研究者業績

橋本 謙二

Kenji Hashimoto

基本情報

所属
千葉大学 社会精神保健教育研究センター 教授
学位
博士(薬学)(九州大学)

研究者番号
10189483
J-GLOBAL ID
200901091404718715
researchmap会員ID
5000098613

外部リンク

2005- 千葉大学社会精神保健教育研究センター・病態解析研究部門・教授

受賞

 2

論文

 572
  • Yukihiko Shirayama, Masaaki Iwata, Kanako Miyano, Yuki Hirose, Yasunori Oda, Yuko Fujita, Kenji Hashimoto
    Brain research 148567-148567 2023年9月7日  
    Beta-hydroxybutyrate (BHB), an endogenous NLRP3 inflammasome inhibitor, has been shown to be associated with the pathophysiology of depression in rodents. However its active mechanism has not been revealed. Herein, we probed both the pathways and brain regions involved in BHB's antidepressant-like effects in a learned helplessness (LH) rat model of depression. A single bilateral infusion of BHB into the cerebral ventricles induced the antidepressant-like effects on the LH rats. The antidepressant-like effects of BHB were blocked by the TrkB inhibitor ANA-12 and the AMPA receptor antagonist NBQX, indicating that the antidepressant-like effects of BHB involve BDNF-TrkB signaling and AMPA receptor activation. Further, infusions of BHB into the prelimbic and infralimbic portions of medial prefrontal cortex, the dentate gyrus of hippocampus, and the basolateral region of amygdala produced the antidepressant-like effects on LH rats. However, infusions of BHB into the central region of amygdala, the CA3 region of hippocampus, and the shell and core regions of nucleus accumbens had no effect. Finally, a single bilateral infusion of BHB into the cerebral ventricles of naive rats strengthened learning ability on repeated active avoidance test where saline-infused animals failed to increase avoidance responses.
  • Xingming Wang, Akifumi Eguchi, Yong Yang, Lijia Chang, Xiayun Wan, Jiajing Shan, Youge Qu, Li Ma, Chisato Mori, Jianjun Yang, Kenji Hashimoto
    Neurobiology of Disease 176 2023年1月  
    Multiple sclerosis (MS) is the most common demyelinating disease that attacks the central nervous system. Dietary intake of cuprizone (CPZ) produces demyelination resembling that of patients with MS. Given the role of the vagus nerve in gut–microbiota–brain axis in development of MS, we performed this study to investigate whether subdiaphragmatic vagotomy (SDV) affects demyelination in CPZ-treated mice. SDV significantly ameliorated demyelination and microglial activation in the brain compared with sham-operated CPZ-treated mice. Furthermore, 16S ribosomal RNA analysis revealed that SDV significantly improved the abnormal gut microbiota composition of CPZ-treated mice. An untargeted metabolomic analysis demonstrated that SDV significantly improved abnormal blood levels of metabolites in CPZ-treated mice compared with sham-operated CPZ-treated mice. Notably, there were correlations between demyelination or microglial activation in the brain and the relative abundance of several microbiome populations, suggesting a link between gut microbiota and the brain. There were also correlations between demyelination or microglial activation in the brain and blood levels of metabolites. Together, these data suggest that CPZ produces demyelination in the brain through the gut–microbiota–brain axis via the subdiaphragmatic vagus nerve.
  • Tsuyoshi Sasaki, Kenji Hashimoto, Tomihisa Niitsu, Yutaka Hosoda, Yasunori Oda, Yuki Shiko, Yoshihito Ozawa, Yohei Kawasaki, Nobuhisa Kanahara, Akihiro Shiina, Tasuku Hashimoto, Takaaki Suzuki, Takeshi Sugawara, Hideki Hanaoka, Masaomi Iyo
    Psychiatry Research 114486-114486 2022年2月  
  • Yukihiko Shirayama, Masaaki Iwata, Yuko Fujita, Yasunori Oda, Kenji Hashimoto
    Behavioural brain research 113769-113769 2022年1月24日  
    Finding from animal models of depression indicated that Toll-like receptor 4 (TLR4) is associated with the pathophysiology of depression. Herein, the TLR4 antagonists TAK-242 and baicalin induced antidepressant-like effects in a rat learned helplessness model of depression. The antidepressant-like effects of both TLR4 antagonists were blocked by the TrkB inhibitor ANA-12. Also, the antidepressant-like effects of TAK-242 were blocked by the treatment with AMPA receptor antagonist NBQX. The antidepressant-like effects of the TLR4 antagonist TAK-242 involves BDNF-TrkB signaling and AMPA receptor activation.
  • Li Ma, Jiancheng Zhang, Yuko Fujita, Youge Qu, Jiajing Shan, Xiayun Wan, Xingming Wang, Tamaki Ishima, Kenta Kobayashi, Long Wang, Kenji Hashimoto
    Translational psychiatry 12(1) 27-27 2022年1月21日  
    (R, S)-ketamine has prophylactic antidepressant-like effects in rodents; however, the precise molecular mechanisms underlying its action remain unknown. Using RNA-sequencing analysis, we searched novel molecular target(s) that contribute to the prophylactic effects of (R)-ketamine, a more potent enantiomer of (R, S)-ketamine. Pretreatment with (R)-ketamine (10 mg/kg, 6 days before) significantly ameliorated body weight loss, splenomegaly, and increased immobility time of forced swimming test in lipopolysaccharide (LPS: 1.0 mg/kg)-treated mice. RNA-sequencing analysis of prefrontal cortex (PFC) and subsequent IPA (Ingenuity Pathway Analysis) revealed that the nuclear factor of activated T cells 4 (NFATc4) signaling might contribute to sustained prophylactic effects of (R)-ketamine. Quantitative RT-PCR confirmed that (R)-ketamine significantly attenuated the increased gene expression of NFATc4 signaling (Nfatc4, Cd4, Cd79b, H2-ab1, H2-aa) in the PFC of LPS-treated mice. Furthermore, pretreatment with NFAT inhibitors (i.e., NFAT inhibitor and cyclosporin A) showed prophylactic effects in the LPS-treated mice. Similar to (R)-ketamine, gene knockdown of Nfatc4 gene by bilateral injection of adeno-associated virus (AAV) into the mPFC could elicit prophylactic effects in the LPS-treated mice. In conclusion, our data implicate a novel NFATc4 signaling pathway in the PFC underlying the prophylactic effects of (R)-ketamine for inflammation-related depression.

MISC

 369
  • 橋本 佐, 橋本 謙二, 松澤 大輔, 清水 栄司, 関根 吉統, 稲田 俊也, 尾崎 紀夫, 岩田 仲生, 原野 睦夫, 小宮山 徳太郎, 山田 光彦, 曽良 一郎, 氏家 寛, 伊豫 雅臣
    精神薬療研究年報 (37) 100-107 2005年3月  
    覚醒剤乱用の病態形成におけるGSTP1の潜在的な役割を明らかにするため,覚醒剤関連性障害と診断された対象者におけるGSTP1遺伝子多型について解析した.覚醒剤乱用者で精神病を伴う患者と健常者との間でgenotype頻度およびallele頻度において有意な差がみられた.GSTP1 exon 5遺伝子の多型が,覚醒剤乱用での精神病発症の脆弱性に関与している可能性が示唆された
  • K Itoh, K Hashimoto, E Shimizu, Y Sekine, N Ozaki, T Inada, M Harano, N Iwata, T Komiyama, M Yamada, Sora, I, K Nakata, H Ujike, M Iyo
    AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS 132B(1) 70-73 2005年1月  
    Several lines of evidence suggest that genetic factors might contribute to drug abuse vulnerability. Recent genomic scans for association demonstrated that the brain-derived neurotrophic factor (BDNF) gene was associated with drug abuse vulnerability. In this study, we analyzed association of two BDNF gene single nucleotide polymorphisms (SNPs), 132C > T (C270T named formerly) in the noncoding region of exon V and 196G > A (val66met) in the coding region of exon XIIIA, with methamphetamine (MAP) abuse in Japan. No significant differences were found in the frequency of the genotype or allele in these two SNPs between MAP abusers and controls (132C > T in exon V: genotype, P = 0.586, allele, P = 0.594; 196G > A (val66met) in exon XIIIA: genotype, P = 0.889, allele, P = 0.713). Furthermore, there was no difference between clinical parameters (e.g., prognosis psychosis, spontaneous relapse, or poly-substance abuse) and the two SNPs of BDNF gene. These results suggest that the two SNPs (132C > T in exon V and 196G > A (val66met) in exon XIIIA) of the BDNF gene may not be associated with Japanese MAP abusers. This article contains supplementary material, which maybe viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148-7299:1/suppmat/index.html. (C) 2004 Wiley-Liss, Inc.
