanese

  • Yilong Cui, Takeo Sako, Kaori Okuyama, Hiroshi Toyoda, Kayo Onoe, Emi Hayashinaka, Yasuhiro Wada, Yasuyoshi Watanabe, Yosky Kataoka
    ELSEVIER IRELAND LTD, 2011, NEUROSCIENCE RESEARCH, 71, E81 - E81, English
    Summary international conference

  • 【肝病態生理研究のあゆみ】 [11C]Telmisartanを用いたPositron Emission Tomography(PET)による肝胆系輸送評価
    高島 忠之, 橋爪 良信, 土居 久志, 和田 康弘, 渡辺 恭良, 千田 道雄, 山根 登茂彦, 佐々木 將博, 清水 敬二, 岩本 明美, 景山 浩充, 前田 和哉, 楠原 洋之, 杉山 雄一
    ライフサイエンス出版(株), Dec. 2010, 薬理と治療, 38(Suppl.2) (Suppl.2), S103 - S109, Japanese

  • N末端Cu結合モチーフ(ATCUN)を用いた64Cu標識法の開発
    長谷川 功紀, 西村 三恵, 林中 恵美, 和田 康弘, 片岡 洋祐, 渡辺 恭良
    (一社)日本核医学会, Sep. 2010, 核医学, 47(3) (3), 386 - 386, Japanese

  • Evaluation of In Vivo Hepatobiliary Transport Using Positron Emission Tomography (PET): Studies in Rats and Application to Microdosing Clinical Studies
    Tadayuki Takashima, Hiroko Nagata, Hideki Ishii, Ryosuke Ijuin, Takahiro Nakae, Masaaki Tanaka, Yoshihito Shigihara, Suzuka Ataka, Hisashi Doi, Yasuhiro Wada, Masaaki Suzuki, Kazuya Maeda, Hiroyuki Kusuhara, Yuichi Sugiyama, Yasuyoshi Watanabe
    TAYLOR & FRANCIS INC, Aug. 2010, DRUG METABOLISM REVIEWS, 42, 311 - 311, English
    Summary international conference

  • 11C-Labeled cetrozole: an excellent PET probe for aromatase in brain in emotional disorders
    高橋 佳代, 細谷 孝充, 尾上 嘉代, 土居 久志, 長田 浩子, 渡辺 由美子, 平松 俊行, Li Xiao-Le, 和田 康弘, 高島 忠之, 片山 由美子, 山中 創, 鈴木 正昭, 尾上 浩隆, 渡辺 恭良
    日本神経化学会, Aug. 2010, 神経化学, 49(2-3) (2-3), 773 - 773, English

  • ヒートアイランドが疲労発生に与える影響
    宮沢和貴, 玄地裕, 井原智彦, 鳴海大典, 福田早苗, 小山英則, 渡辺恭良
    日本疲労学会, 25 Jun. 2010, 日本疲労学会誌, 6(1) (1), 84 - 84, Japanese

  • 芳香物質が自律神経に与える影響について 慢性疲労症候群患者と健常者の比較
    笹部 哲也, 福田 早苗, 山口 浩二, 中富 康仁, 神楽 美香, 倉恒 弘彦, 渡辺 恭良
    日本疲労学会, Jun. 2010, 日本疲労学会誌, 6(1) (1), 103 - 103, Japanese

  • 最近の知見 透析患者における栄養機能飲料摂取による抗疲労効果の検証研究
    福田 早苗, 小山 英則, 藤井 比佐子, 平山 佳伸, 木山 博資, 近藤 一博, 西澤 良記, 渡辺 恭良
    日本疲労学会, Jun. 2010, 日本疲労学会誌, 6(1) (1), 60 - 60, Japanese

  • 小児慢性疲労症候群患児と健常児に共通する疲労と神経過剰賦活の関係
    水野 敬, 田中 雅彰, 鴫原 良仁, 福田 早苗, 山野 恵美, 川谷 淳子, 上土井 貴子, 友田 明美, 三池 輝久, 松村 京子, 田邊 宏樹, 定藤 規弘, 渡辺 恭良
    日本疲労学会, Jun. 2010, 日本疲労学会誌, 6(1) (1), 81 - 81, Japanese

  • 末期腎不全患者における自律神経機能と疲労およびQOL
    藤井 比佐子, 小山 英則, 福田 早苗, 平山 佳伸, 渡辺 恭良, 稲葉 雅章, 西澤 良記
    日本疲労学会, Jun. 2010, 日本疲労学会誌, 6(1) (1), 86 - 86, Japanese

  • N末端Cu結合モチーフ(ATCUN)を用いた64Cu標識法の開発
    長谷川 功紀, 西村 三恵, 林中 美恵, 和田 康弘, 渡辺 恭良
    日本分子イメージング学会, May 2010, JSMI Report, 3(2) (2), 105 - 105, Japanese

  • 炎症モデルにおけるTGF-β活性化反応のPETイメージング
    金山 洋介, 角田 ちぬよ, 長谷川 功紀, 松本 恭子, 和田 康弘, 林中 恵美, 榎本 秀一, 原 詳子, 小嶋 聡一, 渡辺 恭良
    日本分子イメージング学会, May 2010, JSMI Report, 3(2) (2), 108 - 108, Japanese

