Researcher Profile and Settings

Master

Affiliation (Master)

• Faculty of Medicine　Physiological Science　Pharmacology

Affiliation (Master)

• Faculty of Medicine　Physiological Science　Pharmacology

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Profile and Settings

Affiliation

• Department of Neuropharmacology, Hokkaido University Graduate Shool of Medicine

Profile and Settings

• Name (Japanese)

  Naganuma

• Name (Kana)

  Fumito

• Name

  201501089923113025

Alternate Names

https://kaken.nii.ac.jp/d/p/14J07936.ja.html

Affiliation

• Department of Neuropharmacology, Hokkaido University Graduate Shool of Medicine

Achievement

Research Interests

• 神経ペプチド   Sleep   睡眠   Comprihensive Brain Science Network   histamine N-methyltransferase   monoamine transporter   Histamine   

Research Areas

• Life sciences / Neuroscience - general
• Life sciences / Pharmacology / Pharmacology

Research Experience

• 2023/07 - Today 北海道大学大学院医学研究院神経薬理学教室 講師
• 2016/04 - 2023/06 Tohoku Medical and Pharmaceutical Univ. Division of Pharmacology Assistant professor
• 2016/04 - 2018/09 Beth Israel Deaconess Medical Center (Harvard Medical School) Neurology Post-Doctoral Fellow
• 2014/04 - 2016/03 Japan Society for the Promotion of Science Research Fellow (DC)
• 2013/04 - 2016/03 Tohoku Univ. Division For International Advanced Research and Education PhD student

Education

• 2012/04 - 2016/03  Tohoku Univ. graduate school of Medicine  Ph.D. student
• 2010/04 - 2012/03  Tohoku Univ. graduate school of Medicine  Master corse student

Awards

• 2022/12 第96回日本薬理学会年会 優秀ポスター賞
  
• 2021/06 Nishinomiya Basic Research Fund, Japan
   

  受賞者: Fumito Naganuma
• 2017/04 日本私立学校振興・共済事業団 The Science Research Promotion Fund
   若手研究者奨励金 

  受賞者: Fumito Naganuma
• 2015/09 日本神経化学会 神経化学教育口演優秀発表賞
   

  受賞者: 長沼史登
• 2015/05 ヨーロッパヒスタミン学会 奨学賞
  
• 2015/05 European histamine research society First prize in young investigator award
   

  受賞者: Fumito Naganuma
• 2015/03 日本薬理学会 第88回日本薬理学会年会 年会優秀発表賞
   

  受賞者: 長沼史登
• 2015/01 東北医学会 東北医学会奨学賞
   

  受賞者: 長沼史登
• 2014/10 第18回日本ヒスタミン学会 Young Investigator Award（和田賞）
  
• 2014/05 独立行政法人 日本学生支援機構 第１種奨学金返還免除
  
• 2014/01 東北大学大学院第7回リトリート大学院生研究発表会 最優秀ポスター賞
  
• 2013/10 東北大学大学院 ブースター研究助成
  
• 2013/01 東北大学大学院第6回リトリート大学院生研究発表会 優秀ポスター賞
  
• 2012/10 東北大学大学院 スターター研究助成
  
• 2012/09 菅原医学振興基金
   受賞
• 2012/02 東北大学大学院医学系研究科 辛酉優秀学生賞
   

  受賞者: 長沼史登
• 2012/01 The 21st Korea-Japan Joint Seminar on Pharmacology Outstanding Poster Presentation
  
• 2011/11 日本学術振興会 組織的な若手研究者等海外派遣プログラム
  
• 2011/01 東北大学大学院第6回リトリート大学院生研究発表会 優秀ポスター賞
  

Published Papers

• A Novel Near-Infrared Fluorescence Probe THK-565 Enables In Vivo Detection of Amyloid Deposits in Alzheimer's Disease Mouse Model.

  Fumito Naganuma, Daiki Murata, Marie Inoue, Yuri Maehori, Ryuichi Harada, Shozo Furumoto, Yukitsuka Kudo, Tadaho Nakamura, Nobuyuki Okamura

  Molecular imaging and biology 2023/08/14 

  PURPOSE: Noninvasive imaging of protein aggregates in the brain is critical for the early diagnosis, disease monitoring, and evaluation of the effectiveness of novel therapies for Alzheimer's disease (AD). Near-infrared fluorescence (NIRF) imaging with specific probes is a promising technique for the in vivo detection of protein deposits without radiation exposure. Comprehensive screening of fluorescent compounds identified a novel compound, THK-565, for the in vivo imaging of amyloid-β (Aβ) deposits in the mouse brain. This study assessed whether THK-565 could detect amyloid-β deposits in vivo in the AD mouse model. PROCEDURES: The fluorescent properties of THK-565 were evaluated in the presence and absence of Aβ fibrils. APP knock-in (APP-KI) mice were used as an animal model of AD. In vivo NIRF images were acquired after the intravenous administration of THK-565 and THK-265 in mice. The binding selectivity of THK-565 to Aβ was evaluated using brain slices obtained from these mouse models. RESULTS: The fluorescence intensity of the THK-565 solution substantially increased by mixing with Aβ fibrils. The maximum emission wavelength of the complex of THK-565 and Aβ fibrils was 704 nm, which was within the optical window range. THK-565 selectively bound to amyloid deposits in brain sections of APP-KI mice After the intravenous administration of THK-565, the fluorescence signal in the head of APP-KI mice was significantly higher than that of wild-type mice and higher than that after administration of THK-265. Ex vivo analysis confirmed that the THK-565 signal corresponded to Aβ immunostaining in the brain sections of these mice. CONCLUSIONS: A novel NIRF probe, THK-565, enabled the in vivo detection of Aβ deposits in the brains of the AD mouse model, suggesting that NIRF imaging with THK-565 could non-invasively assess disease-specific pathology in AD.
• In vivo [18F]THK-5351 imaging detected reactive astrogliosis in argyrophilic grain disease with comorbid pathology: A clinicopathological study.

  Ryota Kobayashi, Tadaho Nakamura, Fumito Naganuma, Ryuichi Harada, Daichi Morioka, Masafumi Kanoto, Shozo Furumoto, Yukitsuka Kudo, Takanobu Kabasawa, Koichi Otani, Mitsuru Futakuchi, Shinobu Kawakatsu, Nobuyuki Okamura

  Journal of neuropathology and experimental neurology 82 (5) 427 - 437 2023/03/07 [Refereed]
   

  Quantification of in vivo reactive astrogliosis, which represents neural inflammation and remodeling in the brain, is an emerging methodology for the evaluation of patients with neurodegenerative diseases. [18F]THK-5351 is a positron emission tomography (PET) tracer for monoamine oxidase B (MAO-B), a molecular marker of reactive astrogliosis. We performed in vivo [18F]THK-5351 PET in a patient who at autopsy was found to have argyrophilic grain disease (AGD) with comorbid pathology to visualize reactive astrogliosis for the first time. We aimed to validate an imaging-pathology correlation using [18F]THK-5351 PET and the autopsy brain. The patient, a 78-year-old man, was pathologically diagnosed with AGD combined with limbic-predominant age-related transactive response DNA-binding protein of 43 kDa encephalopathy and Lewy body disease without Alzheimer disease-related neuropathological changes. Reactive astrogliosis in the postmortem brain was abundant in the inferior temporal gyrus, insular gyrus, entorhinal cortex, and ambient gyrus where premortem [18F]THK-5351 signals were high. We found a proportional correlation between the amount of reactive astrogliosis in the postmortem brain and the in vivo [18F]THK-5351 standardized uptake value ratio (r = 0.8535, p = 0.0004). These results indicated that reactive astrogliosis in AGD with comorbid pathology could be identified and quantified by in vivo MAO-B imaging.
• Oral histidine intake improves working memory through the activation of histaminergic nervous system in mice.

  Tadaho Nakamura, Fumito Naganuma, Uta Kudomi, Sueji Roh, Kazuhiko Yanai, Takeo Yoshikawa

  Biochemical and biophysical research communications 609 141 - 148 2022/04/09 [Refereed]
   

  Histamine is synthesised from l-histidine through the catalysis of histidine decarboxylase (HDC). In the central nervous system (CNS), histamine is exclusively produced in histaminergic neurons located in the posterior hypothalamus and controls various CNS functions. Although histidine was known as a precursor of histamine, the impact of oral histidine intake on brain histamine concentration and brain function has not been fully elucidated. In the present study, we aimed to elucidate the importance of oral histidine supplementation in the histaminergic nervous system and working memory in stressful conditions. First, we confirmed that sleep deprivation by water-floor stress in male mice increased histamine consumption and resulted in histamine reduction and impaired working memory in the Y-maze test. This memory impairment was rescued by intracerebroventricular injection of histamine and histidine, indicating that oral histidine intake could also improve memory function. Next, we examined the impact of histidine intake on brain histamine concentration and neuronal activity. Histidine intake increased extracellular histamine concentration around the prefrontal cortex (PFC) and the basal forebrain (BF), leading to a robust increase in the number of c-fos-positive cells around these areas. Finally, we investigated the beneficial effects of histidine intake on working memory. Histidine supplementation alleviated impaired memory function induced by sleep deprivation. This beneficial effect of histidine on memory was cancelled by intracerebroventricular injection of the HDC inhibitor α-fluoromethylhistidine. These results demonstrate that oral histidine intake replenishes brain histamine and leads to the recovery of impaired working memory induced by sleep deprivation through histaminergic activation.
• Contribution of astrocytic histamine N-methyltransferase to histamine clearance and brain function in mice

  Rina Otsuka, Fumito Naganuma, Tadaho Nakamura, Hideki Miwa, Rumi Nakayama-Naono, Takuro Matsuzawa, Yurika Komatsu, Yuki Sato, Yuna Takahashi, Haruna Tatsuoka-Kitano, Kazuhiko Yanai, Takeo Yoshikawa

  Neuropharmacology 212 109065 - 109065 0028-3908 2022/04 

  Brain histamine acts as a neurotransmitter in the regulation of various brain activities. Previous studies have shown that histamine N-methyltransferase (HNMT), a histamine-metabolizing enzyme, controls brain histamine concentration and brain function. However, the relative contribution of astrocytic or neuronal HNMT to the regulation of the histaminergic system is still inconclusive. Here, we phenotyped astrocytes-specific HNMT knockout (cKO) mice to clarify the involvement of astrocytic HNMT in histamine clearance and brain function. First, we performed histological examinations using HNMT reporter mice and showed a wide distribution of HNMT in the brain and astrocytic HNMT expression. Then, we created cKO mice by Cre-loxP system and confirmed that HNMT expression in cKO primary astrocytes was robustly decreased. Although total HNMT level in the cortex was not substantially different between control and cKO brains, histamine concentration after histamine release was elevated in cKO cortex. In behavioral tests, impaired motor coordination and lower locomotor activity were observed in the cKO mice. However, anxiety-like behaviors, depression-like behaviors, and memory functions were not altered by astrocytic HNMT disruption. Although sleep analysis demonstrated that the quantity of wakefulness and sleep did not change, the increased power density of delta frequency during wakefulness indicated lower cortical activation in cKO mice. These results demonstrate that astrocytic HNMT contributes to histamine clearance after histamine release in the cortex and plays a role in the regulation of motor coordination, locomotor activity, and vigilance state.
• Chemogenetic modulation of histaminergic neurons in the tuberomamillary nucleus alters territorial aggression and wakefulness.