  • H Okamoto, E Shimizu, K Ozawa, K Hashimoto, M Iyo
    AUSTRALIAN AND NEW ZEALAND JOURNAL OF PSYCHIATRY 39(1-2) 108-108 2005年1月  
  • Kenji Hashimoto, Goran Engberg, Eiji Shimizu, Conny Nordin, Leif H. Lindstrom, Masaomi Iyo
    BMC PSYCHIATRY 5(1) 6 2005年  
    Background: Recent magnetic resonance spectroscopy (MRS) studies report that glutamine is altered in the brains of schizophrenic patients. There were also conflicting findings on glutamate in cerebrospinal fluid (CSF) of schizophrenic patients, and absent for glutamine. This study aims to clarify the question of glutamine and glutamate in CSF of first episode and drug naive schizophrenic patients. Method: Levels of glutamine and glutamate in CSF of 25 first episode and drug-naive male schizophrenic patients and 17 age-matched male healthy controls were measured by a high performance liquid chromatography. Results: The ratio (126.1 (median), 117.7 +/- 27.4 (mean +/- S. D.)) of glutamine to glutamate in the CSF of patients was significantly (z = -3.29, p = 0.001) higher than that (81.01 (median), 89.1 +/- 22.5 (mean +/- S. D.)) of normal controls although each level of glutamine and glutamate in patients was not different from that of normal controls. Conclusion: Our data suggests that a disfunction in glutamate-glutamine cycle in the brain may play a role in the pathophysiology of schizophrenia.
  • HASHIMOTO K.
    Curr Psychiatry Rev 1(2) 151-163 2005年  
  • D Matsuzawa, K Hashimoto, E Shimizu, M Fujisaki, M Iyo
    NEUROPSYCHOBIOLOGY 52(2) 68-70 2005年  
    Background. Several lines of evidence suggest that a certain type of personality or temperament as well as oxidative stress may be implicated in the pathophysiology of neuropsychiatric diseases. Glutathione peroxidase 1 (GPX1) plays a role in the antioxidant defense system. Objectives:The authors studied the association between the GPX1 gene polymorphism and personality traits in healthy subjects. Methods: One hundred forty-nine healthy subjects were enrolled. Analysis of the functional polymorphism (Pro198Leu) in the human GPX1 gene was performed. Results: Subjects with Pro198Pro have significantly higher scores in openness to experience on the Revised NEO Personality Inventory (NEO-PI-R) as compared with subjects with other genotypes (Pro198Leu or Leu198Leu). In contrast, we detected no association between other personality dimensions on the NEO-PI-R and scores on the Temperament and Character Inventory. Conclusion: This study reports that the functional polymorphism (Pro198Leu) in the GPX1 gene might be associated with openness to experience among the personality traits. Copyright (C) 2005 S. Karger AG, Basel.
  • T Yamamoto, R Sakakibara, K Hashimoto, K Nakazawa, T Uchiyama, Z Liu, T Ito, T Hattori
    NEUROSCIENCE 135(1) 299-303 2005年  
    Parkinson's disease is a common neurodegenerative disease that shows not only movement disorder, but also profound urinary dysfunction. Bladder hyperactivity is the major urodynamic abnormality. Therefore, the basal ganglia have been thought to modulate the micturition reflex. In six male adult cats under ketamine anesthesia, in which spontaneous isovolumetric micturition reflexes had been generated, we measured levels of striatal dopamine, in micturition and storage phases, using in vivo microdialysis. The striatal dopamine level significantly increased in the storage phase as compared with that in the micturition phase. It is suggested that striatal dopamine may inhibit the micturition reflex via the dopamine D1 receptor-GABAergic direct striatal output pathway, and that disruption of this pathway may be what leads to bladder hyperactivity in patients with Parkinson's disease. (c) 2005 IBRO. Published by Elsevier Ltd. All rights reserved.
  • Kaori Koike, Kenji Hashimoto, Goro Fukami, Naoe Okamura, Lin Zhang, Shintaro Ohgake, Hiroki Koizumi, Daisuke Matsuzawa, Noriyuki Kawamura, Eiji Shimizu, Masaomi Iyo
    Neuropharmacology 48(3) 391-397 2005年  
    Repeated use of methamphetamine (MAP) is known to cause neurotoxicity in the dopaminergic neurons of the striatum. Recently, we reported that FK506, a calcineurin inhibitor and immunosuppressive agent, could attenuate acute behavioral changes and the development of sensitization after administration of MAP. In this study, we investigated the effects of FK506 on the neurotoxicity in the dopaminergic neurons induced by repeated administration of MAP. BALB/c mice were injected subcutaneously (s.c.) with vehicle (10 ml/kg) or MAP (4 mg/kg) four times every 2 h. Vehicle (10 ml/kg) or FK506 (0.1, 0.3, 1 or 3 mg/kg i.p.) was administered 15 min before the first MAP administration. Three days later, we assessed the contents of dopamine (DA) and its major metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), in the mouse striatum using high-performance liquid chromatography (HPLC). We also examined the immunohistochemistry of dopamine transporter (DAT) and tyrosine hydroxylase (TH) in the mouse brain. Repeated administration of MAP decreased significantly the contents of DA and DOPAC in the mouse striatum, and pretreatment with FK506 inhibited significantly the reduction of DA and DOPAC in the mouse brain by repeated administration of MAP. Furthermore, repeated administration of MAP decreased significantly the immunoreactivity of DAT and TH in the striatum as compared to controls. Pretreatment with FK506 (3 mg/kg) attenuated significantly the reduction of DAT and TH immunoreactivity after repeated administration of MAP. These results suggest that FK506 shows protective effects on the MAP-induced neurotoxicity in the dopaminergic neurons of the mouse striatum. © 2004 Elsevier Ltd. All rights reserved.
  • 橋本謙二, 山田和男, 大西哲生, 清水栄司, 吉川武男, 伊予雅臣
    厚生労働省精神・神経疾患研究委託費による研究報告集 平成16年度 (2年度班・初年度班) 138 2005年  
  • K Hashimoto, H Tsukada, S Nishiyama, D Fukumoto, T Kakiuchi, E Shimizu, M Iyo
    NEUROPSYCHOPHARMACOLOGY 29(11) 2018-2023 2004年11月  
    Several lines of evidence suggest that oxidative stress might contribute to neurotoxicity in the dopaminergic nerve terminals after administration of methamphetamine (MAP), We undertook the present study to determine whether intravenous administration of N-acetyl-L-cysteine (NAC), a potent antioxidant drug, could attenuate the reduction of dopamine transporter (DAT) in the striatum of monkey brain after administration of MAP. Positron emission tomography studies demonstrated that repeated administration of MAP (2 mg/kg as a salt, four times at 2-h intervals) significantly decreased the accumulation of radioactivity in the striatum after intravenous administration of [C-11]beta-CFT. In contrast, the binding of [C-11]SCH 23390 to dopamine D-1 receptors in the monkey striatum was not altered after the administration of MAP. A bolus injection of NAC (150 mg/kg, i.v.) 30 min before MAP administration and a subsequent continuous infusion of NAC (12 mg/kg/h, i.v.) over 8.5 h significantly attenuated the reduction of DAT in the monkey striatum 3 weeks after the administration of MAP, These results suggest that NAC could attenuate the reduction of DAT in the monkey striatum after repeated administration of MAP. Therefore, it is likely that NAC would be a suitable drug for treatment of neurotoxicity in dopaminergic nerve terminals related to chronic use of MAP in humans.