  • 【疲労と機能性食品】抗疲労食の開発
    福田 早苗, 梶本 修身, 渡辺 恭良
    疲労に効果があると謳われている製品は世の中に数多く存在する。その範囲は、医薬品や食品、および食品成分・サプリメントのように身体・脳に直接働いて達成されるものから、我々を取り巻く環境・空間をどのように疲労軽減・回復のために改善していくか、また、理学療法機器や生活空間の工夫による抗疲労・癒し効果までと幅広い。しかしながら、科学的に実証し、製品を売り出すといういわゆるevidenced based(科学的実証に基づく)が十分行えているとは言い難い。近年、疲労度が様々な計測システムにより客観的・定量的にとらえられるようになってきたので、このような観点における様々な取組が鋭意進められてきている。本稿では、最近の取組の中で食品や食事に関連するものを中心に概括して述べる。(著者抄録)
    (有)フジメディカル出版, Apr. 2010, Functional Food, 3(4) (4), 330 - 333, Japanese

  • TGF-β活性化反応検出ELISA法による肝障害患者血漿中のLAP断片量の測定と、局所LAP断片集積のPETイメージングの試み
    桐田 暁子, 原 詳子, 松浦 知和, 斎藤 勝也, 永妻 啓介, 上竹 慎一郎, 瀬嵐 康人, 高木 一郎, 相沢 良夫, 浦島 充佳, 金山 洋介, 角田 ちぬよ, 長谷川 功紀, 渡辺 恭良, 小嶋 聡一
    (一社)日本肝臓学会, Apr. 2010, 肝臓, 51(Suppl.1) (Suppl.1), A178 - A178, Japanese

  • Ko-hei Akazawa, Yilong Cui, Masaaki Tanaka, Yosky Kataoka, Yukio Yoneda, Yasuyoshi Watanabe
    Fatigue is known to be accompanied by a feeling of extreme physical or mental tiredness, resulting from severe stress and hard physical or mental work. To investigate the functional localization of neural activity related to fatigue and recovery, we examined brain c-Fos expression patterns in a rat in a state of fatigue in which rats kept in a cage filled with water to a height of 2.2 cm for 1-5 days. A significant increase in the number of c-Fos-immunopositive cells was observed in the retrosplenial granular b cortex during the fatigue-loading and in the dentate gyrus of the ventral hippocampus after a 24-h recovery. In addition, variable increases in the number of c-Fos-immunopositive cells were observed in the cingulate cortex area 2, ventral part of the lateral septum nucleus, median preoptic nucleus, anterior part of the paraventricular thalamic nucleus, medial parvicellular part of the paraventricular hypothalamic nucleus, and lateral and ventrolateral periaqueductal gray during the fatigue-load period. These results indicate that such regional brain activity would be involved in fatigue or in subsequent recovery and might provide a foothold for further research into the nature of fatigue. (C) 2009 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.
    ELSEVIER IRELAND LTD, Apr. 2010, NEUROSCIENCE RESEARCH, 66(4) (4), 372 - 379, English, International magazine

  • 膵臓癌のPET撮像を目的とした放射標識セクレチンの合成とその評価
    西村 三恵, 長谷川 功紀, 向井 英史, 中村 郁子, 佐古 健生, 林中 恵美, 和田 康弘, 渡辺 恭良
    (公社)日本薬学会, Mar. 2010, 日本薬学会年会要旨集, 130年会(4) (4), 129 - 129, Japanese

  • Yilong Cui, Takeo Sako, Hiroshi Toyoda, Kaori Okuyama, Kayo Onoe, Emi Hayashinaka, Yasuhiro Wada, Yasuyoshi Watanabe, Yosky Kataoka
    ELSEVIER IRELAND LTD, 2010, NEUROSCIENCE RESEARCH, 68, E425 - E425, English
    [Refereed]
    Summary international conference

  • 糖尿病の予防や早期発見・治療のための膵β細胞イメージング
    佐古 健生, 長谷川 功紀, 和田 康弘, 千田 道雄, 渡辺 恭良
    (一社)日本核医学会, Sep. 2009, 核医学, 46(3) (3), 318 - 318, Japanese

  • 疲労関連症状出現と心理社会的予測因子の検討 追跡調査の結果から
    山野 恵美, 福田 早苗, 水野 敬, 田中 雅彰, 片岡 洋祐, 上土井 貴子, 川谷 淳子, 高野 美雪, 友田 明美, 松村 京子, 三池 輝久, 渡辺 恭良
    日本疲労学会, May 2009, 日本疲労学会誌, 5(1) (1), 75 - 75, Japanese

  • 子どもの疲労 小中学校における疲労に関するコホート研究
    福田 早苗, 山野 恵美, 渡辺 恭良
    日本疲労学会, May 2009, 日本疲労学会誌, 5(1) (1), 44 - 44, Japanese

  • 基礎疾患に基づく疲労 腎不全透析患者の疲労とその介入試験の試み
    小山 英則, 福田 早苗, 渡辺 恭良, 藤井 比佐子, 平山 佳伸, 西沢 良記
    日本疲労学会, May 2009, 日本疲労学会誌, 5(1) (1), 33 - 33, Japanese

  • 血中fetuin-A濃度と血管内皮機能との関連性
    川野 直也, 森 克仁, 絵本 正憲, 小山 英則, 菊川 友子, 藤井 比佐子, 福田 早苗, 東海 秀吉, 平山 佳伸, 渡辺 恭良, 西沢 良記
    (一社)日本糖尿病学会, Apr. 2009, 糖尿病, 52(Suppl.1) (Suppl.1), S - 258, Japanese

  • PET技術を利用した消化管インスリン吸収の分子イメージング解析
    亀井 敬泰, 森下 真莉子, 高山 幸三, 金山 洋介, 長谷川 功紀, 西村 三恵, 和田 康弘, 渡辺 恭良
    (公社)日本薬学会, Mar. 2009, 日本薬学会年会要旨集, 129年会(4) (4), 285 - 285, Japanese