  Fumito Naganuma, Tadaho Nakamura, Hiroshi Kuroyanagi, Masato Tanaka, Takeo Yoshikawa, Kazuhiko Yanai, Nobuyuki Okamura

  Scientific reports 11 (1) 17935 - 17935 2045-2322 2021/09/09 

  Designer receptor activated by designer drugs (DREADDs) techniques are widely used to modulate the activities of specific neuronal populations during behavioural tasks. However, DREADDs-induced modulation of histaminergic neurons in the tuberomamillary nucleus (HATMN neurons) has produced inconsistent effects on the sleep-wake cycle, possibly due to the use of Hdc-Cre mice driving Cre recombinase and DREADDs activity outside the targeted region. Moreover, previous DREADDs studies have not examined locomotor activity and aggressive behaviours, which are also regulated by brain histamine levels. In the present study, we investigated the effects of HATMN activation and inhibition on the locomotor activity, aggressive behaviours and sleep-wake cycle of Hdc-Cre mice with minimal non-target expression of Cre-recombinase. Chemoactivation of HATMN moderately enhanced locomotor activity in a novel open field. Activation of HATMN neurons significantly enhanced aggressive behaviour in the resident-intruder test. Wakefulness was increased and non-rapid eye movement (NREM) sleep decreased for an hour by HATMN chemoactivation. Conversely HATMN chemoinhibition decreased wakefulness and increased NREM sleep for 6 h. These changes in wakefulness induced by HATMN modulation were related to the maintenance of vigilance state. These results indicate the influences of HATMN neurons on exploratory activity, territorial aggression, and wake maintenance.
• Lateral hypothalamic neurotensin neurons strongly promote arousal

  Fumito Naganuma, Tadaho Nakamura, Nobuyuki Okamura

  Medical Science Digest (株)ニュー・サイエンス社 47 (8) 430 - 431 1347-4340 2021/07 [Not refereed][Invited]
   

  視床下部外側(LH)は覚醒に重要な脳部位であるが、その神経分子機構は未だ不明なままである。我々はLHに多くの神経核を有するニューロテンシン神経細胞(NtsLH)に着目し、これらが覚醒の調節に関与しているか検討を行っている。NtsLHを長時間活性化すると、マウスは4時間以上1度も入眠せず覚醒し続ける。これに対し、NtsLHをNREM睡眠中に活性化した場合、マウスはほぼ毎回覚醒する。これらのことからNtsLHは強力な覚醒維持作用に加え、NREM睡眠から覚醒への遷移に重要であると考えられる。また神経トレーシング法では、覚醒に重要な脳部位でNtsLHの神経線維が認められている。以上の結果から、NtsLHが有する覚醒調節機構にはこれらの投射先脳部位が重要である可能性が示唆された。今後、NtsLHを中心とした覚醒を司る神経回路基盤の解明により、睡眠障害の新たな病態の理解や治療標的の開発に繋がることが期待される。(著者抄録)
• Organic Cation Transporters in Brain Histamine Clearance: Physiological and Psychiatric Implications.

  Fumito Naganuma, Takeo Yoshikawa

  Handbook of experimental pharmacology 266 169 - 185 2021 [Refereed]
   

  Histamine acts as a neurotransmitter in the central nervous system and is involved in numerous physiological functions. Recent studies have identified the causative role of decreased histaminergic systems in various neurological disorders. Thus, the brain histamine system has attracted attention as a therapeutic target to improve brain function. Neurotransmitter clearance is one of the most important processes for the regulation of neuronal activity and is an essential target for diverse drugs. Our previous study has shown the importance of histamine N-methyltransferase for the inactivation of brain histamine and the intracellular localization of this enzyme; the study indicated that the transport system for the movement of positively charged histamine from the extracellular to intracellular space is a prerequisite for histamine inactivation. Several studies on in vitro astrocytic histamine transport have indicated the contribution of organic cation transporter 3 (OCT3) and plasma membrane monoamine transporter (PMAT) in histamine uptake, although the importance of these transporters in in vivo histamine clearance remains unknown. Immunohistochemical analyses have revealed the expression of OCT3 and PMAT on neurons, emphasizing the importance of investigating neuronal histamine uptake. Further studies using knockout mice or fast-scan cyclic voltammetry will accelerate the research on histamine transporters. In this review article, we summarize histamine transport assays and describe the candidate transporters responsible for histamine transport in the brain.
• Sleep-Wake Control by Melanin-Concentrating Hormone (MCH) Neurons: a Review of Recent Findings.

  Sathyajit S Bandaru, Mudasir A Khanday, Nazifa Ibrahim, Fumito Naganuma, Ramalingam Vetrivelan

  Current neurology and neuroscience reports 20 (12) 55 - 55 1528-4042 2020/10/02 [Refereed][Not invited]
   

  PURPOSE OF THE REVIEW: Melanin-concentrating hormone (MCH)-expressing neurons located in the lateral hypothalamus are considered as an integral component of sleep-wake circuitry. However, the precise role of MCH neurons in sleep-wake regulation has remained unclear, despite several years of research employing a wide range of techniques. We review recent data on this aspect, which are mostly inconsistent, and propose a novel role for MCH neurons in sleep regulation. RECENT FINDINGS: While almost all studies using "gain-of-function" approaches show an increase in rapid eye movement sleep (or paradoxical sleep; PS), loss-of-function approaches have not shown reductions in PS. Similarly, the reported changes in wakefulness or non-rapid eye movement sleep (slow-wave sleep; SWS) with manipulation of the MCH system using conditional genetic methods are inconsistent. Currently available data do not support a role for MCH neurons in spontaneous sleep-wake but imply a crucial role for them in orchestrating sleep-wake responses to changes in external and internal environments.
• Chronic brain histamine depletion in adult mice induced depression-like behaviors and impaired sleep-wake cycle

  Y Yamada, T Yoshikawa, F Naganuma, T Kikkawa, N Osumi, K Yanai

  Neuropharmacology 15 (175) 1081179 - 108179 0028-3908 2020/09 [Refereed][Not invited]
   

  Histamine acts as a neurotransmitter to regulate various physiological processes. Brain histamine is synthesized from an essential amino acid histidine in a reaction catalysed by histidine decarboxylase (Hdc). Hdc-positive neurons exist mainly in the tuberomammillary nucleus (TMN) of the posterior hypothalamus and project their axons to the entire brain. Recent studies have reported that a chronic decrease in histamine levels in the adult human brain was observed in several neurological disorders. However, it is poorly understood whether lower histamine levels play a causative role in those disorders. In the present study, we induced chronic histamine deficiency in the brains of adult mice to allow direct interpretation of the relationship between an impaired histaminergic nervous system and the resultant phenotype. To induce chronic brain histamine deficiency starting in adulthood, adeno-associated virus expressing Cre recombinase was microinjected into the TMN of Hdc flox mice (cKO mice) at the age of 8 weeks. Immunohistochemical analysis showed expression of Cre recombinase in the TMN of cKO mice. The reduction of histamine contents with the decreased Hdc expression in cKO brain was also confirmed. Behavioural studies revealed that chronic histamine depletion in cKO mice induced depression-like behaviour, decreased locomotor activity in the home cage, and impaired aversive memory. Sleep analysis showed that cKO mice exhibited a decrease in wakefulness and increase in non-rapid eye movement sleep throughout the day. Taken together, this study clearly demonstrates that chronic histamine depletion in the adult mouse brain plays a causative role in brain dysfunction.
• Histamine H1 receptor on astrocytes and neurons controls distinct aspects of mouse behaviour.

  Anikó Kárpáti, Takeo Yoshikawa, Fumito Naganuma, Takuro Matsuzawa, Haruna Kitano, Yo Yamada, Mariko Yokoyama, Akira Futatsugi, Katsuhiko Mikoshiba, Kazuhiko Yanai

  Scientific reports 9 (1) 16451 - 16451 2045-2322 2019/11/11 [Refereed][Not invited]
   

  Histamine is an important neurotransmitter that contributes to various processes, including the sleep-wake cycle, learning, memory, and stress responses. Its actions are mediated through histamine H1-H4 receptors. Gene knockout and pharmacological studies have revealed the importance of H1 receptors in learning and memory, regulation of aggression, and wakefulness. H1 receptors are abundantly expressed on neurons and astrocytes. However, to date, studies selectively investigating the roles of neuronal and astrocytic H1 receptors in behaviour are lacking. We generated novel astrocyte- and neuron-specific conditional knockout (cKO) mice to address this gap in knowledge. cKO mice showed cell-specific reduction of H1 receptor gene expression. Behavioural assessment revealed significant changes and highlighted the importance of H1 receptors on both astrocytes and neurons. H1 receptors on both cell types played a significant role in anxiety. Astrocytic H1 receptors were involved in regulating aggressive behaviour, circadian rhythms, and quality of wakefulness, but not sleep behaviour. Our results emphasise the roles of neuronal H1 receptors in recognition memory. In conclusion, this study highlights the novel roles of H1 receptors on astrocytes and neurons in various brain functions.
• Lateral hypothalamic neurotensin neurons promote arousal and hyperthermia.