  • O Kubota, K Hattori, K Hashimoto, T Yagi, T Sato, M Iyo, S Yuasa
    MOLECULAR BRAIN RESEARCH 130(1-2) 149-160 2004年11月  
    Fyn-tyrosine-kinase-deficient mice exhibit increased fearfulness. To elucidate the neural mechanisms of their emotional defects, we compared fyn(-/-) and fyn(+/-) mice by behavioral analysis of conditioned fear and by functional neuroanatomical analysis of the distribution of highly responsive neurons associated with conditioned fear. The mice were exposed to the auditory conditioned stimulus paired with electric shock as the unconditioned stimulus. After the fear conditioning, auditory stimulus-induced freezing behavior was enhanced in fyn(-/-) mice. When the occurrence of c-Fos-immunoreactive neurons in the brain of fear-conditioned mice was examined following exposure to the auditory stimulus, a significant increase in immunoreactive neurons was found in the amygdala, hypothalamus, and midbrain of both genotypes. The occurrence of conditioned-fear-dependent c-Fos-immumoreactive neurons was enhanced in the central, medial, cortical, and basomedial amygdaloid subdivisions, the hypothalamic nuclei, and the midbrain periaqueductal gray of the fyn(-/-) mice in comparison with the fyn(+/-) mice. However, remarkably, the occurrence of conditioned-fear-dependent c-Fos-immunoreactive neurons was very low in the basolateral and lateral amygdaloid subdivisions of the fyn(-/-) mice, in striking contrast to a significant increase in c-Fos-immunoreactive neurons in these subdivisions in the fyn(+/-) mice. These findings suggest that the increased excitability of the specific amygdaloid subdivisions including the central nucleus, and of the projection targets such as the hypothalamus and midbrain in fyn(-/-) mice, is directly related to the enhanced fear response, and that the decreased excitability in the basolateral and lateral amygdaloid subdivisions is involved in the defective control of the neural circuit for emotional expression in this mutant. (C) 2004 Elsevier B.V. All rights reserved.
  • M Nakazato, K Hashimoto, A Shiina, H Koizumi, M Mitsumoti, M Imai, E Shimizu, M Iyo
    PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY 28(7) 1181-1184 2004年11月  
    It has been reported that fasting plasma ghrelin levels may play a role in the pathophysiology of eating disorders. In this study, the authors examined whether serum levels of ghrelin were altered in the patients with bulimia nervosa (BN). We enrolled 18 female patients with BN, and 21 age-matched female controls for this study. Eating-related psychopathology, depressive symptoms were evaluated by using the Bulimic Investigatory Test, Edinburgh (BITE) and the 17-item Hamilton Depression Rating Scale (HDRS). Serum levels of ghrelin were measured by Ghrelin enzyme immunoassay kit. There were no significant differences in serum ghrelin levels between the patients with BN and normal controls. Furthermore, the authors did not found correlation between serum ghrelin levels and clinical parameters in the patients with BN. Our study suggests that serum ghrelin levels in the patients with BN were indistinguishable from normal controls. Therefore, it is unlikely that ghrelin plays a role in the pathophysiology of BN. (C) 2004 Elsevier Inc. All rights reserved.
  • E Shimizu, A Otsuka, K Hashimoto, M Iyo
    EUROPEAN PSYCHIATRY 19(6) 389-389 2004年9月  
  • TATSUMI R, SEIO K, FUJIO M, KATAYAMA J, HORIKAWA T, HASHIMOTO K, TANAKA H
    Bioorg Med Chem Lett 14(14) 3781-3784 2004年7月  
  • G Fukami, K Hashimoto, K Koike, N Okamura, E Shimizu, M Iyo
    BRAIN RESEARCH 1016(1) 90-95 2004年7月  
    Several lines of evidence suggest that oxidative stress may play a role in the behavioral changes and neurotoxicity in rats after administration of methamphetamine (MAP). N-acetyl-L-cysteine (NAC) is a precursor of glutathione, and it also exerts as an antioxidant. In this study, we investigated the effects of NAC on the behavioral changes (hyperlocomotion and development of sensitization) and neurotoxicity in male Wistar rats after administration of MAP. Pretreatment with NAC (30, 100 or 300 mg/kg, i.p.) attenuated significantly hyperlocomotion in rats induced by a single administration of MAP (2 mg/kg, i.p.), in a dose-dependent manner. Furthermore, pretreatment with NAC (100 mg/kg, i.p., 15 min before MAP injection, once daily for 5 consecutive days) blocked significantly the development of behavioral sensitization in rats after repeated administration of MAP (2 mg/kg, once daily for 5 consecutive days), whereas the behaviors in rats after repeated administration of NAC plus saline groups were not different from those of control (vehicle plus saline) groups. One week after administration of MAP (7.5 mg/kg x 4, 2-h intervals), levels of dopamine (DA) in rat striatum were significantly decreased as compared with control groups. Pretreatment with NAC (1, 3, 10 or 30 mg/kg, i.p., 30 min before each MAP injection) attenuated significantly the MAP-induced reduction of DA in rat striatum, in a dose-dependent manner. These results suggest that NAC could prevent the behavioral changes (acute hyperlocomotion and development of behavioral sensitization) in rats and neurotoxicity in rat striatum after administration of MAP, and that NAC would be a useful drug for treatment of several symptoms associated with MAP abuse. (C) 2004 Elsevier B.V. All rights reserved.
  • 橋本 謙二, 伊豫 雅臣
    分子精神医学 4(3) 238-241 2004年7月  
  • S Yanahashi, K Hashimoto, K Hattori, S Yuasa, M Iyo
    BRAIN RESEARCH 1011(1) 84-93 2004年6月  
    The increase of Fos expression in the striatum induced by haloperidol, an antagonist of the dopamine D-2 receptor, might be related to the activation of glutamatergic neurotransmission, especially that of N-methyl-D-aspartate (NMDA) receptors. In this study, using behavioral and immunohistochemical techniques, we examined the effects of a noncompetitive NMDA antagonist, (+)-MK-801, and an NMDA receptor NR2B subunit antagonist, ifenprodil, on catalepsy, an extrapyramidal symptom; in this context, we also considered the expression of Fos protein in the forebrain after the administration of haloperidol. Catalepsy in mice, induced by the administration of haloperidol (1 mg/kg), was inhibited by pretreatment with (+)-MK-801 (0.2 mg/kg) or ifenprodil (10 mg/kg). Furthermore, pretreatment with (+)-MK-801 (0.2 mg/kg) significantly attenuated the induction of Fos-immunoreactive (IR) cells in the dorsomedial, dorsolateral, and ventrolateral striatum, but not in the shell region of the nucleus accumbens after the administration of haloperidol, whereas pretreatment with ifenprodil (10 mg/kg) significantly attenuated the induction of Fos-IR cells in all of these areas. It is known that ifenprodil binds sigma receptors and alpha-1 adrenergic receptors with high affinity. Pretreatment with the sigma receptor antagonist BD-1407 (3 mg/kg) or the alpha-1 adrenergic receptor antagonist prazosin (3 mg/kg) affected neither catalepsy nor the expression of Fos-IR cells after the administration of haloperidol. However, pretreatment with CP-101,606 (1 mg/kg), a selective antagonist for the NR2B subunit of the NMDA receptor, significantly attenuated catalepsy and the expression of Fos-IR cells in the forebrain after the administration of haloperidol. These results suggest that the NMDA receptor antagonists attenuated the induction of catalepsy and Fos-IR cells in forebrain after the administration of haloperidol. It was also suggested that haloperidol-induced expression of Fos-IR cells in the shell region of the nucleus accumbens might be differentially regulated by NMDA receptor subunits. Therefore, it appears that selective antagonists for the NR2B subunit of the NMDA receptor (e.g., CP-101,606) might be useful drugs for the treatment of extrapyramidal side effects (EPS) associated with the chronic use of typical antipsychotics such as haloperidol. (C) 2004 Elsevier B.V. All rights reserved.