  • CENTRAL CHANGES IN EXPERIMENTAL GLAUCOMA
    Kazuyuki Imamura, Hirotaka Onoe, Masamitsu Shimazawa, Satoshi Nozaki, Hiroshi Mizuma, Yasuhiro Wada, Kayo Onoe, Kiyoshi Ishii, Chihiro Mayama, Takazumi Taniguchi, Masaaki Sasaoka, Hajime Yamanaka, Hideaki Hara, Shigeru Tanaka, Makoto Araie, Yasuyoshi Watanabe
    BMC, 2009, JOURNAL OF PHYSIOLOGICAL SCIENCES, 59, 524 - 524, English
    Summary international conference

  • Chihiro Yokoyama, Hajime Yamanaka, Kayo Onoe, Akihiro Kawasaki, Hiroko Nagata, Keiko Shirakami, Hisashi Doi, Yasuyoshi Watanabe, Hirotaka Onoe
    ELSEVIER IRELAND LTD, 2009, Neuroscience Research, 65, S227 - S227, English
    Summary international conference

  • Yilong Cui, Tadayuki Takashima, Kayo Onoe, Miho Shukuri, Misato Takashima-Hirano, Takeo Sako, Emi Hayashinaka, Yasuhiro Wada, Hisashi Doi, Hirotaka Onoe, Yasuyoshi Watanabe, Yosky Kataoka
    ELSEVIER IRELAND LTD, 2009, NEUROSCIENCE RESEARCH, 65, S258 - S258, English
    Summary international conference

  • NEURAL AND MOLECULAR MECHANISMS OF CENTRAL FATIGUE IN THE ANIMAL MODELS
    Yilong Cui, Yasuyoshi Watanabe, Yosky Kataoka
    SPRINGER TOKYO, 2009, JOURNAL OF PHYSIOLOGICAL SCIENCES, 59, 107 - 107, English
    [Refereed]
    Summary international conference

  • 芳香療法に使用される香気吸入時の心拍変動について
    笹部 哲也, 福田 早苗, 山野 恵美, 山口 浩二, 渡辺 恭良, 古郷 幹彦
    (一社)日本歯科心身医学会, Dec. 2008, 日本歯科心身医学会雑誌, 23(1-2) (1-2), 73 - 73, Japanese

  • 鴫原 良仁, 田中 雅彰, 露口 尚弘, 渡辺 恭良
    (一社)日本臨床神経生理学会, Oct. 2008, 臨床神経生理学, 36(5) (5), 538 - 538, Japanese

  • 香りの抗疲労作用に関する生理心理学的研究
    福田 早苗, 渡辺 恭良
    (公社)日本心理学会, Jul. 2008, 日本心理学会大会発表論文集, 72回, 1059 - 1059, Japanese

  • 疲労時の神経-免疫-内分泌相互作用系の低下:中枢神経系の過剰活性化後の疲労と睡眠の誘導(Deterioration of neuro-immuno-endocrine interaction in fatigue: Fatigue and sleep induction following excessive activation of the central nervous system)
    Kataoka Yosky, Cui Yilong, Tamura Yasuhisa, Yamato Masanori, Jin Guanghua, Watanabe Yasuyoshi
    (一社)日本生理学会, Apr. 2008, The Journal of Physiological Sciences, 58(Suppl.) (Suppl.), S18 - S18, English

  • 疲労の分子神経メカニズム 質問紙に見る慢性疲労病態の特徴
    福田 早苗, 渡辺 恭良
    日本疲労学会, Feb. 2008, 日本疲労学会誌, 4(1) (1), 47 - 47, Japanese

  • 疲労と食生活、栄養素との関連
    藤井 比佐子, 福田 早苗, 渡辺 恭良, 小山 英則, 西沢 良記, 塚田 定信, 古澤 美香, 平山 佳伸
    日本疲労学会, Feb. 2008, 日本疲労学会誌, 4(1) (1), 68 - 68, Japanese

  • 小中学生の意欲・疲労と学習効率に関するコホート研究 気質・性格と疲労の関連性の時系列的検討
    山野 恵美, 福田 早苗, 水野 敬, 田中 雅彰, 上土井 貴子, 川谷 淳子, 友田 明美, 松村 京子, 三池 輝久, 渡辺 恭良
    日本疲労学会, Feb. 2008, 日本疲労学会誌, 4(1) (1), 67 - 67, Japanese

  • 疲労の評価法 疲労の生物学的評価法から見えてきた疲労の分子メカニズム
    近藤 一博, 小林 伸行, 清水 昭宏, 倉恒 弘彦, 渡辺 恭良
    日本疲労学会, Feb. 2008, 日本疲労学会誌, 4(1) (1), 56 - 56, Japanese

  • Yasuyoshi Watanabe, Birgitta Evengård, Benjamin H. Natelson, Leonard A. Jason, Hirohiko Kuratsune
    Fatigue is quite a familiar sensation, one that everyone is likely to have experienced. Its molecular and neural mechanisms have not yet been elucidated, however, probably because of the complicated nature of its causes. To provide a broad forum for discussion, the International Conference on Fatigue Science was organized, the first being held in 2002 in Sandhamn, Sweden, and the second in 2005 in Karuizawa, Japan. Subsequently it was decided that the papers presented at the two conferences should be collected and incorporated in this pioneering work, Fatigue Science for Human Health. The book summarizes fatigue researchers' achievements, explains the status of the research on fatigue, and presents perspectives on remedies for chronic fatigue and chronic fatigue syndrome. The result is an authoritative guide to recent progress in the molecular and neural mechanisms of fatigue and in the development of the ways to prevent and overcome fatigue and chronic fatigue. This book provides a valuable resource not only for physicians but for all who work in public health. © Springer 2008. All rights are reserved.
    Springer Japan, 2008, Fatigue Science for Human Health, 1 - 236, English
    Others