  Fumito Naganuma, Daniel Kroeger, Sathyajit S Bandaru, Gianna Absi, Joseph C Madara, Ramalingam Vetrivelan

  PLoS biology 17 (3) e3000172  1544-9173 2019/03 [Refereed][Not invited]
   

  Sleep and wakefulness are greatly influenced by various physiological and psychological factors, but the neuronal elements responsible for organizing sleep-wake behavior in response to these factors are largely unknown. In this study, we report that a subset of neurons in the lateral hypothalamic area (LH) expressing the neuropeptide neurotensin (Nts) is critical for orchestrating sleep-wake responses to acute psychological and physiological challenges or stressors. We show that selective activation of NtsLH neurons with chemogenetic or optogenetic methods elicits rapid transitions from non-rapid eye movement (NREM) sleep to wakefulness and produces sustained arousal, higher locomotor activity (LMA), and hyperthermia, which are commonly observed after acute stress exposure. On the other hand, selective chemogenetic inhibition of NtsLH neurons attenuates the arousal, LMA, and body temperature (Tb) responses to a psychological stress (a novel environment) and augments the responses to a physiological stress (fasting).
• Melanin-concentrating hormone neurons promote rapid eye movement sleep independent of glutamate release.

  Fumito Naganuma, Sathyajit S Bandaru, Gianna Absi, Melissa J Chee, Ramalingam Vetrivelan

  Brain structure & function 224 (1) 99 - 110 1863-2653 2019/01 [Refereed][Not invited]
   

  Neurons containing melanin-concentrating hormone (MCH) in the posterior lateral hypothalamus play an integral role in rapid eye movement sleep (REMs) regulation. As MCH neurons also contain a variety of other neuropeptides [e.g., cocaine- and amphetamine-regulated transcript (CART) and nesfatin-1] and neurotransmitters (e.g., glutamate), the specific neurotransmitter responsible for REMs regulation is not known. We hypothesized that glutamate, the primary fast-acting neurotransmitter in MCH neurons, is necessary for REMs regulation. To test this hypothesis, we deleted vesicular glutamate transporter (Vglut2; necessary for synaptic release of glutamate) specifically from MCH neurons by crossing MCH-Cre mice (expressing Cre recombinase in MCH neurons) with Vglut2flox/flox mice (expressing LoxP-modified alleles of Vglut2), and studied the amounts, architecture and diurnal variation of sleep-wake states during baseline conditions. We then activated the MCH neurons lacking glutamate neurotransmission using chemogenetic methods and tested whether these MCH neurons still promoted REMs. Our results indicate that glutamate in MCH neurons contributes to normal diurnal variability of REMs by regulating the levels of REMs during the dark period, but MCH neurons can promote REMs even in the absence of glutamate.
• Melanin-concentrating hormone neurons contribute to dysregulation of rapid eye movement sleep in narcolepsy.

  Fumito Naganuma, Sathyajit S Bandaru, Gianna Absi, Carrie E Mahoney, Thomas E Scammell, Ramalingam Vetrivelan

  Neurobiology of disease 120 (120) 12 - 20 2018/12 [Refereed][Not invited]
   

  The lateral hypothalamus contains neurons producing orexins that promote wakefulness and suppress REM sleep as well as neurons producing melanin-concentrating hormone (MCH) that likely promote REM sleep. Narcolepsy with cataplexy is caused by selective loss of the orexin neurons, and the MCH neurons appear unaffected. As the orexin and MCH systems exert opposing effects on REM sleep, we hypothesized that imbalance in this REM sleep-regulating system due to activity in the MCH neurons may contribute to the striking REM sleep dysfunction characteristic of narcolepsy. To test this hypothesis, we chemogenetically activated the MCH neurons and pharmacologically blocked MCH signaling in a murine model of narcolepsy and studied the effects on sleep-wake behavior and cataplexy. To chemoactivate MCH neurons, we injected an adeno-associated viral vector containing the hM3Dq stimulatory DREADD into the lateral hypothalamus of orexin null mice that also express Cre recombinase in the MCH neurons (MCH-Cre::OX-KO mice) and into control MCH-Cre mice with normal orexin expression. In both lines of mice, activation of MCH neurons by clozapine-N-oxide (CNO) increased rapid eye movement (REM) sleep without altering other states. In mice lacking orexins, activation of the MCH neurons also increased abnormal intrusions of REM sleep manifest as cataplexy and short latency transitions into REM sleep (SLREM). Conversely, a MCH receptor 1 antagonist, SNAP 94847, almost completely eliminated SLREM and cataplexy in OX-KO mice. These findings affirm that MCH neurons promote REM sleep under normal circumstances, and their activity in mice lacking orexins likely triggers abnormal intrusions of REM sleep into non-REM sleep and wake, resulting in the SLREM and cataplexy characteristic of narcolepsy.
• Histamine N-methyltransferase regulates aggression and the sleep-wake cycle.

  Fumito Naganuma, Tadaho Nakamura, Takeo Yoshikawa, Tomomitsu Iida, Yamato Miura, Anikó Kárpáti, Takuro Matsuzawa, Atushi Yanai, Asuka Mogi, Takatoshi Mochizuki, Nobuyuki Okamura, Kazuhiko Yanai

  Scientific reports 7 (1) 15899 - 15899 2045-2322 2017/11/21 [Refereed][Not invited]
   

  Histamine is a neurotransmitter that regulates diverse physiological functions including the sleep-wake cycle. Recent studies have reported that histaminergic dysfunction in the brain is associated with neuropsychiatric disorders. Histamine N-methyltransferase (HNMT) is an enzyme expressed in the central nervous system that specifically metabolises histamine; yet, the exact physiological roles of HNMT are unknown. Accordingly, we phenotyped Hnmt knockout mice (KO) to determine the relevance of HNMT to various brain functions. First, we showed that HNMT deficiency enhanced brain histamine concentrations, confirming a role for HNMT in histamine inactivation. Next, we performed comprehensive behavioural testing and determined that KO mice exhibited high aggressive behaviours in the resident-intruder and aggressive biting behaviour tests. High aggression in KO mice was suppressed by treatment with zolantidine, a histamine H2 receptor (H2R) antagonist, indicating that abnormal H2R activation promoted aggression in KO mice. A sleep analysis revealed that KO mice exhibited prolonged bouts of awakening during the light (inactive) period and compensatory sleep during the dark (active) period. Abnormal sleep behaviour was suppressed by treatment with pyrilamine, a H1R antagonist, prior to light period, suggesting that excessive H1R activation led to the dysregulation of sleep-wake cycles in KO mice. These observations inform the physiological roles of HNMT.
• JNJ10181457, a histamine H3 receptor inverse agonist, regulates in vivo microglial functions and improves depression-like behaviours in mice.

  Tomomitsu Iida, Takeo Yoshikawa, Anikó Kárpáti, Takuro Matsuzawa, Haruna Kitano, Asuka Mogi, Ryuichi Harada, Fumito Naganuma, Tadaho Nakamura, Kazuhiko Yanai

  Biochemical and biophysical research communications 488 (3) 534 - 540 0006-291X 2017/07/01 [Refereed][Not invited]
   

  Brain histamine acts as a neurotransmitter and regulates various physiological functions, such as learning and memory, sleep-wake cycles, and appetite regulation. We have recently shown that histamine H3 receptor (H3R) is expressed in primary mouse microglia and has a strong influence on critical functions in microglia, including chemotaxis, phagocytosis, and cytokine secretion in vitro. However, the importance of H3R in microglial activity in vivo remains unknown. Here, we examined the effects of JNJ10181457 (JNJ), a selective and potent H3R inverse agonist, on microglial functions ex vivo and in vivo. First, we injected ATP, which is a typical chemoattractant, into hippocampal slices to investigate the effect of JNJ on chemotaxis. ATP-induced microglial migration toward the injected site was significantly suppressed by JNJ treatment. Next, we examined whether JNJ affected microglial phagocytosis in hippocampal slices and in the prefrontal cortex. Microglial engulfment of dead neurons induced by N-methyl-(D)-aspartate was inhibited in the presence of JNJ. The increase in zymosan particle uptake by activated microglia in the prefrontal cortex was prevented by JNJ administration. Finally, we determined the importance of JNJ in a lipopolysaccharide (LPS)-induced depression model. JNJ reduced the LPS-induced upregulation of microglial pro-inflammatory cytokines and improved depression-like behaviour in the tail-suspension test. These results demonstrate the inhibitory effects of JNJ on chemotaxis, phagocytosis, and cytokine production in microglia inside the brain, and highlight the importance of microglial H3R for brain homeostasis. (C) 2017 Elsevier Inc. All rights reserved.
• Histamine induced gliotransmitter release from cortical rat astrocytes

  Aniko Karpati, Takeo Yoshikawa, Tadaho Nakamura, Fumito Naganuma, Tomomitsu Iida, Kazuhiko Yanai

  JOURNAL OF PHARMACOLOGICAL SCIENCES 133 (3) S89 - S89 1347-8613 2017/03
• Role of histamine receptors in desflurane anesthesia

  Toru Tamii, Tadaho Nakamura, Takeo Yoshikawa, Fumito Naganuma, Tomomitsu Iida, Aniko Karpati, Takuro Matsuzawa, Haruna Kitano, Nobuyuki Okamura, Kazuhiko Yanai

  JOURNAL OF PHARMACOLOGICAL SCIENCES 133 (3) S171 - S171 1347-8613 2017/03
• Characterization of murine polyspecific monoamine transporters.

  Yamato Miura, Takeo Yoshikawa, Fumito Naganuma, Tadaho Nakamura, Tomomitsu Iida, Anikó Kárpáti, Takuro Matsuzawa, Asuka Mogi, Ryuichi Harada, Kazuhiko Yanai

  FEBS open bio 7 (2) 237 - 248 2211-5463 2017/02 [Refereed][Not invited]
   

  The dysregulation of monoamine clearance in the central nervous system occurs in various neuropsychiatric disorders, and the role of polyspecific monoamine transporters in monoamine clearance is increasingly highlighted in recent studies. However, no study to date has properly characterized polyspecific monoamine transporters in the mouse brain. In the present study, we examined the kinetic properties of three mouse polyspecific monoamine transporters [organic cation transporter 2 (Oct2), Oct3, and plasma membrane monoamine transporter (Pmat)] and compared the absolute mRNA expression levels of these transporters in various brain areas. First, we evaluated the affinities of each transporter for noradrenaline, dopamine, serotonin, and histamine, and found that mouse ortholog substrate affinities were similar to those of human orthologs. Next, we performed drug inhibition assays and identified interspecies differences in the pharmacological properties of polyspecific monoamine transporters; in particular, corticosterone and decynium-22, which are widely recognized as typical inhibitors of human OCT3, enhanced the transport activity of mouse Oct3. Finally, we quantified absolute mRNA expression levels of each transporter in various regions of the mouse brain and found that while all three transporters were ubiquitously expressed, Pmat was the most highly expressed transporter. These results provide an important foundation for future translational research investigating the roles of polyspecific monoamine transporters in neurological and neuropsychiatric disease.
• Role of brain histamine in glutamate release from cultured astrocytes