  • E Shimizu, K Hashimoto, K Kobayashi, M Mitsumori, S Ohgake, H Koizumi, N Okamura, K Koike, C Kumakiri, M Nakazato, N Komatsu, M Iyo
    NEUROSCIENCE LETTERS 363(1) 81-83 2004年6月  
    Family and twin studies have indicated that genes influence susceptibility to panic disorder, but the genes involved remain unknown. The neuropeptide angiotensin II has been found to be involved in anxiety and regulation of respiration which are important in the pathophysiology of panic attacks. Assuming that angiotensins may be candidate genes in panic disorder, we analyzed the association between panic disorder and angiotensin I-converting enzyme (ACE) insertion (I)/deletion (D) gene functional polymorphism. We recruited 101 patients with panic disorder diagnosed according to DSM-IV criteria, and 184 control subjects in the study. No significant differences in the frequency of the genotype or allele in the polymorphism between patient and control groups were found (genotype, X-2 = 0.56, d.f. = 2, P = 0.77; allele, X-2 = 0.074, d.f. = 1, P = 0.78). This study suggests that the ACE I/D gene polymorphism is not directly associated with panic disorder in our Japanese patient group. (C) 2004 Elsevier Ireland Ltd. All rights reserved.
  • K Koike, K Hashimoto, N Okamura, S Ohgake, E Shimizu, H Koizumi, N Komatsu, M Iyo
    PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY 28(3) 517-520 2004年5月  
    It is suggested that deficits of alpha7 nicotinic acetylcholine receptors (nAChRs) might be associated with the cognitive impairments of Alzheimer's disease and schizophrenia, and that agonists for alpha7 nAChR could be useful for treatment of cognitive dysfunction in these diseases. This study was undertaken to examine the role of nAChRs on hippocampal cellular proliferation of adult mice. The number of 5-bromo-2'-deoxyuridine (BrdU)-immunoreactive cells in the granule cell layer (GCL) and hilus of alpha7 nAChR heterozygous (+/-) mice was significantly decreased as compared with that of wild-type (+/+) mice. In contrast, the number of BrdU-immunoreactive cells in GCL and hilus of alpha7 nAChR homozygous ( - / -) mice was not different from that of wild-type mice. The results suggest that reduced levels of alpha7 nAChRs may decrease cell proliferation of adult hippocampus. (C) 2004 Elsevier Inc. All rights reserved.
  • H Koizumi, K Hashimoto, K Itoh, M Nakazato, E Shimizu, S Ohgake, K Koike, N Okamura, S Matsushita, K Suzuki, M Murayama, S Higuchi, M Iyol
    AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS 127B(1) 125-127 2004年5月  
    Several lines of evidence suggest that genetic factors might contribute to the pathogenesis of eating disorders and that brain-derived neurotrophic factor (BDNF) plays a role in the pathophysiology of eating disorders. To investigate the role of the BDNF gene in the susceptibility to eating disorders, we analyzed the BDNF 196G/A gene polymorphism in female patients with eating disorders and female normal controls. The difference in the genotype frequency between patients (n = 198) and normal controls (n = 222) was statistically significant (P = 0.029). Interestingly, a significant (P = 0.015) difference in the genotype frequency between normal controls and bulimia nervosa patients (n = 101) with binge-purging type was detected. This study suggests that the BDNF 196G/A gene polymorphism might be associated with a susceptibility to eating disorders. (C) 2003 Wiley-Liss, Inc.
  • K Hashimoto, E Shimizu, M Iyo
    BRAIN RESEARCH REVIEWS 45(2) 104-114 2004年5月  
    The purpose of this review is to integrate what is currently known about the role of brain-derived neurotrophic factor (BDNF) in the pathophysiology of mood disorders including major depressive disorder (MDD) and bipolar disorder (BD). We reviewed the pre-clinical and clinical papers demonstrating that BDNF plays a role in the pathophysiology of mood disorders and in the mechanism of action of therapeutic agents. Pre-clinical studies suggest that the expression of BDNF might be a downstream target of antidepressant treatments and mood stabilizers such as lithium and valproate, and that BDNF exerts antidepressant activity in animal models of depression. Furthermore, BDNF protects against stress-induced neuronal damage, and it might affect neurogenesis in the hippocampus, which is thought to be involved in the pathogenesis of mood disorders. Clinical studies have demonstrated that serum levels of BDNF in drug-naive patients with MDD are significantly decreased as compared with normal controls, and that BDNF might be an important agent for therapeutic recovery from MDD. Moreover, recent findings from family-based association studies have suggested that the BDNF gene is a potential risk locus for the development of BD. These findings suggest that BDNF plays a critical role in the pathophysiology of mood disorders and in the activity of therapeutic agents in patients with mood disorders. New agents capable of enhancing BDNF levels may lead aid the development of novel therapeutic drugs for patients with mood disorders. (C) 2004 Elsevier B.V. All rights reserved.
  • Y Minabe, Y Shirayama, K Hashimoto, C Routledge, JJ Hagan, CR Ashby
    SYNAPSE 52(1) 20-28 2004年4月  
    This study examined the effect of the acute and repeated per os (p.o.) administration of the selective 5-HT6 receptor antagonist SB-271046, on the number, as well as the firing pattern of spontaneously active dopamine (DA) neurons in the rat substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) in anesthetized male Sprague-Dawley rats. This was accomplished using the technique of extracellular in vivo electrophysiology. A single p.o. administration of either 1, 3, or 10 mg/kg of SB-271046 did not significantly alter the number of spontaneously active SNC DA neurons per stereotaxic electrode tract compared to vehicle-treated animals. The acute administration of either 1 or 3 mg/kg of SB-271046 did not significantly alter the number of spontaneously active VTA DA neurons. In contrast, a significant decrease in the number of spontaneously active VTA DA neurons was observed after a single administration of 10 mg/kg of SB-271046 compared to vehicle-treated animals. The acute p.o. administration of SB-271046 significantly altered the firing pattern parameters of all (bursting + nonbursting DA neurons) DA neurons, particularly those in the VTA, compared to vehicle-treated animals. The repeated p.o. administration (once per day for 21 days) of 1, 3, or 10 mg/kg of SB-271046 did not significantly alter the number of spontaneously active VTA DA neurons compared to vehicle-treated animals. The repeated administration of 3 or 10 mg/kg of SB-271046 significantly increased the number of spontaneously active SNC DA neurons compared to vehicle controls. Overall, the repeated administration of SB-271046 had relatively little effect on the firing pattern of midbrain DA neurons. The results obtained following the chronic administration of SB-271046 show that this compound has a profile different from that of typical or atypical antipsychotic drugs in this model. Clinical studies are required to understand what role 5-HT6 receptor blockade might eventually play in the treatment of schizophrenia. (C) 2004Wiley-Liss,Inc.