  • Hirohiko Kuratsune, Yasuyoshi Watanabe
    Chronic fatigue syndrome (CFS) is an operational concept for clarifying the unknown etiology of the syndrome characterized by the sensation of abnormally prolonged fatigue. The vast majority of patients with CFS are interrupted in their daily or social lives by prolonged fatigue, headache, myalgia, arthralgia, sleep disturbance, or brain dysfunctions. However, the pathogenesis of CFS remains unclear, and so there are still many medical doctors around the world who are skeptical about the disease. Recently, we organized a study group of Japanese investigators from various fields, such as virology, immunology, endocrinology, physiology, biochemistry, psychiatry, and neuroscience, and as a result of the efforts of this group the mechanism underlying CFS is now becoming a little clearer. We are now able to suggest that CFS can be understood to be a special condition based on an abnormality of the psycho-neuro-endocrino- immunological system caused by psycho-social stress, and which has some genetic components. A reactivation of various types of herpes virus infections and/or chronic mycoplasma infection might occur as a result of immune dysfunction, causing the abnormal production of several cytokines. A distinctive feature of CFS is thought to be a secondary brain dysfunction caused by the abnormal production of such cytokines. In this chapter, we would like to introduce not only the recent findings on the pathogenesis of CFS, but also the prevalence, diagnosis, therapy, and prognosis of CFS in Japan. © 2008 Springer Japan.
    Springer Japan, 2008, Fatigue Science for Human Health, 67 - 88, English

  • PET imaging of microglia activation with [C-11]PK11195 in the rat model of migraine
    Yilong Cui, Tadayuki Takashima, Yasuhisa Tamura, Yasuhiro Wada, Hisashi Doi, Misato H. Takashima, Hiroko Nagata, Yosky Kataoka, Yasuyoshi Watanabe
    ELSEVIER IRELAND LTD, 2008, NEUROSCIENCE RESEARCH, 61, S210 - S210, English
    Summary international conference

  • 老齢ラット大脳皮質におけるNG2陽性細胞の領域特異的な変化について(Region-specific degeneration of NG2+ cells in the cerebral cortex of aged rats)
    Tamura Yasuhisa, Cui Yilong, Watanabe Yasuyoshi, Kataoka Yosky
    日本神経化学会, Aug. 2007, 神経化学, 46(2-3) (2-3), 518 - 518, English

  • Micro PETを用いた片頭痛病態モデルラットの評価(Evaluation of pathophysiological features of migraine by micro PET study using rats)
    Cui Yilong, Wada Yasuhiro, Yamato Masanori, Tamura Yasuhisa, Kataoka Yosky, Watanabe Yasuyoshi
    日本神経化学会, Aug. 2007, 神経化学, 46(2-3) (2-3), 564 - 564, English

  • 実験的疲労モデルを用いた精神神経内分泌学的検討
    福田 早苗, 渡辺 恭良
    日本生理心理学会, Aug. 2007, 生理心理学と精神生理学, 25(2) (2), 129 - 129, Japanese

  • 小学中学生における学習意欲、疲労と生活習慣に関する学校コホート研究
    福田 早苗, 渡辺 恭良
    (公社)日本心理学会, Jul. 2007, 日本心理学会大会発表論文集, 71回, 1125 - 1125, Japanese

  • 慢性疲労症候群患者における精神障害のcomorbidityについて
    松井 徳造, 切池 信夫, 福田 早苗, 田島 成貴, 倉恒 弘彦, 西沢 良記, 渡辺 恭良
    大阪市立大学病院の疲労クリニカルセンターにおいて2005年6月より半年間に慢性疲労を主訴に受診した患者105例を対象に、慢性疲労症候群(CFS)と精神障害のcomorbidityを調査した。その結果、105例中51例がCFSと診断され、29例が精神障害のcomorbidityを示した。その内訳は、大うつ病性障害(MDD)が最多(20例)で、過半数がCFSの発症後にMDDを発症していた。慢性疲労を訴えたがCFSと診断されなかった46例についてみると、MDDが28例で最多だった。以上より、CFSとMDDはcomorbidityが高く、慢性疲労とMDDとの関連性も示唆された。
    (株)医学書院, Jun. 2007, 精神医学, 49(6) (6), 591 - 597, Japanese

  • CFSの診断基準と関係する精神障害、特に気分変調性障害・身体表現性障害について
    松井 徳造, 切池 信夫, 倉恒 弘彦, 福田 早苗, 田島 成貴, 松田 泰範, 片岡 浩平, 西沢 良記, 渡辺 恭良
    日本疲労学会, Jun. 2007, 日本疲労学会誌, 3(1) (1), 72 - 72, Japanese

  • 慢性腎不全透析患者の疲労の実態
    小山 英則, 福田 早苗, 庄司 哲雄, 田畑 勉, 奥野 仙二, 岡村 幹夫, 岡田 茂樹, 倉恒 弘彦, 渡辺 恭良, 西沢 良記
    日本疲労学会, Jun. 2007, 日本疲労学会誌, 3(1) (1), 84 - 84, Japanese

  • 小中学生の意欲・疲労と学習効率に関するコホート研究 気質・性格と疲労の関連性の検討
    山野 恵美, 福田 早苗, 水野 敬, 田中 雅彰, 吉田 かおる, 上土井 貴子, 川谷 淳子, 友田 明美, 松村 京子, 三池 輝久, 渡辺 恭良
    日本疲労学会, Jun. 2007, 日本疲労学会誌, 3(1) (1), 76 - 76, Japanese

  • 新たな疲労/疲労感の評価法 可視-近赤外スペクトルを用いた慢性疲労症候群(CFS)診断法開発
    作道 章一, 倉恒 弘彦, 小林 孝徳, 計屋 由紀子, 田島 世貴, 山口 浩二, 渡辺 恭良, 生田 和良
    日本疲労学会, Jun. 2007, 日本疲労学会誌, 3(1) (1), 65 - 65, Japanese