  Aniko Karpati, Takeo Yoshikawa, Tadaho Nakamura, Fumito Naganuma, Tomomitsu Iida, Yamato Miura, Kazuhiko Yanai

  JOURNAL OF PHARMACOLOGICAL SCIENCES 130 (3) S83 - S83 1347-8613 2016/03
• Histamine N-methyltransferase deficiency causes abnormal sleep-wake cycles and aggressive behaviors

  Fumito Naganuma, Takeo Yoshikawa, Tadaho Nakamura, Ai Horigome, Yamato Miura, Atsushi Yanai, Takatoshi Mochizuki, Kazuhiku Yanai

  JOURNAL OF PHARMACOLOGICAL SCIENCES 130 (3) S112 - S112 1347-8613 2016/03
• Interactions between histaminergic neuronal system and isoflurane anesthesia in mice

  Tadaho Nakamura, Takeo Yoshikawa, Fumito Naganuma, Tomomitsu Iida, Yamato Miura, Aniko Karpati, Takatoshi Mochizuki, Kazuhiko Yanai

  JOURNAL OF PHARMACOLOGICAL SCIENCES 130 (3) S98 - S98 1347-8613 2016/03
• Analysis of skeletal muscle-specific Ext1 lacking mice

  Yamato Miura, Takeo Yoshikawa, Tadaho Nakamura, Fumito Naganuma, Tomomitsu Iida, Kazuhiko Yanai

  JOURNAL OF PHARMACOLOGICAL SCIENCES 128 (3) S94 - S94 1347-8613 2015/07
• Analysis of Histamine N-methyltransferase deficitent mice

  Fumito Naganuma, Takeo Yoshikawa, Yamato Miura, Ayano Yagyuu, Tadaho Nakamura, Kazuhiko Yanai

  JOURNAL OF PHARMACOLOGICAL SCIENCES 128 (3) S87 - S87 1347-8613 2015/07
• Role of neuronal histamine and histamine H-1 receptor in isoflurane anesthesia

  Tadaho Nakamura, Takeo Yoshikawa, Fumito Naganuma, Tomomitsu Iida, Yamato Miura, Kazuhiko Yanai

  JOURNAL OF PHARMACOLOGICAL SCIENCES 128 (3) S189 - S189 1347-8613 2015/07
• Histamine H3 receptor in primary mouse microglia inhibits chemotaxis, phagocytosis, and cytokine secretion.

  Tomomitsu Iida, Takeo Yoshikawa, Takuro Matsuzawa, Fumito Naganuma, Tadaho Nakamura, Yamato Miura, Attayeb S Mohsen, Ryuichi Harada, Ren Iwata, Kazuhiko Yanai

  Glia 63 (7) 1213 - 25 0894-1491 2015/07 [Refereed][Not invited]
   

  Histamine is a physiological amine which initiates a multitude of physiological responses by binding to four known G-protein coupled histamine receptor subtypes as follows: histamine H-1 receptor (H1R), H2R, H3R, and H4R. Brain histamine elicits neuronal excitation and regulates a variety of physiological processes such as learning and memory, sleep-awake cycle and appetite regulation. Microglia, the resident macrophages in the brain, express histamine receptors; however, the effects of histamine on critical microglial functions such as chemotaxis, phagocytosis, and cytokine secretion have not been examined in primary cells. We demonstrated that mouse primary microglia express H2R, H3R, histidine decarboxylase, a histamine synthase, and histamine N-methyltransferase, a histamine metabolizing enzyme. Both forskolin-induced cAMP accumulation and ATP-induced intracellular Ca2+ transients were reduced by the H3R agonist imetit but not the H2R agonist amthamine. H3R activation on two ubiquitous second messenger signalling pathways suggests that H3R can regulate various microglial functions. In fact, histamine and imetit dose-dependently inhibited microglial chemotaxis, phagocytosis, and lipopolysaccharide (LPS)-induced cytokine production. Furthermore, we confirmed that microglia produced histamine in the presence of LPS, suggesting that H3R activation regulate microglial function by autocrine and/or paracrine signalling. In conclusion, we demonstrate the involvement of histamine in primary microglial functions, providing the novel insight into physiological roles of brain histamine. GLIA 2015;63:1213-1225
• Role of histamine H3 receptor in glucagon-secreting αTC1.6 cells.

  Tadaho Nakamura, Takeo Yoshikawa, Fumito Naganuma, Attayeb Mohsen, Tomomitsu Iida, Yamato Miura, Akira Sugawara, Kazuhiko Yanai

  FEBS open bio 5 36 - 41 2211-5463 2015 [Refereed][Not invited]
   

  Pancreatic alpha-cells secrete glucagon to maintain energy homeostasis. Although histamine has an important role in energy homeostasis, the expression and function of histamine receptors in pancreatic alpha-cells remains unknown. We found that the histamine H-3 receptor (H3R) was expressed in mouse pancreatic alpha-cells and alpha TC1.6 cells, a mouse pancreatic alpha-cell line. H3R inhibited glucagon secretion from alpha TC1.6 cells by inhibiting an increase in intracellular Ca2+ concentration. We also found that immepip, a selective H3R agonist, decreased serum glucagon concentration in rats. These results suggest that H3R modulates glucagon secretion from pancreatic alpha-cells. (C) 2014 The Authors. Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. This
• Insufficient intake of L-histidine reduces brain histamine and causes anxiety-like behaviors in male mice.

  Takeo Yoshikawa, Tadaho Nakamura, Tetsuro Shibakusa, Mayu Sugita, Fumito Naganuma, Tomomitsu Iida, Yamato Miura, Attayeb Mohsen, Ryuichi Harada, Kazuhiko Yanai

  The Journal of nutrition 144 (10) 1637 - 41 0022-3166 2014/10 [Refereed][Not invited]
   

  L-histidine is one of the essential amino acids for humans, and it plays a critical role as a component of proteins. L-histidine is also important as a precursor of histamine. Brain histamine is synthesized from L-histidine in the presence of histidine decarboxylase, which is expressed in histamine neurons. In the present study, we aimed to elucidate the importance of dietary L-histidine as a precursor of brain histamine and the histaminergic nervous system. C57BL/6J male mice at 8 wk of age were assigned to 2 different diets for at least 2 wk: the control (Con) diet (5.08 g L-histidine/kg diet) or the low L-histidine diet (LHD) (1.28 g L-histidine/kg diet). We measured the histamine concentration in the brain areas of Con diet fed mice (Con group) and LHD-fed mice (LHD group). The histamine concentration was significantly lower in the LHD group [Con group vs. LHD group, histamine in cortex (means +/- SEs): 13.9 +/- 1.25 vs. 9.36 +/- 0.549 ng/g tissue; P = 0.002]. Our in vivo microdialysis assays revealed that histamine release stimulated by high K from the hypothalamus in the LHD group was 60% of that in the Con group (P = 0.012). However, the concentrations of other monoamines and their metabolites were not changed by the LH D. The open-field tests showed that the LH D group spent a shorter amount of time in the central zone (87.6 +/- 14.1 vs. 50.0 +/- 6.03 s/10 min; P = 0.019), and the light/dark box tests demonstrated that the LHD group spent a shorter amount of time in the light box (198 +/- 8.19 vs. 162 +/- 14.1 s/10 min; P=0.048), suggesting that the LHD induced anxiety-like behaviors. However, locomotor activity, memory functions, and social interaction did not differ between the 2 groups. The results of the present study demonstrated that insufficient intake of histidine reduced the brain histamine content, leading to anxiety-like behaviors in the mice.
• Mechanism of the histamine H-3 receptor-mediated increase in exploratory locomotor activity and anxiety-like behaviours in mice

  Attayeb Mohsen, Takeo Yoshikawa, Yamato Miura, Tadaho Nakamura, Fumito Naganuma, Katsuhiko Shibuya, Tomomitsu Iida, Ryuichi Harada, Nobuyuki Okamura, Takehiko Watanabe, Kazuhiko Yanai

  NEUROPHARMACOLOGY 81 188 - 194 0028-3908 2014/06 [Refereed][Not invited]
   

  Histaminergic neurons are activated by histamine H-3 receptor (H3R) antagonists, increasing histamine and other neurotransmitters in the brain. The prototype H3R antagonist thioperamide increases locomotor activity and anxiety-like behaviours; however, the mechanisms underlying these effects have not been fully elucidated. This study aimed to determine the mechanism underlying H3R-mediated behavioural changes using a specific H3R antagonist, JNJ-10181457 (JNJ). First, we examined the effect of JNJ injection to mice on the concentrations of brain monoamines and their metabolites. JNJ exclusively increased N-J-methylhistamine, the metabolite of brain histamine used as an indicator of histamine release, suggesting that JNJ dominantly stimulates the release of histamine release but not of other monoamines. Next, we examined the mechanism underlying JNJ-induced behavioural changes using open-field tests and elevated zero maze tests. JNJ-induced increase in locomotor activity was inhibited by a-fluoromethyl histidine, an inhibitor of histamine synthesis, supporting that H3R exerted its effect through histamine neurotransmission. The JNJ-induced increase in locomotor activity in wild-type mice was preserved in H1R gene knockout mice but not in histamine H-2 receptor (H2R) gene knockout mice. JNJ-induced anxiety-like behaviours were partially reduced by diphenhydramine, an HiR antagonist, and dominantly by zolantidine, an H2R antagonist. These results suggest that H3R blockade induces histamine release, activates H2R and elicits exploratory locomotor activity and anxiety-like behaviours. (c) 2014 Elsevier Ltd. All rights reserved.
• Predominant role of plasma membrane monoamine transporters in monoamine transport in 1321N1, a human astrocytoma-derived cell line.

  Fumito Naganuma, Takeo Yoshikawa, Tadaho Nakamura, Tomomitsu Iida, Ryuichi Harada, Attayeb S Mohsen, Yamato Miura, Kazuhiko Yanai

  Journal of neurochemistry 129 (4) 591 - 601 0022-3042 2014/05 [Refereed][Not invited]
   

  Monoamine neurotransmitters should be immediately removed from the synaptic cleft to avoid excessive neuronal activity. Recent studies have shown that astrocytes and neurons are involved in monoamine removal. We aimed to elucidate the transporters responsible for monoamine transport by astrocytes in 1321N1, a human astrocytoma-derived cell line. Kinetics analysis suggested the involvement of low-affinity monoamine transporters, e.g., organic cation transporter (OCT) 2 and 3 and plasma membrane monoamine transporter (PMAT). Our results indicate that PMAT and OCT3 in human astrocytes are involved in monoamine clearance.
• Molecular mechanism of histamine clearance by primary human astrocytes.