  • H Koizumi, K Hashimoto, C Kumakiri, E Shimizu, Y Sekine, N Ozaki, T Inada, M Harano, T Komiyama, M Yamada, Sora, I, H Ujike, N Takei, M Iyo
    AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS 126B(1) 43-45 2004年4月  
    Several lines of evidence suggest that increased generation of auto-oxidized dopamine (DA) o-quinone is associated with the neurotoxicity of methamphetamine (MAP) in the brain, and that, as a cellular defenses against DA-derived quinines, glutathione S-transferase (GST) detoxifies auto-oxidized DA o-quinone in the brain. Glutathione S-transferase M1 (GSTM1) of the mu-class of GSTs catalyzes reaction between glutathione and catecholamine o-quinones under physiological conditions. This study was undertaken to investigate the role of the GSTM1 gene deletion polymorphism in the neuropathology of MAP abuse. One hundred fifty-seven MAP abusers and 200 healthy comparison subjects were tested for a genetic polymorphism of GSTM1. The difference in the frequency of deletion (D)/nondeletion (N) alleles between the female abusers and female controls was close to statistical significance (P=0.071), although there was no statistical difference (P=0.651) between male abusers and male controls. Furthermore, the number of female abusers with deletion alleles was significantly (P=0.007, odds ratio: 2.77, 95% CI 1.30-5.89) higher than that of male abusers with deletion alleles. These findings suggest that GSTM1 gene deletion may contribute to a vulnerability to MAP abuse in female subjects, but not in male subjects. (C) 2003 Wiley-Liss, Inc.
  • E Shimizu, K Hashimoto, M Iyo
    AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS 126B(1) 122-123 2004年4月  
  • K Hashimoto, T Fukushima, E Shimizu, SI Okada, N Komatsu, N Okamura, K Koike, H Koizumi, C Kumakiri, K Imai, M Iyo
    PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY 28(2) 385-388 2004年3月  
    Several lines of evidence suggest that D-serine may function as an endogenous agonist of the glycine site on the N-methyl-D-aspartate (NMDA) receptor that has been implicated in the pathophysiology of Alzheimer's disease (AD). The purpose of the study was to determine whether serum levels of D- and L-serine in patients with AD are altered as compared with normal controls. Serum levels of D- and L-serine in patients of AD and age- and gender-matched normal controls were determined using a high-performance liquid chromatography (HPLC). Serum levels Of D-serine in the patients with AD were slightly (z = -1.77, p = 0.078) lower than those of normal controls. In contrast, serum levels of L-serine in the patients were slightly (z = -1.73, p = 0.083) higher than those of controls. In addition, the percentage (%) of D-serine in the total (L + D) serine in the patients was significantly (z = -2.36, p = 0.018) lower than that of controls. The present study suggests that the reduced activity of serine racemase, an enzyme catalyzing the formation of D-serine from L-serine may play a role in the pathophysiology of AD. (C) 2003 Elsevier Inc. All rights reserved.
  • N Okamura, K Hashimoto, E Shimizu, C Kumakiri, N Komatsu, M Iyo
    NEUROPSYCHOPHARMACOLOGY 29(3) 544-550 2004年3月  
    Noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine ((+)-MK-801) is known to induce neurotoxicity in rat retrosplenial cortex after systemic administration. The present study was undertaken to examine the effects of adenosine A, receptor agonists on the neurotoxicity in rat retrosplenial cortex after administration of dizocilpine. Pretreatment with adenosine A, receptor agonists, 2-chloro-N-6-cyclopentyladenosine (CCPA) (0.1, 03, 1, or 3 mg/kg, intraperitoneally (i.p.)), or N-6-cyclopentyladenosine (CPA) (1, 3, or 10 mg/kg, i.p;); attenuated neurotoxicity by dizocilpine (0.5 mg/kg, i.p), in a dose-dependent manner. Coadministration with adenosine A(1) receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 3 mg/kg, i.p.) significantly blocked the protective effects of CCPA for dizocilpine-induced neurotoxicity. Furthermore, pretreatment with CCPA (3 mg/kg) attenuated significantly the dizocilpine-induced expression of HSP-70 protein, which is known as a sensitive marker of reversible neuronal damage, and coadministration with DPCPX (3 mg/kg) blocked the inhibitory effects of CCPA for marked expression of HSP-70 protein by administration of dizocilpine. Moreover, pretreatment with CCPA (3 mg/kg, i.p.) significantly suppressed the increase of extracellular acetylcholine (ACh) levels in the retrosplenial cortex by administration of dizocilpine (0.5 mg/kg). In contrast, local perfusion of CCPA (1 muM) into the retrosplenial cortex via the dialysis probe did not alter the ACh levels by administration of dizocilpine (0.5 mg/kg), suggesting that the locus of action of CCPA is not in the retrosplenial cortex. These findings suggest that adenosine A, receptors agonists could protect against neuropathological changes in rat retrosplenial cortex after administration of the NMIDA receptor antagonist dizocilpine.
  • Synapse 51(1) 19-26 2004年1月  
    Effect of the acute and chronic administration of the putative atypical antipsychotic drug Y-931 (8-fluoro-12- (4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3b][1,5] benzodiazepine maleate) on spontaneously active rat midbrain dopamine neurons: an in vivo electrophysiological study
  • K Itoh, K Hashimoto, C Kumakiri, E Shimizu, M Iyo
    AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS 124B(1) 61-63 2004年1月  
    Several lines of evidence suggest that a certain type of personality or temperament is at risk for developing neuropsychiatric diseases, and that brain-derived neurotrophic factor (BDNF) might be involved in pathophysiology of neuropsychiatric diseases such as mood disorders. Considering the role of BDNF and personality traits in the neuropsychiatric diseases, it is of interest to examine the association between BDNF gene polymorphism and personality test scores. In this study, we examined the association between 196 G/A the polymorphism. in the coding region of the BDNF gene and personality traits scores (temperament and character inventory (TCI) and NEO personality inventory (NEO-PI)) in Japanese healthy subjects. We found that female, but not male, subjects with BDNF genotype A/A have high scores in reward dependence on TCI and high scores in extraversion on NEO-PI as compared with other genotypes (G/A or G/G), suggesting an association between reward dependence (or extraversion) personality traits and BDNF genotype in female subjects. Our findings suggest that BDNF 196 G/A polymorphism might be associated with personality traits in female, but not male, healthy subjects. (C) 2003 Wiley-Liss, Inc.
  • M Fujisaki, K Hashimoto, M Iyo, T Chiba
    NEUROSCIENCE 124(1) 247-260 2004年  
    Using pre- and post-training lesions of the amygdalo-hippocampal transition area (AHi), the role of the AHi in the fear conditioning of rats was examined. Pretraining lesions by N-methyl-D-aspartate led to the enhancement of freezing behavior in auditory fear conditioning and contextual conditioning. However, the freezing of post-training-lesioned rats did not differ from that of the sham-lesioned rats. There were several regions of the brain observed in this study in which c-Fos and/or Egr-1 immunoreactive-positive cell expression changed in diverse manners after the test session. In the pretraining lesioned rats that were trained for auditory conditioning, the number of c-Fos and Egr-1 decreased in the infralimbic cortex (IL) and the number of Egr-1 increased in the basomedial amygdaloid nucleus (BM). In the pretraining AHi-lesioned rats that were trained for contextual conditioning, the number of c-Fos increased in the lateral periaqueductal gray (LPAG) and the number of Egr-1 increased in the BM. These results suggest that the AHi plays an important role in the acquisition of memory during conditioning alone, whereas it is improbable that the AHi had an effect on consolidation, retrieval, and expression in the case of either auditory or contextual fear conditioning. The findings also suggest that the freezing behavior was related to the changes in c-Fos and/or Egr-1 in the IL, BM, and LPAG. As in the case of the BM, the number of Egr-1 immunoreactive-positive cells was increased in both experiments, and it was possible that the activation of neurons with high basal levels of expression might be associated with memory retrieval or expression as a freezing behavior observed in the test session. (C) 2004 IBRO. Published by Elsevier Ltd. All rights reserved.