  • 慢性腎不全血液透析患者の疲労度実態調査
    小山 英則, 庄司 哲雄, 高島 昇子, 福田 早苗, 田畑 勉, 奥野 仙二, 岡村 幹夫, 岡田 茂樹, 倉恒 弘彦, 渡辺 恭良, 西沢 良記
    (一社)日本透析医学会, May 2007, 日本透析医学会雑誌, 40(Suppl.1) (Suppl.1), 563 - 563, Japanese

  • Accumulated fatigue induces over-activation and subsequent degeneration of melanotrophs in rat pituitary gland
    Tokiko Ogawa, Hiroyuki Konishi, Masaaki Tanaka, Sumiko Kiryu-Seo, Saya Nakagomi, Yasuyoshi Watanabe, Hiroshi Kiyama
    ELSEVIER IRELAND LTD, 2007, NEUROSCIENCE RESEARCH, 58, S222 - S222, English
    Summary international conference

  • Yasuhisa Tamura, Yilong Cui, Yasuyoshi Watanabe, Yosky Kataoka
    ELSEVIER IRELAND LTD, 2007, NEUROSCIENCE RESEARCH, 58, S144 - S144, English
    [Refereed]
    Summary international conference

  • [C-11]Pittsburgh Compound-B(PIB)PETによる軽度認知機能障害(MCI)の脳内アミロイドイメージング
    川村 悦史, 河邉 讓治, 林 健博, 麻植 愛, 東山 滋明, 黒岡 浩子, 鳥居 顯二, 和田 康弘, 渡辺 恭良, 塩見 進
    (一社)日本核医学会, Oct. 2006, 核医学, 43(3) (3), 266 - 266, Japanese

  • ラットの長期頭蓋内自己-刺激におけるアラキドン酸カスケードの関与(Involvement of arachidonic acid cascade in long-term intracranial self-stimulation in rats)
    Cui Yilong, Kataoka Yosky, Tamura Yasuhisa, Watanabe Yasuyoshi, Yamada Hisao
    エルゼビア・ジャパン(株), Jul. 2006, Neuroscience Research, 55(Suppl.1) (Suppl.1), S94 - S94, English
    Summary international conference

  • 身体的・精神的ストレスと疲労 実験負荷と質問票の両面からの急性疲労とストレスメカニズムの検討
    福田 早苗, 田中 雅彰, 水野 敬, 田島 世貴, 渡辺 恭良
    日本疲労学会, Jul. 2006, 日本疲労学会誌, 2(1) (1), 32 - 32, Japanese

  • 疲労の定量とメカニズム 疲労および意欲の脳神経メカニズムについての検討
    田中 雅彰, 水野 敬, 福田 早苗, 田島 世貴, 定藤 規弘, 渡辺 恭良
    日本疲労学会, Jul. 2006, 日本疲労学会誌, 2(1) (1), 48 - 48, Japanese

  • 精神科・慢性疲労外来の受診患者の動向
    松井 徳造, 切池 信夫, 福田 早苗, 倉恒 弘彦, 田島 世貴, 渡辺 恭良, 西沢 良記
    日本疲労学会, Jul. 2006, 日本疲労学会誌, 2(1) (1), 106 - 106, Japanese

  • 慢性疲労症候群(CFS)患者における気質・性格評価 Temperament and Character Inventoryを用いた検討
    福田 早苗, 倉恒 弘彦, 高島 昇子, 田島 世貴, 山口 浩二, 渡辺 恭良, 西沢 良記
    日本疲労学会, Jul. 2006, 日本疲労学会誌, 2(1) (1), 108 - 108, Japanese

  • 病的疲労と慢性疲労 慢性疲労症候群(CFS)患者における疲労関連質問票64項目の適応について
    高島 昇子, 倉恒 弘彦, 福田 早苗, 田島 世貴, 山口 浩二, 岩瀬 真生, 渡辺 恭良, 西沢 良記
    日本疲労学会, Jul. 2006, 日本疲労学会誌, 2(1) (1), 66 - 66, Japanese

  • 疲労のバイオマーカー 新しい慢性疲労症候群(CFS)診断法開発 CFS患者血清の可視-近赤外スペクトル多変量解析
    作道 章一, 倉恒 弘彦, 小林 孝徳, 田島 世貴, 渡辺 恭良, 生田 和良
    日本疲労学会, Jul. 2006, 日本疲労学会誌, 2(1) (1), 24 - 24, Japanese

  • Hirohiko Kuratsune, Hirohiko Kuratsune, Hirohiko Kuratsune, Akira Shimizu, Yasuyoshi Watanabe
    Chronic fatigue syndrome (CFS) is an operational concept to clarify the unknown etiology of the syndrome characterized by the sensation of abnormally prolonged fatigue, somatic symptoms (low-grade fever, headache, sore throat, myalgia, muscle weakness, althralgia, etc.) and neuro-psychiatric symptoms (photophobia, transient visual scotomata, forgetfulness, excessive irritability, confusion, difficulty thinking, inability to concentrate, and depression). The pathogenesis of CFS was studied by investigators from various fields, such as virology, immunology, endocrinology, physiology, biochemistry, psychiatry and neuroscience, but it seems to be difficult to understand the etiology of CFS by monism. However, our recent studies suggested that CFS can be understood as a special condition based on abnormality of the psycho-neuro-endocrino- immunological system, with the distinguishing feature of CFS seeming to be the secondary brain dysfunction caused by several cytokines and/or autoantibodies. Furthermore, recent study of polymorphism on the promoter region of the serotonin transporter gene suggested that genetic background is also closely linked to CFS and may be one of the risk factors for this disorder.
    01 Jan. 2006, Biotherapy, 20, 1 - 11