  Takeo Yoshikawa, Fumito Naganuma, Tomomitsu Iida, Tadaho Nakamura, Ryuichi Harada, Attayeb S Mohsen, Atsuko Kasajima, Hironobu Sasano, Kazuhiko Yanai

  Glia 61 (6) 905 - 16 0894-1491 2013/06 [Refereed][Not invited]
   

  Histamine clearance is an essential process for avoiding excessive histaminergic neuronal activity. Previous studies using rodents revealed the predominant role of astrocytes in brain histamine clearance. However, the molecular mechanism of histamine clearance has remained unclear. We detected histamine N-methyltransferase (HNMT), a histamine-metabolizing enzyme, in primary human astrocytes and the astrocytes of human brain specimens. Immunocytochemical analysis and subcellular fractionation assays revealed that active HNMT localized to the cytosol, suggesting that histamine transport into the cytosol is crucial for histamine inactivation. We showed that primary human astrocytes transported histamine in a time-dependent manner. Kinetics analysis showed that two low-affinity transporters were involved in histamine transport. Histamine uptake by primary human astrocytes was not dependent on the extracellular Na+/Cl- concentration. Histamine is reported to be a substrate for three low-affinity and Na+/Cl--independent transporters: organic cation transporter 2 (OCT2), OCT3, and plasma membrane monoamine transporter (PMAT). RT-PCR analysis revealed that OCT3 and PMAT were expressed in primary human astrocytes. Immunohistochemistry confirmed OCT3 and PMAT expression in the astrocytes of human brain specimens. Drug inhibition assays and gene knockdown assays revealed the major contribution of PMAT and the minor contribution of OCT3 to histamine transport. The present study demonstrates for the first time that the molecular mechanism of histamine clearance is by primary human astrocytes. These findings might indicate that PMAT, OCT3 and HNMT in human astrocytes play a role in the regulation of extraneuronal histamine concentration and the activities of histaminergic neurons. © 2013 Wiley Periodicals, Inc.
• Histamine stimulated phagocytosis of the primary rat microglia

  Tomomitsu Iida, Takeo Yoshikawa, Akihiro Kondo, Tadaho Nakamura, Fumito Naganuma, Ryuichi Harada, Ren Iwata, Kazuhiko Yanai

  JOURNAL OF PHARMACOLOGICAL SCIENCES 121 217P - 217P 1347-8613 2013
• [(11)C]Doxepin binding to histamine H1 receptors in living human brain: reproducibility during attentive waking and circadian rhythm.

  Katsuhiko Shibuya, Yoshihito Funaki, Kotaro Hiraoka, Takeo Yoshikawa, Fumito Naganuma, Masayasu Miyake, Shoichi Watanuki, Hirotoshi Sato, Manabu Tashiro, Kazuhiko Yanai

  Frontiers in systems neuroscience 6 (2012) 45 - 45 1662-5137 2012/06/11 [Refereed][Not invited]
   

  Molecular imaging in neuroscience is a new research field that enables visualization of the impact of molecular events on brain structure and function in humans. While magnetic resonance-based imaging techniques can provide complex information at the level of system, positron emission tomography (PET) enables determination of the distribution and density of receptor and enzyme in the human brain. Previous studies using [ 11C]raclopride and [ 11C]FLB457 revealed that the release of neuronal dopamine was increased in human brain by psychostimulants or reward stimuli. Following on from these previous [ 11C]raclopride studies, we examined whether the levels of neuronal release of histamine might change [ 11C]doxepin binding to the H1 receptors under the influence of physiological stimuli. The purpose of the present study was to evaluate the test-retest reliability of quantitative measurement of [ 11C]doxepin binding between morning and afternoon and between resting and attentive waking conditions in healthy human subjects. There was a trend for a decrease in [ 11C]doxepin binding during attentive calculation tasks compared with that in resting conditions, but the difference (less than 10%) was not significant. Similarly, the binding potential of [ 11C]doxepin in the cerebral cortex was slightly higher in the morning than that in the afternoon, but it was also insignificant. These data suggest that higher histamine release during wakefulness could not decrease the [ 11C]doxepin binding in the brain. This study confirmed the reproducibility and reliability of [ 11C]doxepin in the previous imaging studies to measure the H1 receptor. © 2012 Shibuya,Funaki, Hiraoka, Yoshikawa, Naganuma, Miyake, Watanuki, Sato, Tashiroand Yanai.
• Positron emission tomography evaluation of sedative properties of antihistamines.

  Kazuhiko Yanai, Dongying Zhang, Manabu Tashiro, Takeo Yoshikawa, Fumito Naganuma, Ryuichi Harada, Tadaho Nakamura, Katsuhiko Shibuya, Nobuyuki Okamura

  Expert opinion on drug safety 10 (4) 613 - 22 1474-0338 2011/07 [Refereed][Not invited]
   

  Introduction: H-1 antihistamines are often used in the medication for allergic diseases, coughs and colds, and insomnia, with or without prescription, even though their sedative properties are a potentially dangerous unwanted side effect that is not properly recognized. These sedative properties have been evaluated using the incidence of subjective sleepiness, objective cognitive and psychomotor functions, and positron emission tomography (PET) measurement of H-1 receptor occupancy. Areas covered: This article reviews the current updated literature on the sedative properties of antihistamines examined by PET measurement of H-1 receptor occupancy. Expert opinion: The use of PET to examine antihistamine penetration in the human brain in relation to psychometric and other functional measures of CNS effects is a major breakthrough and provides a new standard by which the functional CNS effects of antihistamines can be related directly to H-1 receptor occupancy. Therapy with antihistamines can be better guided by considering histamine H-1 receptor occupancy from the view of their sedative properties.

MISC

• 扁桃体中心核ニューロテンシン神経細胞の睡眠覚醒サイクルにおける役割の検討

  中村 正帆, 長沼 史登, 田中 聖人, 井上 まり絵, 直野 留美, 吉川 雄朗, 岡村 信行  応用薬理  102-  (5-6)  128  -128  2022/08
• Neurotensinergic neurons in the lateral hypothalamus are important for physiological sleep-wake cycle.

  Naganuma Fumito, Nakamura Tadaho, Vetrivelan Ramalingam, Yoshikawa Takeo, Okamura Nobuyuki  Proceedings for Annual Meeting of The Japanese Pharmacological Society  96-  3-B-P-185  2022  

  Neurotensin works as a neuropeptide in the brain. We have reported that experimental stimulation of neurotensinergic neurons in the lateral hypothalamus (Nts-LH) caused hyperarousal in mice. However, it remains unclear whether Nts-LH is involved in the physiological sleep-wake cycle. Thus, in the present study, we investigated the effect of Nts-LH selective lesion on physiological sleep-wake cycle. We also measured neuronal activities of Nts-LH during sleep and wakefulness. First, we performed Nts-LH lesion induced by diphtheria toxin-A. The Nts-LH lesion caused a fragmentation of wakefulness and decreased total amount of wakefulness, implying that Nts-LH was critical in the transition and maintenance of wakefulness. Next, we measured the neuronal activities of Nts-LH during sleep and wakefulness by using fiber photometory with a Ca²⁺ sensor, GCaMP7f. The calcium imaging clearly showed that Nts-LH was simultaneously activated at the transition from sleep to wakefulness, followed by continuous excitation during wakefulness. These data emphasize that Nts-LH mediate sleep-to-wake transition then their activation promote the following wakefulness. Taken together, the neuronal activity of Nts-LH maintains wakefulness, which is important for physiological sleep-wake cycles
• Assessment of learning achievement using self-assessment rubric in the role-play for pharmacological education.

  Nakamura Tadaho, Kimura Takeshi, Naganuma Fumito, Yoshikawa Takeo, Okamura Nobuyuki, Yanagita Toshihiko  Proceedings for Annual Meeting of The Japanese Pharmacological Society  96-  4-B-O13-6  2022  

  Background. The role-play for pharmacological education (RPPE) provides a practical training focused on the basis of drug therapy. Learning achievement in RPPE, however, has not been researched precisely. In this study, we assessed the learning achievement in RPPE by using a self-assessment rubric. Methods. Participants: Fourth grade medical students at Tohoku Medical and Pharmaceutical University who took the online RPPE (oRPPE) in 2022. Measurements: Self-assessment rubric was presented to participants on the first day of the course. Four following categories were scored on a five-point scale: I) Understanding: a. health problems of the case in charge; b. drug therapy of the case in charge; c. role-play performed by the others, II) Preparation, III) Performance and IV) Discussion and dialogue. Students were directed to assess themselves during preparation and performance of oRPPE. Data collection and analysis: Scores were collected after course completion. All data are presented as the mean ± standard error of the mean (S.E.M.). Results. The self-assessment showed high scores in the following 3 categories: I) Understanding (a. 4.10 ± 0.06; b. 4.10 ± 0.06; c. 3.94 ± 0.07), II) Preparation (4.32 ± 0.06) and III) Performance (4.21 ± 0.07). These results indicate that RPPE could provide basic practice for drug therapy. It also implies that specification of expected outcomes through rubric beforehand might be useful to guide self- and peer-learning during preparation and performance. On the other hand, the score in IV) Discussion and dialogue (3.75 ± 0.09) might reflect difficulties to discuss the whole process of clinical practice in each case, which requires advanced professional competencies. Conclusion. The self-assessment rubric is a useful tool for assessing achievement of learning in RPPE.
• 脳内ヒスタミン代謝酵素の機能解析

  吉川雄朗, 小松由梨香, 松澤健介, 大塚里奈, 長沼史登, 長沼史登, 中村正帆, 中村正帆, 谷内一彦  日本ヒスタミン学会プログラム・講演要旨集  23rd (CD-ROM)-  2022
• ヒスタミン神経細胞特異的な活性変化が攻撃行動と睡眠覚醒サイクルに及ぼす影響

  中村正帆, 長沼史登, 黒柳浩志, 田中聖人, 吉川雄朗, 谷内一彦, 岡村信行  日本ヒスタミン学会プログラム・講演要旨集  23rd (CD-ROM)-  2022
• 中脳水道周辺灰白質へ投射するヒスタミン神経は神経因性疼痛を緩和する

  長沼史登, 梅ゆう, 松澤拓郎, 中村正帆, 岡村信行, 谷内一彦, 吉川雄朗  日本ヒスタミン学会プログラム・講演要旨集  23rd (CD-ROM)-  2022
• Important role of neuronal histamine N-methyltransferase in brain functions