  • Kenji Hashimoto, Naoe Okamura, Eiji Shimizu, Masaomi Iyo
    Current Medicinal Chemistry - Central Nervous System Agents 4(2) 147-154 2004年  
    L-Glutamic acid (glutamate) is a major excitatory amino acid in the nervous system, and it is known that glutamate plays a major role in brain development, affecting neuronal migration, neuronal differentiation, axon genesis, and neuronal survival. Several lines of evidence suggest that a dysfunction in glutamatergic neurotransmission via the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors might be involved in the pathophysiology of schizophrenia. In this review, we discuss the NMDA receptor hypofunction hypothesis of schizophrenia and the role of glutamate in the action of atypical antipsychotic drugs such as clozapine. In addition, as novel targets for therapeutic drugs for the treatment of schizophrenia, we focus on the glycine sites on NMDA receptors, metabotropic glutamate (mGlu) receptors, and AMPA receptors. This review covers known information about agonists for the glycine site on NMDA receptors, the glycine transporter inhibitors, the mGlu II receptor agonists, and the allosteric modulators of AMPA receptors.
  • K Hashimoto, H Tsukada, S Nishiyama, D Fukumoto, T Kakiuchi, E Shimizu, M Iyo
    CURRENT STATUS OF DRUG DEPENDENCE / ABUSE STUDIES: CELLULAR AND MOLECULAR MECHANISMS OF DRUGS OF ABUSE AND NEUROTOXICITY 1025 231-235 2004年  
    Several lines of evidence suggest that oxidative stress might contribute to neurotoxicity in the dopaminergic nerve terminals after administration of methamphetamine (MAP). The present study undertakes to determine whether intravenous administration of N-acetyl-L-cysteine (NAC), a potent antioxidant drug, could attenuate the reduction of dopamine transporter (DAT) in the striatum of monkey brain after administration of MAP. Positron emission tomography (PET) studies demonstrated that repeated administration of MAP (2 mg/kg as a salt, four times at 2-h intervals) significantly decreased the accumulation of radioactovity in the striatum after intravenous administration of [C-11]beta-CFT (for DAT). In contrast, the binding of [C-11]DASB to 5-hydroxytryptamine transporter (5-HTT) in the monkey brain was slightly decreased after the administration of MAP, although the difference was not statistically significant. The binding of [C-11]SCH 23390 to dopamine D-1 receptors in the striatum was also not altered after the administration of MAP. A bolus injection of NAC (150 mg/kg, i.v.) 30 min before administration of MAP and a subsequent continuous infusion of NAC (12 mg/kg/h, i.v.) over 8.5 h significantly attenuated the reduction of DAT in the monkey striatum 3 weeks after the administration of MAP. These results suggest that NAC could attenuate the reduction of DAT in the monkey striatum after repeated administration of MAP. Therefore, it is likely that NAC would be a suitable drug for treatment of neurotoxicity on dopaminergic nerve terminals related to chronic use of MAP in humans.
  • Yoshio Minabe, Kenji Hashimoto, Yukihiko Shiraya, Charles R. Ashby Jr.
    Synapse 51(1) 19-26 2004年1月  
    This study examined the effect of the p.o. administration of the putative atypical antipsychotic drug Y-931 (8-fluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3b] [1,5] benzodiazepine maleate) on the activity of spontaneously active dopamine (DA) neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNC) in anesthetized male Sprague-Dawley rats. This was accomplished using in vivo electrophysiology. The acute p.o. administration of Y-931 did not significantly alter the number of spontaneously active SNC DA neurons compared to vehicle-treated animals. A single p.o. administration of 3 and 10 mg/kg of Y-931 significantly increased and decreased, respectively, the number of spontaneously active VTA DA neurons compared to vehicle-treated animals. The acute administration of 3 mg/kg of Y-931 significantly altered the firing pattern parameters for all spontaneously active SNC DA. The 3 and 10 mg/kg doses of Y-931 significantly increased the degree of bursting and irregular activity of spontaneously active VTA and SNC DA neurons firing in a bursting pattern. The repeated p.o. administration (21 days) of 1, 3, or 10 mg/kg of Y-931 significantly decreased the number of spontaneously active VTA DA neurons but had no significant effect on SNC DA neurons compared to vehicle-treated animals. The repeated administration of Y-931 did not significantly alter the firing pattern of all spontaneously active SNC or VTA DA neurons. Our findings indicate that the acute and chronic administration of Y-931 significantly alters the activity of midbrain DA neurons in rats and the electrophysiological profile of chronic Y-931 resembles that of atypical antipsychotic agents. © 2003 Wiley-Liss, Inc.
  • M Fujisaki, K Hashimoto, M Iyo, T Chiba
    NEUROSCIENCE 124(1) 247-260 2004年  
    Using pre- and post-training lesions of the amygdalo-hippocampal transition area (AHi), the role of the AHi in the fear conditioning of rats was examined. Pretraining lesions by N-methyl-D-aspartate led to the enhancement of freezing behavior in auditory fear conditioning and contextual conditioning. However, the freezing of post-training-lesioned rats did not differ from that of the sham-lesioned rats. There were several regions of the brain observed in this study in which c-Fos and/or Egr-1 immunoreactive-positive cell expression changed in diverse manners after the test session. In the pretraining lesioned rats that were trained for auditory conditioning, the number of c-Fos and Egr-1 decreased in the infralimbic cortex (IL) and the number of Egr-1 increased in the basomedial amygdaloid nucleus (BM). In the pretraining AHi-lesioned rats that were trained for contextual conditioning, the number of c-Fos increased in the lateral periaqueductal gray (LPAG) and the number of Egr-1 increased in the BM. These results suggest that the AHi plays an important role in the acquisition of memory during conditioning alone, whereas it is improbable that the AHi had an effect on consolidation, retrieval, and expression in the case of either auditory or contextual fear conditioning. The findings also suggest that the freezing behavior was related to the changes in c-Fos and/or Egr-1 in the IL, BM, and LPAG. As in the case of the BM, the number of Egr-1 immunoreactive-positive cells was increased in both experiments, and it was possible that the activation of neurons with high basal levels of expression might be associated with memory retrieval or expression as a freezing behavior observed in the test session. (C) 2004 IBRO. Published by Elsevier Ltd. All rights reserved.
  • 清水 栄司, 橋本 謙二, SALAMA Ragaa H. M, 渡邉 博幸, 小松 尚也, 岡村 斉恵, 小池 香, 篠田 直之, 中里 道子, 熊切 力, 岡田 真一, 村松 寿子, 村松 喬, 伊豫 雅臣
    日本神経精神薬理学雑誌 = Japanese journal of psychopharmacology 23(6) 264-264 2003年12月25日  
  • Y Minabe, L Schechter, K Hashimoto, Y Shirayama, CR Ashby
    SYNAPSE 50(3) 181-190 2003年12月  
    In this study, we examined the effect of the acute and chronic administration of WAY-405, a selective 5-HT(1A) receptor antagonist, on the number and firing pattern of spontaneously active substantia nigra pars compacta (A9) and ventral tegmental area (A10) dopamine (DA) neurons in anesthetized rats. This was accomplished using in vivo, extracellular single unit recording. The i.v. administration of WAY-405 (5-640 mug/kg) did not significantly alter the basal firing rate or pattern of spontaneously active A9 and A10 DA neurons. A single injection of 10 mug/kg of WAY-405 decreased the number of spontaneously active A10 DA neurons and the 100 mug/kg dose significantly decreased the number of spontaneously active A9 and A10 DA neurons compared to vehicle-treated animals. A single injection of 1, 10, or 100 mug/kg of WAY-405 significantly decreased the degree of bursting of A10 DA neurons. In contrast, 1 mug/kg i.p. of WAY-405 significantly increased the percent of A9 DA neurons exhibiting a bursting pattern. The repeated administration of 10 or 100 mug/kg i.p. of WAY-405 (21 days) significantly decreased the number of spontaneously active DA neurons in both the A9 and A10 compared to vehicle-treated animals and this decrease was not reversed by i.v. (+)-apomorphine. The repeated administration of WAY-405 significantly altered the firing pattern of DA neurons, particularly those in the A10 area. Overall, these results indicate that the antagonism of the 5-HT(1A) receptor significantly alters the activity of midbrain DA neurons in anesthetized rats. (C) 2003 Wiley-Liss, Inc.