  • Yasuyoshi Watanabe, Hirohiko Kuratsune, Hirohiko Kuratsune
    The sense of fatigue is one of the important bio-alarm systems like pain or fever. However, the neural and molecular mechanisms of fatigue remain unclear. Chronic fatigue syndrome (CFS), involving a long-lasting sensation of fatigue, seems to be a good model for studying these mechanisms underlying chronic fatigue sensation. Recently, to explore the neural and molecular mechanisms of fatigue/chronic fatigue and to investigate the pathogenesis of CFS, we organized a study group of Japanese investigators from various fields, such as virology, immunology, endocrinology, physiology, biochemistry, psychiatry, and neuroscience. From our recent results, CFS can be understood as a special condition based on abnormality of the psycho-neuroendocrino-immunological system, with the distinguishing feature of CFS seeming to be the secondary brain dysfunction caused by several cytokines and/or autoantibodies.
    01 Jan. 2006, Japan Medical Association Journal, 49, 19 - 26

  • 四塩化炭素誘導肝硬変ラットにおける[18F]FDGを用いた疲労時の脳糖代謝変動の検討
    横屋 史彦, 河邉 譲治, 川村 悦史, 塩見 進, 水間 広, 渡邉 恭良
    (一社)日本核医学会, Dec. 2005, 核医学, 42(4) (4), 441 - 441, Japanese

  • 四塩化炭素誘導肝硬変ラットにおける[F-18]FDGを用いた疲労時の脳糖代謝変動の検討
    横屋 史彦, 河邊 譲治, 川村 悦史, 塩見 進, 水間 広, 渡辺 恭良
    (一社)日本核医学会, Sep. 2005, 核医学, 42(3) (3), 304 - 304, Japanese

  • 渡辺 恭良, 油谷 浩幸, 山口 浩二, 倉恒 弘彦
    公益社団法人 日本ビタミン学会, 2005, ビタミン, 79(7) (7), 352 - 353, Japanese

  • M Suzuki, H Doi, T Hosoya, B Langstrom, Y Watanabe
    To develop novel short-lived C-11 radionuclide-incorporated PET tracers with high metabolic tolerance, we performed rapid methylation using (CH3I)-C-11, a frequently used precursor for C-11-labeled tracers, on sp- and sp(2)-carbon frameworks. Methyl iodide was trapped using an excess of tributylphenylstannane for 5 min at 60 degreesC in the presence of Pd[P-(o-tolyl)(3)](2), a copper(I) salt (CuCl or CuBr), and K2CO3, resulting in a greater than 90% yield of toluene. A trapping reaction with tributyl-1-hexynylstannane for 5 min at 60 degreesC in the presence of Pd[P(t-C4H9)(3)](2) and a fluoride ion (KF or CsF) gave a high yield (>90%) of 2-heptyne. Since these reactions are applicable to a wide range of organic molecules, we synthesized 15R-[C-11]TIC methyl ester, a PET tracer targeting the CNS-specific prostacyclin receptor (IP2), by rapid sp(2)-sp(3) coupling with some modifications. Radiolabeled (CH3I)-C-11 Was trapped with the methyl ester of the corresponding stannyl precursor via two steps. In the first, (CH3I)-C-11 and Pd[P(o-tolyl)(3)](2) were mixed to form a methylpalladium complex, and in the second, the methylpalladium complex was mixed with the other reagents necessary for the coupling reaction. The yield of radiolabeled 15R-[C-11]TIC methyl ester was 80-90% and it had a radioactivity of 2.0-2.5 GBq, sufficient for an in vivo human PET study with high reproducibility. We used this tracer in; PET studies imaging the IP2 receptor in living monkey and human brains. Following its penetration of the blood-brain barrier, the tracer underwent ester hydrolysis and bound to its specific receptor in the brain. A protocol for sp-sp(3) coupling would be used to synthesize [C-11]iloprost methyl ester, a PET tracer for the peripheral-type prostacyclin receptor (IP1). A methyl group is the least bulky, unpolarized organic group, suggesting that it would have little effect on the biological activity of its parent compound. Thus, [C-11]methylated compounds may be applicable to a wide range of biologically active molecules, converting them to PET tracers that can be utilized for in vivo molecular imaging. (C) 2004 Elsevier Ltd. All rights reserved.
    ELSEVIER SCI LTD, Sep. 2004, TRAC-TRENDS IN ANALYTICAL CHEMISTRY, 23(8) (8), 595 - 607, English

  • 精神作業疲労により惹起される血液中アミノ酸レベルの変化(Changes in amino acids levels caused by mental fatigue)
    水野 敬, 野崎 聡, 山口 浩二, 水間 広, 田中 雅彰, 笹部 哲也, 杉野 友啓, 乾 富士男, 白井 智子, 須賀 裕子, 梶本 佳孝, 梶本 修身, 倉恒 弘彦, 渡辺 恭良
    日本神経化学会, Aug. 2004, 神経化学, 43(2-3) (2-3), 513 - 513, English

  • ラットにおける長期間頭蓋内自己刺激における自己刺激の抑制期間及びセロトニン作動性神経系の関与(Inhibition period of self-stimulation and the involvement of the serotonergic nervous system in long-term intracranial self-stimulation in rats)
    Cui Yilong, Kataoka Yosky, Li Qing-Hua, Nozaki Satoshi, Mizuma Hiroshi, Watanabe Yasuyoshi, Yamada Hisao
    (一社)日本生理学会, Jun. 2004, The Japanese Journal of Physiology, 54(Suppl.) (Suppl.), S209 - S209, English