  Yoshikawa Takeo, Komatsu Yurika, Matsuzawa Kensuke, Otsuka Rina, Naganuma Fumito, Nakamura Tadaho, Yanai Kazuhiko  Proceedings for Annual Meeting of The Japanese Pharmacological Society  95-  1-O-001  2022
• Oral L-histidine supplementation improves working memory through the activation of brain histamine system in male mice

  Sueji Roh, Nakamura Tadaho, Naganuma Fumito, Yanai Kazuhiko, Yoshikawa Takeo  Proceedings for Annual Meeting of The Japanese Pharmacological Society  95-  1-LBS-01  2022
• Learning outcomes of the online role-play for pharmacological education: comparison between players and audiences

  Nakamura Tadaho, Naganumra Fumito, Okamura Nobuyuki, Yanagita Toshihiko  Proceedings for Annual Meeting of The Japanese Pharmacological Society  95-  2-O-060  2022  

  Background: The goal of the role-play for pharmacological education (RPPE) is to acquire fundamental competences for drug therapy. These competences are based on presentation and communication skills as well as understanding of pharmacology and pathophysiology. The conventional face-to-face RPPE exhibited much higher learning effects in players than audiences, although audiences also established efficient learning through observation and discussion. However, the learning outcomes of the online RPPE (oRPPE) has not been determined. In this study, we evaluated oRPPE learning effects. Methods: Participants: 4^th grade medical student at Tohoku Medical and Pharmaceutical University who took oRPPE in 2020 and 2021. Measurements: The questionnaire was used to evaluate learning effects. Four following items were asked on a five-point scale after the course completion. 1) Knowledge. Was oRPPE effective in understanding drug therapy? 2) Patients. Was oRPPE effective in understanding the patient's feelings? 3) Motivation. Has your motivation as a medical student improved through oRPPE? 4) Behavioral changes. Will oRPPE bring you a change in learning attitude? Analysis: Each item was compared between players and audiences. Differences were considered significant at P < 0.01. Results: Total participants were 194 students (Players: 110, Audiences: 84) who completed the course. We collected questionnaire from players (n=106) and audiences (n=72). Knowledge, Motivation and Behavioral changes were significantly higher in players [Mean score (95% CI). Players vs. Audiences. Knowledge 4.509 (4.317-4.702) vs. 4.139 (3.948-4.329) (p<0.001); Motivation 4.434 (4.244-4.624) vs. 3.972 (3.746-4.199) (p<0.001); Behavioral changes 4.283 (4.107-4.459) vs. 4.042 (3.847-4.237) (p=0.0098)]. On the other hand, Patients was not statistically significant between players and audiences [4.377 (4.178-4.577) vs. 4.208 (4.007-4.409) (p=0.0216)]. Conclusions: Players showed much higher learning effects in Knowledge, Motivation and Behavioral changes. Learning as an audience, however, also established a better understanding of Patient's feeling.
• In vivo evaluation of novel near-infrared fluorescence probe THK565 for imaging amyloid β and tau protein deposits in Alzheimer‘s mouse models

  Naganuma Fumito, Murata Daiki, Inoue Marie, Harada Ryuichi, Kudo Yukitsuka, Nakamura Tadaho, Okamura Nobuyuki  Proceedings for Annual Meeting of The Japanese Pharmacological Society  95-  3-O-113  2022  

  Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by the accumulation of amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles. Thus, noninvasive detection of accumulated Aβ and tau in the brain would be beneficial for an early diagnosis of AD. We developed a novel near-infrared fluorescence (NIRF) probe named THK565 for in vivo imaging of Aβ and tau in the brain. In the present study, we evaluated whether THK565 can noninvasively detect Aβ and tau deposits using 2 lines of AD-model mice. We used APP-KI and rTg4510 mice which show progressive accumulation of Aβ and tau in the brain, respectively. Mice were intravenously injected with 0.3 mg/kg of THK565, and then in vivo fluorescence signals were measured using IVIS imaging system at different time point. After in vivo imaging, we harvested brain and confirmed the existence of Aβ and tau deposits by immunohistochemistry. In vivo NIRF imaging demonstrated higher fluorescent intensity in the brains of APP-KI and rTg4510 than in those of age-matched control mice. The histological analysis confirmed that THK565 clearly labeled Aβ and tau plaques in the brain section. These findings imply that THK565 is useful for noninvasive assessment of Aβ and tau pathology in the brain.
• Histaminergic activation of periaqueductal grey matter and somatosensory cortex relieves mechanical allodynia in nerve-injury model mice.

  梅いく, 吉川雄朗, 長沼史登, 谷内一彦  日本薬理学雑誌  156-  (Supplement)  2021
• アストロサイトによる脳内ヒスタミン系制御の重要性について

  大塚里奈, 吉川雄朗, 長沼史登, 佐藤夕季, 高橋佑奈, 谷内一彦  日本薬理学雑誌  156-  (Supplement)  2021
• Chemogenetic inhibition of histaminergic neurons significantly decreased wakefulness during the dark periods in mice.

  Kuroyanagi Hiroshi, Tanaka Masato, Naganuma Fumito, Nakamura Tadaho, Okamura Nobuyuki  Proceedings for Annual Meeting of The Japanese Pharmacological Society  94-  2-Y-G1-1  2021  [Not refereed]
   

  Histaminergic neurons are localized in the tuberomammillary nucleus (TMN) of the posterior hypothalamus. These neurons have been postulated to have wake-promoting and arousal-maintaining functions. Previously, we found that the acute and specific activation of histaminergic neurons in the TMN slightly increased wakefulness in mice during the light periods. However, the precise neural mechanism of histaminergic neurons in the regulation of sleep-wake cycles have remained to be elucidated. In this study, we examined the wake-regulatory mechanism of histaminergic neurons by using chemogenetic inhibition methods. We virally expressed hM4Di specifically in the TMN-histaminergic neurons of histidine decarboxylase (Hdc)-Cre mice. Then clozapine-N-oxide (CNO) or saline (SA) were injected at ZT3 (light period) or ZT12 (dark period). We found that CNO injection at ZT12 significantly decreased wakefulness and increased NREM sleep due to prolonged duration of NREM sleep. We also found that the wake to wake transition was significantly decreased and NREM to NREM sleep transition was increased in the CNO group. On the other hand, CNO injection at ZT3 did not alter sleep-wake status. These results indicated that histaminergic neurons in the TMN are important for maintaining the arousal status in mice during the dark periods.
• Astrocytic histamine N-methyltransferase controls locomotor activity and vigilance state

  Otsuka Rina, Naganuma Fumito, Sato Yuki, Takahashi Yuna, Yanai Kazuhiko, Yoshikawa Takeo  Proceedings for Annual Meeting of The Japanese Pharmacological Society  94-  1-O-B3-2  2021  [Not refereed]
   

  Brain histamine plays a role as a neurotransmitter in the regulation of various brain activities. Previously, we demonstrated that histamine N-methyltransferase (HNMT), a histamine-metabolizing enzyme, controls brain histamine concentration and brain functions. However, it is still unknown whether neuronal Hnmt or astrocytic Hnmt contributes to the regulation of histaminergic system. Here, we phenotyped astrocytes-specific Hnmt knockout (cKO) mice to elucidate the role of Hnmt in astrocytes. First, we made cKO mice by crossing Hnmt flox mice and Gfap-Cre mice which expressed Cre recombinase in astrocytes. Although Hnmt expression in the cKO cerebellum was decreased, brain histamine concentrations in the cKO brain homogenates was not significantly different from those of control mice. In behavioral tests, locomotor activity of cKO mice in novel environment and in their home cages were decreased during the dark phase. Anxiety- and depression-like behaviors were not changed by Hnmt deletion in astrocytes. Sleep analysis showed that the power density of delta frequency was increased in cKO mice, indicating the lower cortical activation of cKO mice. These results demonstrate that astrocytic Hnmt is important for locomotor activity and vigilance state, although the impact of Hnmt in astrocytes on histamine concentration was limited.
• Histamine activation of periaqueductal grey matter and somatosensory cortex exerts an antinociceptive effect in mechanical allodynia.

  Yu Mei, Yoshikawa Takeo, Naganuma Fumito, Yanai Kazuhiko  Proceedings for Annual Meeting of The Japanese Pharmacological Society  94-  1-O-B2-1  2021  [Not refereed]
   

  Histamine is a bioactive amine which is involved in diverse physiological functions including allergic reaction and gastric acid secretion. In the central nervous system (CNS), histamine acts as a neurotransmitter to control various brain functions such as sleep-wake cycle. Recent studies have shown the therapeutic action of central histamine on mechanical allodynia. However, the mechanism(s) by which histamine attenuates allodynia remain unknown. First, we investigated responsible histamine receptors for histamine-induced pain relief. Pharmacological assays showed that the activation of postsynaptic histamine H1 and H2 receptors were important for pain relief. Next, we examined which brain regions were important for pain alleviation by histamine. We decreased the function of histamine system in several brain regions by adeno-associated viruses and revealed that periaqueductal gray matter (PAG) and somatosensory cortex (SS) were involved in histamine-induced pain relief. Histaminergic activation by DREADDs (designer receptors exclusively activated by designer drugs) also confirmed the importance of PAG for pain relief by histamine.  These data demonstrates that histamine activation in PAG and SS has antinociceptive effects on mechanical allodynia.
• Chronic histamine deletion in adult mouse brain induced depression-like behaviors, impairment of memory function and decrease of locomotor activity

  吉川雄朗, 長沼史登, 長沼史登, 山田瑶, 吉川貴子, 大隅典子, 谷内一彦  日本神経精神薬理学会プログラム・抄録集  50回・42回・4回-  179  -179  2020/08
• Histamine H1 receptor on neurons and astrocytes plays different roles in mouse behavior

  Yoshikawa Takeo, Karpati Aniko, Naganuma Fumito, Matsuzawa Takuro, Yanai Kazuhiko  Proceedings for Annual Meeting of The Japanese Pharmacological Society  93-  2-O-033  2020  [Not refereed]
   

  Histamine acts as a neurotransmitter in the brain and controls diverse brain functions. Recently, we elucidated the important roles of histamine H1 receptors (H1R) on intracellular signaling in 1321N1 cells, an astrocytoma-derived cell line. However, it was still unknown the impact of astrocytic H1R on brain functions. In the present study, we deleted mouse H1R gene from astrocytes and neurons and analyzed the phenotype of astrocyte- and neuron-specific conditional knockout mice (cKO). First, we confirmed that cell-specific reduction of H1R gene expression in cKO mice. Behavioral studies revealed that H1R on both astrocytes and neurons played an important role of anxiety-like behavior. Neuronal H1R was also involved in recognition memory. Astrocytic H1R contributed to the regulation of aggressive behavior, circadian rhythms and quality of wakefulness. In conclusion, our study stresses the importance of H1R on neurons and astrocytes in distinct physiological processes.
• Chronic histamine decrease in adult mice induced depression-like behavior and impaired sleep-wake cycle