  • E Shimizu, K Hashimoto, H Watanabe, N Komatsu, N Okamura, K Koike, N Shinoda, M Nakazato, C Kumakiri, S Okada, M Iyo
    NEUROSCIENCE LETTERS 351(2) 111-114 2003年11月  
    Our previous study showed that serum brain-derived neurotrophic factor (BDNF) was significantly decreased in the antidepressant-naive patients with major depressive disorders. However, it was still unclear whether serum BDNF level was altered in drug-naive patients with schizophrenia. Using ELISA, we measured serum BDNF levels in antipsychotic-naive (n = 15) and medicated (n = 25) patients with schizophrenia, and in age- and sex-matched normal controls (n = 40). There were no significant differences in serum BDNF levels among antipsychotic-naive (n = 15) and medicated (n = 25) patients and normal controls (n = 40). Possible factors such as duration of illness, age of onset, Brief Psychiatric Rating Scale scores, and chlorpromazine equivalent dosages of antipsychotics did not reveal any significant correlations with BDNF levels. Our results do not support the view that serum BDNF levels are associated with schizophrenia. (C) 2003 Elsevier Ireland Ltd. All rights reserved.
  • N Okamura, K Hashimoto, E Shimizu, K Koike, S Ohgake, H Koizumi, C Kumakiri, N Komatsu, M Iyo
    BRAIN RESEARCH 992(1) 114-119 2003年11月  
    In the present study, we examined the effects of LY379268, the group II metabotropic glutamate receptor (mGluR) agonist, on the neuropathological changes in the rat retrosplenial cortex induced by noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine ((+)-MK-801). Administration of LY379268 (1, 3, 10 mg/kg, i.p.) reduced dizocilpine (0.5 mg/kg, i.p.)-induced neuropathological changes in the retrosplenial cortex, in a dose-dependent manner. Co-administration of LY379268 (10 mg/kg, i.p.) with group 11 mGluR antagonist LY341495 (5 mg/kg, i.p.) blocked the effects of LY379268. Furthermore, LY379268 (10 mg/kg, i.p.) significantly reduced the expression of heat shock protein HSP-70, a marker of reversible neuronal injury, in the rat retrosplenial cortex after administration of dizocilpine (0.5 mg/kg, i.p.). Moreover, pretreatment with LY379268 (10 mg/kg, i.p.) significantly suppressed the increase in extracellular acetylcholine (ACh) levels in the retrosplenial cortex induced by administration of dizocilpine (0.5 mg/kg, i.p.). These results suggest that LY379268 has a protective effect on the neurotoxicity in the rat retrosplenial cortex after administration of NMDA receptor antagonists such as dizocilpine. (C) 2003 Elsevier B.V. All rights reserved.
  • K Hashimoto, E Shimizu, N Komatsu, M Nakazato, N Okamura, H Watanabe, C Kumakiri, N Shinoda, S Okada, N Takei, M Iyo
    PSYCHIATRY RESEARCH 120(3) 211-218 2003年10月  
    Basic fibroblast growth factor (bFGF) is a multifunctional growth factor that has been implicated in a variety of neurodevelopmental processes. The aim of the present study was to examine whether bFGF contributes to the pathophysiology of schizophrenia. Serum bFGF levels in 40 patients with schizophrenia (15 drug-naive and 25 medicated patients) and in 40 age- and sex-matched healthy normal controls were measured. Serum bFGF levels were significantly higher in the medicated patients than in the normal controls. Analysis of partial correlation coefficients showed that the increased bFGF levels might not be attributable to antipsychotic medication. Although there was no significant overall difference in bFGF levels between drug-naive patients and normal controls, the bFGF levels in these patients significantly correlated with the severity of negative symptoms. Furthermore, we found a significant negative correlation between serum bFGF levels and the age of onset in the entire patient group. Our finding of elevated bFGF levels in the serum of patients with schizophrenia, especially in earlier age-of-onset cases considered to have more neurodevelopmental insults, suggests that bFGF abnormalities may be involved in the pathophysiology of schizophrenia. (C) 2003 Elsevier Ireland Ltd. All rights reserved.
  • H Okamoto, Y Shino, K Hashimoto, C Kumakiri, E Shimizu, H Shirasawa, M Iyo
    NEUROPHARMACOLOGY 45(2) 251-259 2003年8月  
    The present study was undertaken to examine the effects of the antidepressant, amitriptyline, and brain-derived neurotrophic factor (BDNF) on activator protein-1 (AP-1) DNA binding activity in the rat brain. Acute administration of amitriptyline (5 or 10 mg/kg) initially increased but then decreased AP-1 DNA binding activity in the rat frontal cortex and hippocampus. Chronic administration of amitriptyline (5 or 10 mg/kg, once daily for 3 weeks) initially decreased AP-1 DNA binding activity but ultimately resulted in its persistent elevation in the rat frontal cortex. In contrast, the chronic administration of amitriptyline did not affect the low activity of AP-1 DNA binding in the hippocampus. However, chronic administration of amitriptyline (10 mg/kg, once daily for 3 weeks) significantly increased BDNF protein levels in the hippocampus (by 26.9%) and frontal cortex (by 24.6%). Direct infusion of BDNF (1 mug) into the hippocampal dentate gyrus significantly increased hippocampal AP-1 DNA binding activity. These results suggest that AP-1 transcription factor may be modulated by BDNF and that it may be an important target for the action of antidepressants. (C) 2003 Elsevier Science Ltd. All rights reserved.