  • SUZUKI Masaaki, DOI Hisashi, HOSOYA Takamitsu, WATANABE Yasuyoshi
    Positron emission tomography (PET) is a powerful noninvasive method for molecular imaging in living systems, including the brain, heart, and other active tissues and organs. The need to develop new PET tracers has grown with the increase in use of this technique in biochemistry, medicine (diagnosis), and drug development. We here describe the overview of the recent advances and perspective in this interdisciplinary scientific area, focusing on current PET technology and new tracer synthesis particularly based on new methodologies for incorporating a short-lived ^<11>C-nuclide into bioactive organic molecules through Pd (O)-mediated rapid methylation and carbonylations. The former method has been applied to the synthesis of 15R-[^<11>C] TIC methyl ester, an efficient PET tracer for imaging a novel CNS-type prostacyclin receptor (IP_2) in living human brain.
    The Biophysical Society of Japan General Incorporated Association, 2004, Biophysics, 44(6) (6), 265 - 270, Japanese

  • 大脳皮質の過剰興奮モデルにおける脳実質と髄膜の機能的関係(Functional relationship between brain parenchyma and meninges in an excessive excitation model of the cerebral cortex)
    Yamada Hisao, Kataoka Yosky, Cui Yilong, Tamura Yasuhisa, Osawa Manabu, Koumoto Ryousuke, Yonemura Takuma, Watanabe Yasuyoshi
    エルゼビア・ジャパン(株), May 2003, Neuroscience Research, (Suppl.26) (Suppl.26), S93 - S93, English

  • A NEurite outgrowth-promoting prostaglandin that may enhance higher neuronal functions
    T Satoh, K Furuta, M Suzuki, Y Watanabe
    JAPANESE PHARMACOLOGICAL SOC, 2002, JAPANESE JOURNAL OF PHARMACOLOGY, 88, 92P - 92P, English
    Summary international conference

  • H Takamatsu, H Tsukada, Y Watanabe, YL Cui, Y Kataoka, T Hosoya, M Suzuki, Y Watanabe
    The neuroprotective effect of a central type prostacyclin receptor ligand was examined in a rat model of focal cerebral ischemia. Under halothane anesthesia, male Sprague-Dawley rats were subjected to left middle cerebral artery occlusion. A selective central type prostacyclin receptor ligand, 15-deoxy-(16-m-tolyl)-17,18,19,20-tetranorisocarbacyclin methylester, or a peripheral type prostacyclin receptor ligand, iloprost methylester, were administered intravenously immediately after ischemia. Twenty-four hours after ischemia, brain damage was evaluated. In separate experiments, concentrations of 15-deoxy-(16-in-tolyl)-17,18,19,20-tetranorisocarbacyclin in ischemic brain tissue were measured by injection of a tritium labeled compound. Treatment with 15-deoxy-(16-m-tolyl)-17,18,19,20-tetranorisocarbacyclin methylester (0.03 mg/kg) significantly (P<0.05) reduced the volume of brain damage by 35%. With this treatment, the concentration of this compound in the brain was more than 10 nM. Treatment with iloprost methylester did not show a neuroprotective effect. These results indicated that activation of a central type prostacyclin receptor attenuates ischemic brain damage. The present study demonstrated that the intravenous application of a central type prostacyclin receptor ligand could be a novel therapeutic agent for acute stroke. (C) 2002 Published by Elsevier Science B.V.
    ELSEVIER SCIENCE BV, Jan. 2002, BRAIN RESEARCH, 925(2) (2), 176 - 182, English, International magazine

  • 刺激依存性・海馬歯状回特異的新規ホスホリパーゼA2(KIDScPLA2)の酵素学的性質の検討
    白川 純, 岸本 幸治, 魚住 尚紀, 和泉 孝志, 黒柳 秀人, 鈴木 陽一, 白澤 卓二, 中舘 和彦, 渡辺 恭良, 清水 孝雄
    (公社)日本生化学会, Aug. 2001, 生化学, 73(8) (8), 845 - 845, Japanese

  • S Sihver, N Marklund, L Hillered, B Langstrom, Y Watanabe, M Bergstrom
    Adult rats were subjected to a moderate lateral fluid percussion injury (FPI), followed by survival periods of 2 and 12 h. Regional NMDA subtype glutamate, muscarinic acetylcholine and GABAA receptor binding in various brain regions was analysed by quantitative in vitro autoradiography and short-lived positron emission tomography tracers [C-11]cyanodizocilpine, 4-N-[C-11]methylpiperidylbenzilate (4-N-[C-11]MPB), and [C-11]flumazenil, respectively. The binding potential (BP, B-max/K-D) was calculated. The data with [C-11]cyano-dizocilpine showed a significant decrease in BP bilaterally for the frontoparietal cortex and hippocampus at both time points, in comparison with that of the sham-operated controls. At 12 h the decrease was significantly more prominent for the ipsilateral cortex and hippocampus than for the contralateral side. The BP of 4-N-[C-11]MPB was significantly decreased after 2 h for the trauma-side hippocampus, and after 12 h it had decreased for the trauma-site cortex and the bilateral hippocampus. The [C-11]flumazenil exhibited a significant decrease in BP for the trauma-site cortex and the underlying hippocampus by 2 h after the traumatic brain injury. After 12 h a significantly decreased BP was observed only for the trauma-site cortex. The finding of a decreased BP demonstrates the involvement of these receptor systems in the development of cellular dysfunction, which is widespread and not limited to the site of lateral FPI.
    BLACKWELL SCIENCE LTD, Aug. 2001, JOURNAL OF NEUROCHEMISTRY, 78(3) (3), 417 - 423, English