  Yamada Yo, Yoshikawa Takeo, Naganuma Fumito, Yanai Kazuhiko  Proceedings for Annual Meeting of The Japanese Pharmacological Society  93-  1-YIA-01  2020  [Not refereed]
   

  Histamine acts as a neurotransmitter in the brain. Histamine is synthesized from histidine by histidine decarboxylase (HDC). In the central nervous system, HDC-positive neurons exist in tuberomammillary nucleus (TMN) of posterior hypothalamus and project their axons to entire brain. Recent studies showed that chronic histamine decrease in adult was observed in several neurological disorders such as narcolepsy and Alzheimer's disease. However, it is still unknown whether this histamine decrease plays a causative role in the disorders or not. In present study, we induced chronic histamine deficiency in adult mice to reveal the direct involvement of impaired histaminergic nervous system in brain dysfunction. We stereotaxically microinjected adeno-associated virus expressing Cre-recombinase into TMN of adult HDC flox mice (HDC cKO mice) for long-term brain histamine decrease. Immunohistochemical analysis showed Cre expression in TMN in HDC cKO mice. We confirmed the reduced HDC mRNA expression and the decreased histamine content in HDC cKO brain. In the tail suspension test, immobility time was prolonged in HDC cKO mice. In home-cage locomotor activity test, activity counts during light period were decreased in HDC cKO mice. Additionally, we performed sleep analysis by measuring electroencephalogram and electromyogram. The analysis showed that cKO mice exhibited decreased wakefulness during light period. These results indicated that chronic dysfunction of histamine system caused depression-like behavior and impaired sleep-wake cycle in mice.
• 成体マウス脳内の慢性的ヒスタミン減少は,うつ様行動の増加及び自発行動量の減少を惹起する

  山田瑶, 吉川雄朗, 長沼史登, 長沼史登, 谷内一彦  日本ヒスタミン学会プログラム・講演要旨集  22nd-  2020
• 扁桃体ニューロテンシン神経細胞はREM睡眠を調節する

  田中聖人, 黒柳浩志, 長沼史登, 中村正帆, 岡村信行  日本薬理学雑誌  155-  (Supplement)  2020
• ニューロテンシン神経細胞特異的活性化はセボフルラン麻酔からの覚醒を促進する

  中村正帆, 長沼史登, 岡村信行  日本麻酔科学会学術集会(Web)  67th-  2020
• 中枢ヒスタミン神経細胞の急性刺激はマウス攻撃行動を惹起する

  黒柳浩志, 田中聖人, 長沼史登, 中村正帆, 岡村信行  日本薬理学雑誌  155-  (Supplement)  2020
• 脳内ヒスタミン減少による成熟マウスでの行動変化について

  山田瑶, 吉川雄朗, 長沼史登, 谷内一彦  日本薬理学雑誌  155-  (Supplement)  2020
• ヒスタミン神経細胞の薬理遺伝学的活性化が睡眠覚醒に及ぼす影響

  中村正帆, 長沼史登, 黒柳浩志, 田中聖人, 吉川雄朗, 谷内一彦, 岡村信行  日本ヒスタミン学会プログラム・講演要旨集  22nd-  2020
• Pharmacokinetic training of aspirin for medical undergraduate students to understand the concept of ion trap

  Sato Takeya, Saito Masaki, Yoshikawa Takeo, Naganuma Fumito, Nakamura Tadaho, Okamura Nobuyuki, Yanagisawa Teruyuki, Yanai Kazuhiko  Proceedings for Annual Meeting of The Japanese Pharmacological Society  93-  (0)  1  -S16-2  2020  [Not refereed]
   

  Medical undergraduate students who will become medical doctors should have enough knowledge and understandings of medication since they will administer medical drugs to cure or examine the patients in hospital. Our current pharmacological practice is intended for the students to learn pharmacokinetics of drugs by focusing on administration, metabolism and excretion of aspirin. In this practice, the volunteers are recruited from students who take aspirin with or without another agent that changes the urine to acidic or basic pH. They collect the urine during 3.5 hours after taking aspirin and analyze the metabolites of aspirin in the urine. Through this practice, the students understand how aspirin is metabolized and excreted to urine and also how the urine pH affects the excretion of the metabolites in urine. The students, who will need to administer medicine to patients as physicians, are expected to acquire basic aspects of pharmacokinetics and clinical trials through this practice.

• Role of glutamate release from melanin-concentrating hormone neurons in REM sleep regulation

  Naganuma Fumito, Nakamura Tadaho, Vetrivelan Ramalingam, Okamura Nobuyuki  Proceedings for Annual Meeting of The Japanese Pharmacological Society  93-  (0)  1  -O-014  2020  [Not refereed]
   

  Neurons containing melanin-concentrating hormone (MCH) localized in the posterior lateral hypothalamus and have a crucial role in rapid eye movement sleep (REMs) regulation. As MCH neurons also contain a variety of other neurotransmitters such as glutamate. However, the specific neurotransmitter responsible for REMs regulation is not known. We hypothesized that glutamate, the primary fast-acting neurotransmitter in MCH neurons, is necessary for REMs regulation. To test this hypothesis, we generated mice deleted vesicular glutamate transporter (Vglut2; necessary for synaptic release of glutamate) specifically from MCH neurons by crossing MCH-Cre mice (expressing Cre recombinase only in MCH neurons) with Vglut2^flox/flox mice (expressing LoxP-modified alleles in Vglut2). We then studied the amounts, architecture and diurnal variation of sleep-wake states in baseline conditions. Next, we activated the MCH neurons lacking glutamate release using chemogenetic methods and tested whether these MCH neurons still promoted REMs. Our results indicate that glutamate in MCH neurons contributes to normal diurnal variability of REMs by regulating the levels of REMs during the dark period, but MCH neurons can promote REMs even in the absence of glutamate.

• 経口デスロラタジンの脳内ヒスタミンH1受容体結合 陽電子放出断層撮影を用いたin vivoランダム割付二重盲検クロスオーバー臨床試験

  中村 正帆, 平岡 宏太良, 原田 龍一, 松澤 拓郎, 吉川 雄朗, 長沼 史登, 田代 学, 谷内 一彦, 岡村 信行  臨床薬理  50-  (Suppl.)  S262  -S262  2019/11
• 経口デスロラタジンの脳内ヒスタミンH1受容体結合 陽電子放出断層撮影を用いたin vivoランダム割付二重盲検クロスオーバー臨床試験

  中村 正帆, 平岡 宏太良, 原田 龍一, 松澤 拓郎, 吉川 雄朗, 長沼 史登, 田代 学, 谷内 一彦, 岡村 信行  臨床薬理  50-  (Suppl.)  S262  -S262  2019/11  [Not refereed][Not invited]
  
• 眠り その新規機構と作用物質 視床下部ニューロテンシン神経系が関与する新規覚醒機構

  長沼 史登, 中村 正帆, Ramalingam Vetrivelan, 岡村 信行  応用薬理  96-  (5-6)  121  -121  2019/07  [Not refereed][Not invited]
  
• Deletion of brain histidine decarboxylase by adeno-associated virus induced anxiety-like behaviors in adult mice.

  Yamada Yo, Yoshikawa Takeo, Naganuma Fumito, Yanai Kazuhiko  Proceedings for Annual Meeting of The Japanese Pharmacological Society  92-  1-P-005  2019  [Not refereed]
   

  Histamine acts as a neurotransmitter in the brain. Histamine is synthesized from histidine by catalyzing histidine decarboxylase (HDC). In the central nervous system, HDC-positive neurons are in tuberomammillary nucleus of posterior hypothalamus and project their axons to entire brain. However, the roles of HDC in brain functions are not fully elucidated. In the present study, we generated mice with brain-specific deletion of HDC to investigate the importance of histamine for adult brain. We stereotaxically microinjected adeno-associated virus (AAV) expressing Cre-recombinase into tuberomammillary nucleus of adult HDC flox mice (HDC cKO mice). Immunohistochemical analysis showed Cre expression in tuberomammillary nucleus in HDC cKO mice. We confirmed the reduced HDC mRNA expression and the decreased histamine content in HDC cKO brain. Light/dark box tests showed that HDC cKO mice spent a shorter amount of time in the light room. In the tail suspension tests, immobility time was prolonged in HDC cKO mice. These results indicated that the inhibition of HDC activity in adult brain reduced histamine content and induced anxiety- and depression-like behaviors in mice.
• Melanin-concentrating hormone neurons contribute to dysregulation of rapid eye movement sleep in narcolepsy-model mouse

  Naganuma Fumito, Nakamura Tadaho, Ramalingam Vetrivelan, Okamura Nobuyuki  Proceedings for Annual Meeting of The Japanese Pharmacological Society  92-  (0)  3  -O-18  2019  [Not refereed]
   

  Orexin and melanin-concentrating hormone (MCH) neurons innervate each other and have opposite effects for rapid eye movement sleep (REMs) regulation. Narcolepsy patients appear abnormal REMs behaviors such as rapid transitions into REMs. The causal role of orexin neurons in narcolepsy is well established, but that of MCH neurons remains unclear. We hypothesized that in the absence of orexins, the effects of MCH on REMs can be unbalanced, potentially contributing to aspects of abnormal REMs observed in narcolepsy. To test this hypothesis, we generated MCH-Cre::OX-KO mice and characterized sleep-wake behaviors and cataplexy with chemogenetic activation and pharmacological inhibition of MCH signaling.

  In mice lacking orexins, activation of the MCH neurons also increased abnormal intrusions of REMs manifest as cataplexy and short latency transitions into REMs (SLREM). Conversely, a MCH receptor 1 antagonist, SNAP 94847, almost completely eliminated SLREM and cataplexy in OX-KO mice. These findings affirm that MCH neurons promote REMs under normal circumstances, and their activity in mice lacking orexins likely triggers abnormal intrusions of REMs into non-REMs and wake, resulting in the SLREM and cataplexy characteristic of narcolepsy.