  • M Nakazato, K Hashimoto, E Shimizu, C Kumakiri, H Koizumi, N Okamura, M Mitsumori, N Komatsu, M Iyo
    BIOLOGICAL PSYCHIATRY 54(4) 485-490 2003年8月  
    Background: Several lines of evidence suggest that brain-derived neurotrophic factor (BDNF) plays a role in the regulation of eating behavior. Because of its role in eating behavior, which is especially relevant to eating disorders, BDNF is an attractive candidate for investigation of potential biological markers of eating disorders such as bulimia nervosa (BN) and anorexia nervosa (AN). Methods: We enrolled 18 female patients with BN, 12 female patients with AN, and 21 age-matched female normal control subjects in this study. Eating-related psychopathology and depressive symptoms were evaluated using the Bulimic Investigatory Test, Edinburgh (BITE) and the Hamilton Depression Rating Scale (HDRS). Serum BDNF levels were measured by a sandwich enzyme-linked inummosorbent assay. Results: Serum levels of BDNF in the patients with AN or BN were significantly (p < .0001) decreased compared with those of normal control subjects, and serum BDNF levels in the patients with AN were significantly (p = .027) lower than those in patients with BN. A significant positive correlation (r = .378, p = .006) between serum BDNF levels and body mass index in all of the subjects was detected. Furthermore, there was a significant positive correlation (r = .435, p = .015) between the BITE symptom scale score and HDRS in these patients. Conclusions: The present study suggests that BDNF may play a role in the pathophysiology of eating disorders. (C) 2003 Society of Biological Psychiatry
  • 岡村 斉恵, 橋本 謙二, 清水 栄司, 熊切 力, 小松 尚也, 伊豫 雅臣, 金原 信久
    千葉医学雑誌 = Chiba medical journal 79(4) 158-158 2003年8月1日  
  • E Shimizu, K Hashimoto, N Okamura, K Koike, N Komatsu, C Kumakiri, M Nakazato, H Watanabe, N Shinoda, S Okada, M Iyo
    BIOLOGICAL PSYCHIATRY 54(1) 70-75 2003年7月  
    Background: Because researchers have reported that antidepressants increase the expression of brain-derived neurotrophic factor (BDNF) in the rat hippocampus, we investigated whether serum BDNF levels may be used as a putative biological marker for major depressive disorders (MDD). Methods: We measured serum BDNF in the following three groups: antidepressant-naive patients with MDD (n = 16), antidepressant-treated patients with MDD (n = 17), and normal control subjects (n = 50). Patients were evaluated using the Hamilton Rating Scale for Depression (HAM-D). Serum BDNF was assayed with the sandwich ELISA method. Results: We found that serum BDNF was significantly lower in the antidepressant-naive group (mean, 17.6 ng/mL; SD, 9.6) than in the treated (mean, 30.6 ng/mL; SD, 12.3; p =.001) or in the control group (mean, 27.7 ng/mL; SD, 11.4; p = .002). There was a significant negative correlation (r = -.350, z = -2.003, p =.045) between serum BDNF and HAM-D scores in all patients. In a preliminary examination, reduced BDNF values of three drug-naive patients recovered to basal levels after antidepressant treatment. Conclusions: Our study suggests that low BDNF levels may play a pivotal role in the pathophysiology of MDD and that antidepressants may increase BDNF in depressed patients. Biol Psychiatry 2003;54:70-75 (C) 2003 Society of Biological Psychiatry.
  • E Shimizu, K Hashimoto, RHM Salama, H Watanabe, N Komatsu, N Okamura, K Koike, N Shinoda, M Nakazato, C Kumakiri, S Okada, H Muramatsu, T Muramatsu, M Iyo
    NEUROSCIENCE LETTERS 344(2) 95-98 2003年6月  
    Midkine (MK) is a heparin-binding growth factor implicated in various biological phenomena such as development of the hippocampus and anxiety. We evaluated serum MK levels of drug-naive (n = 15) and medicated (n = 25) patients with schizophrenia, and age- and sex-matched normal controls (n = 38). The patients showed two clusters in the levels. Four drug-naive patients (26.7%) and two medicated patients (8.0%) had abnormally high values, but no controls did, there being a significant difference in the numbers (P = 0.003, Fisher's exact test). Furthermore, in other patients, the mean MK levels in drug-naive schizophrenia (0.30 +/- 0.10 ng/ml) were significantly (P = 0.018, Fisher's protected least significant difference test) decreased than those in the controls (0.40 +/- 0.12 ng/ml). These suggest that there are two clusters of serum MK abnormalities in drug-naive patients with schizophrenia. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved.
  • K Hashimoto, T Fukushima, E Shimizu, N Komatsu, H Watanabe, N Shinoda, M Nakazato, C Kumakiri, S Okada, H Hasegawa, K Imai, M Iyo
    ARCHIVES OF GENERAL PSYCHIATRY 60(6) 572-576 2003年6月  
    Background: The hypofunction of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors has been implicated in the pathophysiology of schizophrenia. Several lines of evidence suggest that D-serine may function as an endogenous agonist of the glycine site of the NMDA receptor. The aim of this study was to examine whether serum levels of D- and L-serine in patients with schizophrenia are different from those of healthy controls. Methods: Forty-two patients with schizophrenia and 42 age- and sex-matched healthy controls were enrolled in this study. Symptoms were assessed using the Brief Psychiatric Rating Scale. Serum levels of total serine and D and L-serine were measured by high-performance liquid chromatography. Results: Serum levels of D-serine in the patients with schizophrenia were significantly (z=-3.30, P=.001) lower than those of healthy controls. In contrast, serum levels of total (D and L) serine (z=-2.40, P=.02) and L-serine (z=-2.49, P=.01) in the schizophrenic patients were significantly higher than those of controls. In addition, the percentage of D-serine in the total serine in the schizo phrenic patients was significantly (z=-4.78, P<.001) lower than that of controls, suggesting that the activity of serine racemase, an enzyme catalyzing the formation of D-serine from L-serine, may have been reduced in the schizophrenic patients. Conclusions: Reduced levels of D-serine may play a role in the pathophysiology of schizophrenia, and serum D-and L-serine levels might provide a measurable biological marker for schizophrenia.
  • N Okamura, K Hashimoto, N Kanahara, E Shimizu, C Kumakiri, N Komatsu, M Iyo
    EUROPEAN JOURNAL OF PHARMACOLOGY 461(2-3) 93-98 2003年2月  
    An atypical antipsychotic drug, zotepine, which is pharmacologically and clinically related to clozapine, has unique therapeutic effects on patients with schizophrenia. It has been demonstrated that clozapine blocks neurotoxicity in the rat retrosplenial cortex induced by administration of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine ((+)-MK-801). We examined whether or not zotepine has the ability to block neurotoxicity in the rat retrosplenial cortex induced by administration of dizocilpine. Female Sprague-Dawley rats were injected intraperitoneally (i.p.) with vehicle (1 mg/kg), zotepine (5, 10 or 20 mg/kg) or clozapine (20 mg/kg). Fifteen minutes later, animals were injected intraperitoneally (i.p.) with vehicle (1 ml/kg) or dizocilpine (0.5 mg/kg). Neuropathological changes (neuronal vacuolization) were assessed 4 h after administration of dizocilpine. Immunohistochemical analysis of heat shock protein HSP-70, a marker of reversible neuronal injury, was performed 24 h after administration of dizocilpine. The pretreatment with zotepine (5, 10 or 20 mg/kg) significantly decreased the number of vacuolized neurons in the rat retrosplenial cortex 4 h after the administration of dizocilpine (0.5 mg/kg), in a dose-dependent manner. The potency of zotepine (20 mg/kg) for dizocilpine-induced neurotoxicity was similar to that of clozapine (20 mg/kg). Furthermore, similar to the case with clozapine (20 mg/kg, i.p.), zotepine (20 mg/kg, i.p.) significantly attenuated the expression of HSP-70 in the rat retrosplenial cortex induced by dizocilpine (0.5 mg/kg, i.p.). The present study suggests that the neuroprotective effects of zotepine- on dizocilpine-induced neurotoxicity are equipotent to those of clozapine. Based on the NMDA receptor hypofunction hypothesis of schizophrenia, the efficacy of zotepine in this study may partly contribute to the unique therapeutic effects of zotepine in patients with schizophrenia. (C) 2003 Elsevier Science B.V. All rights reserved.
  • 清水 栄司, 橋本 謙二, 小松 尚也, 伊豫 雅臣
    日本神経精神薬理学雑誌 = Japanese journal of psychopharmacology 22(6) 294-294 2002年12月25日  
  • 深見 悟郎, 橋本 謙二, 小池 香, 岡村 斉恵, 清水 栄司, 伊豫 雅臣
    日本神経精神薬理学雑誌 = Japanese journal of psychopharmacology 22(6) 293-293 2002年12月25日  
  • 岡村 斉恵, 橋本 謙二, 伊豫 雅臣
    千葉医学雑誌 78(5) 236-236 2002年10月1日  

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