  • Middle cerebral artery occlusion and reperfusion in primates monitored microdialysis and sequential positron emission tomography
    P Enblad, P Frykholm, J Valtysson, HCS Silander, J Andersson, KJ Fasth, Y Watanabe, B Langstrom, L Hillered, L Persson
    Background and Purpose-In a previous investigation concerning the hemodynamic and metabolic changes over time displayed by sequential positron emission tomography (PET) in a middle cerebral artery (MCA) occlusion/reperfusion primate model, a metabolic threshold for irreversible ischemia could be identified (reduction of metabolic rate of oxygen [CMRO2] to approximate to 60% of the contralateral hemisphere). To evaluate the potential of microdialysis (MD) as an instrument for chemical brain monitoring, the aim of this subsequent study was to relate the chemical changes in MD levels directly to the regional metabolic status (CMRO2 above or below the metabolic threshold) and the occurrence of reperfusion, as assessed by PET. Methods-Continuous MD (2 probes in each brain) and sequential PET measurements were performed during MCA occlusion (2 hours) and 18 hours (mean) of reperfusion in 8 monkeys (Macaca mulatta). Energy-related metabolites (lactate, pyruvate, and hypoxanthine) and glutamate were analyzed. The MD probe regions were divided into 3 categories on the basis of whether CMRO2 was below Or above 60% of the contralateral region (metabolic threshold level) during MCA occlusion and whether;reperfusion was obtained: severe ischemia with reperfusion (n=4), severe ischemia without reperfusion (n=4), and penumbra with reperfusion (n=5). Results-The lactate/pyruvate ratio, hypoxanthine, and glutamate showed similar patterns. MD probe regions with severe ischemia and reperfusion and probe regions with severe ischemia and no reperfusion displayed high and broad peaks, respectively, during MCA occlusion, and the levels almost never decreased to baseline. Penumbra MD probe regions displayed only slight transient increases during MCA occlusion and returned to baseline. Conclusions-This experimental study of focal ischemia showed that the extracellular changes of energy-related metabolites and glutamate differed depending on the ischemic state of the brain during MCA occlusion and depending on whether reperfusion occurred. If MD proves to be beneficial in clinical practice, it appears important to observe relative changes over time.
    LIPPINCOTT WILLIAMS & WILKINS, Jul. 2001, STROKE, 32(7) (7), 1574 - 1580, English

  • K Nakadate, K Imamura, Y Watanabe
    To examine how adrenergic receptors are regulated by experimental manipulation of sensory afferents, we performed immunohistochemical analysis on alpha1-, and beta1-adrenergic receptors in the brain of kittens. In normal development, these receptors were similarly expressed in both hemispheres of the occipital and frontal cortices. Notably, monocular deprivation during the sensitive period of ocular dominance plasticity significantly increased beta1-adrenergic receptor immunoreactivity in the visual cortex ipsilateral to the deprived eye. No increase in the intensity of the immunoreactivity for beta1-adrenergic receptors following monocular deprivation was found in the frontal and parietal regions of the cerebral cortex and subcortical structures, including the lateral geniculate nucleus and superior colliculus. Furthermore, such hemispheric change was not found in the alpha1-adrenergic receptor immunoreactivity following monocular deprivation. Comparisons of images, obtained by double staining for microtubule-associated protein-2 or glial fibrillary acidic protein, indicated that the increased immunoreactivity was localized on both apical dendrites of deep layer neurons and glial cells. These results indicate that the monocular deprivation during the sensitive period of ocular dominance plasticity modified beta1-adrenergic receptor immunoreactivity, including that in glial cells. Therefore, it was suggested that beta1-adrenergic receptors in the glial cells also play important roles in the regulation of ocular dominance plasticity.
    ELSEVIER SCI IRELAND LTD, Jun. 2001, Neuroscience research, 40(2) (2), 155 - 62, English, International magazine
    [Refereed]

  • Coexpression of microsomal-type prostaglandin E synthase with cyclooxygenase-2 in brain endothelial cells of rats during endotoxin-induced fever
    K Yamagata, K Matsumura, W Inoue, T Shiraki, K Suzuki, S Yasuda, H Sugiura, CY Cao, Y Watanabe, S Kobayashi
    Fever is triggered by an elevation of prostaglandin E-2 (PGE(2)) in the brain. However, the mechanism of its elevation remains unanswered. We herein cloned the rat glutathione-dependent microsomal prostaglandin E synthase (mPGES), the terminal enzyme for PGE(2) biosynthesis, and examined its induction in the rat brain after intraperitoneal injection of pyrogen lipopolysaccharide (LPS). In Northern blot analysis, mPGES mRNA was weakly expressed in the brain under the normal conditions but was markedly induced between 2 and 4 hr after the LPS injection. In situ hybridization study revealed that LPS-induced mPGES mRNA signals were mainly associated with brain blood vessels, especially vein or venular-type ones, in the whole brain area. Immunohistochemical study demonstrated that mPGES-like immunoreactivity was expressed in the perinuclear region of brain endothelial cells, which were identified as von Willebrand factor-positive cells. Furthermore, in the perinuclear region of the endothelial cells, mPGES was colocalized with cyclooxygenase-2 (COX-2), which is the enzyme essential for the production of the mPGES substrate PGH(2). Inhibition of cyclooxygenase-2 activity resulted in suppression of both PGE(2) level in the CSF and fever (Cao et at., 1997), suggesting that the two enzymes were functionally linked and that this link is essential for fever. These results demonstrate that brain endothelial cells play an essential role in the PGE(2) production during fever by expressing COX-2 and mPGES.
    SOC NEUROSCIENCE, Apr. 2001, JOURNAL OF NEUROSCIENCE, 21(8) (8), 2669 - 2677, English

  • 巣状脳虚血のラットモデルにおける中枢型プロスタサイクリン受容体リガンドの神経保護作用(Neuroprotective effect of a central type prostacyclin receptor ligand in a rat model of focal cerebral ischemia)