• 【Glymphatic system-脳のゴミ処理とその異常】βアミロイド 機能画像

  岡村 信行, 中村 正帆, 長沼 史登  Clinical Neuroscience  37-  (1)  65  -67  2019/01  [Refereed][Not invited]
  
• 脳内ヒスタミン神経系の過剰な興奮はH2受容体を介してマウスの攻撃性を増加させる

  吉川 雄朗, 飯田 智光, 長沼 史登, 中村 正帆, 岡村 信行, 谷内 一彦  日本生物学的精神医学会・日本神経精神薬理学会合同年会プログラム・抄録集  39回・47回-  151  -151  2017/09  [Not refereed][Not invited]
  
• The effect of H3 receptor antagonism on rat neuropathic nociception

  Tadaho Nakamura, Takuro Matsuzawa, Maria Mogilevskaya, Takeo Yoshikawa, Fumito Naganuma, Nobuyuki Okamura, Kazuhiko Yanai  Inflammation Research  66-  (S1)  S22  -SS22  2017/07  [Not refereed][Not invited]
  
• 認知症治療薬開発のための画像バイオマーカーの臨床評価

  岡村 信行, 原田 龍一, 長沼 史登, 中村 正帆, 谷内 一彦  臨床薬理の進歩  (38)  10  -16  2017/06  [Not refereed][Not invited]
   

  アルツハイマー病(AD)患者12名(男性5名、女性7名、平均72.9±8.1歳)、軽度認知障害(MCI)9名(男性3名、女性6名、平均78.9±5.5歳)、健常被検者12名(男性9名、女性3名、平均76.7±9.4歳)を対象とした。AD患者では、側頭葉を中心とした大脳皮質における18F-THK-5351の集積が健常高齢者に比べて顕著であった。MCI患者では、側頭葉皮質における18F-THK-5351の集積がAD患者ほど顕著ではなく、健常人とADの中間であった。アミロイド陽性MCI症例における11C-PiB集積量は、AD患者と同等レベルにまで上昇した。18F-THK-5351、11C-PiBの脳各領域におけるSUVR値は、AD、MCI症例では海馬傍回、側頭葉皮質で有意に高かった。単独の関心領域におけるSUVR値を用いることで、感度・特異度ともに90%以上で健常人群とAD患者群の鑑別が可能であった。海馬傍回、中下側頭回、上頭頂小葉におけるTHK-5351 SUVR値はMCI、AD症例のADAS-cogスコアと有意な正の相関を示した。中下側頭回におけるTHK-5351の集積は同領域の脳容積と有意な負の相関を示した。
• アメリカ留学における研究生活ならびに私生活について

  長沼 史登  (3)  63  -65  2017/03
• 【自動車運転を考える】《自動車運転と薬物問題》 薬理からみた自動車運転の諸問題

  岡村 信行, 長沼 史登, 中村 正帆  Modern Physician  37-  (2)  147  -148  2017/02  [Refereed][Not invited]
   

  ＜ポイント＞意識レベルに影響を与える薬物は数多く存在し、自動車事故の潜在的リスクとなる。高齢者では中枢神経系作用薬の半減期の延長を考え、投与量や服薬時間を適切にコントロールする。睡眠薬の一部では薬物相互作用により、ほかの薬剤との併用時に著しく鎮静作用が増強する場合がある。抗てんかん薬では、治療効果不十分による発作リスクに加えて、薬物そのものの副作用にも注意を払う。(著者抄録)
• 吸入麻酔薬の意識消失作用におけるヒスタミン受容体の役割

  民井亨, 民井亨, 中村正帆, 吉川雄朗, 長沼史登, 飯田智光, KARPATI Aniko, 松澤拓郎, 北野陽菜, 山内正憲, 岡村信行, 谷内一彦  日本薬理学会北部会プログラム・抄録集  68th-  2017
• Electroencephalogram of H1KO mice under isoflurane anesthesia

  Tadaho Nakamura, Takeo Yoshikawa, Fumito Naganuma, Tomomitsu Iida, Aniko Karpati, Toru Tamii, Nobuyuki Okamura, Kazuhiko Yanai  Inflammation Research  65-  (S1)  S26  -S26  2016/07  [Not refereed][Not invited]
  
• Histamine N-methyltransferase is important for the normal sleep-wake cycles and aggression through the regulation of brain histamine concentration.

  Fumito Naganuma, Takeo Yoshikawa, Tadaho Nakamura, Kazuhiko Yanai  INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY  19-  316  -316  2016/06  [Not refereed][Not invited]
  
• DDSが創る健康長寿社会 アルツハイマー病の分子イメージング

  岡村 信行, 長沼 史登, 中村 正帆  日本DDS学会学術集会プログラム予稿集  32回-  75  -75  2016/06  [Not refereed][Not invited]
  
• 大学院進学と医学系大学院について

  長沼 史登  (2)  92  -96  2016/03
• Histamine H 1 Receptor Occupancy in the Human Brain Measured by Positron Emission Tomography

  Kazuhiko Yanai, Kotaro Hiraoka, Anikó Kárpáti, Fumito Naganuma, Nobuyuki Okamura, Manabu Tashiro, Tadaho Nakamura, Takeo Yoshikawa  Histamine Receptors Preclinical and Clinical Aspects  311  -325  2016  [Not refereed][Not invited]
  
• Histamine N-methyltransferaseの欠損はマウスにおいて攻撃性を高め、睡眠サイクルの異常を引き起こす

  長沼 史登, 吉川 雄朗, 堀米 愛, 三浦 大和, 中村 正帆, 矢内 敦, 望月 貴年, 谷内 一彦  日本生物学的精神医学会・日本神経精神薬理学会合同年会プログラム・抄録集  37回・45回-  163  -163  2015/09  [Not refereed][Not invited]
  
• H1-knocked out mouse has high sensitivity to isoflurane-induced anesthesia

  Tadaho Nakamura, Takeo Yoshikawa, Fumito Naganuma, Tomomitsu Iida, Yamato Miura, Kazuhiko Yanai  Inflammation Research  64-  (S1)  S22  -S22  2015/07  [Not refereed][Not invited]
  
• ANALYSIS OF HISTAMINE N-METHYLTRANSFERASE DEFICIENT MICE

  F. Naganuma, T. Yoshikawa, T. Nakamura, Y. Miura, A. Horigome, T. Matsuzawa, K. Yanai  INFLAMMATION RESEARCH  64-  S19  -S19  2015/07  [Not refereed][Not invited]
  
• Histamine N-methyltransferaseの欠損はマウスにおいて攻撃性を高め,睡眠サイクルの異常を引き起こす

  長沼史登, 吉川雄朗, 堀米愛, 三浦大和, 中村正帆, 矢内敦, 矢内敦, 望月貴年, 谷内一彦  日本神経精神薬理学会プログラム・抄録集  45th-  2015
• ヒスタミン神経系におけるイソフルランの作用

  中村正帆, 吉川雄朗, 長沼史登, 三浦大和, 飯田智光, 松澤拓郎, 堀米愛, KARPATI Aniko, 谷内一彦  日本ヒスタミン学会プログラム・講演要旨集  19th-  2015
• 生体内ミクログリアにおける中枢ヒスタミン系の役割

  飯田智光, 吉川雄朗, 松澤拓郎, 長沼史登, 中村正帆, 三浦大和, 谷内一彦  日本薬理学会北部会プログラム・抄録集  66th-  2015
• イソフルランの麻酔作用におけるヒスタミン神経系の役割

  中村正帆, 吉川雄朗, 長沼史登, 三浦大和, 飯田智光, 松澤拓郎, 堀米愛, ANIKO Karpati, 谷内一彦  日本薬理学会北部会プログラム・抄録集  66th-  2015
• Expression and function of histamine H3 receptor in pancreatic islets

  Tadaho Nakamura, Takeo Yoshikawa, Fumito Naganuma, Ryuichi Harada, Attayb Mohsen, Kazuhiko Yanai  Basic & Clinical Pharmacology & Toxicology  115-  S241  -S241  2014/07  [Not refereed][Not invited]
  
• THE INHIBITORY EFFECT OF HISTAMINE IN MOUSE PRIMARY MICROGLIA

  T. Iida, T. Yoshikawa, Y. Asami, F. Naganuma, Y. Miura, T. Nakamura, A. Mohsen, R. Iwata, K. Yanai  Inflammation Research  63-  (S1)  S12  -S12  2014/07  [Not refereed][Not invited]
  
• THE MECHANISM OF MONOAMINE TRANSPORT IN HUMAN ASTROCYTES

  F. Naganuma, T. Yoshikawa, T. Nakamura, T. Iida, Y. Miura, K. Yanai  BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY  115-  325  -325  2014/07  [Not refereed][Not invited]
  
• ヒスタミン代謝酵素欠損マウスの解析

  吉川雄朗, 長沼史登, 三浦大和, 柳生彩乃, 谷内一彦  日本薬理学会北部会プログラム・抄録集  65th-  2014
• Analysis of mouse polyspecific transporters

  Yamato Miura, Takeo Yoshikawa, Fumito Naganuma, Tadaho Nakamura, Attayeb Mohsen, Tomomitsu Iida, Kazuhiko Yanai  JOURNAL OF PHARMACOLOGICAL SCIENCES  124-  178P  -178P  2014  [Not refereed][Not invited]
  
• The role of histamine H-3 receptor in pancreatic alpha-cells

  Tadaho Nakamura, Takeo Yoshikawa, Fumito Naganuma, Tomomitsu Iida, Yamato Miura, Attayeb Mohsen, Kazuhiko Yanai  JOURNAL OF PHARMACOLOGICAL SCIENCES  124-  102P  -102P  2014  [Not refereed][Not invited]
  
• Dietary histidine is important for histaminergic nervous system

  Takeo Yoshikawa, Tetsuro Shibakusa, Mayu Sugita, Attayeb Mohsen, Fumito Naganuma, Kazuhiko Yanai  JOURNAL OF PHARMACOLOGICAL SCIENCES  124-  218P  -218P  2014  [Not refereed][Not invited]
  
• The roles of histamine in mouse primary microglia

  Tomomitsu Iida, Takeo Yoshikawa, Yuuta Asami, Tadaho Nakamura, Fumito Naganuma, Yamato Miura, Mohsen Attyeb, Ren Iwata, Kazuhiko Yanai  JOURNAL OF PHARMACOLOGICAL SCIENCES  124-  75P  -75P  2014  [Not refereed][Not invited]
  
• Histamine H3 receptors regulated locomotor activity via histamine H2 receptors

  Attayeb Mohsen, Takeo Yoshikawa, Fumito Naganuma, Tadaho Nakamura, Tomomitsu Iida, Yamato Miura, Kazuhiko Yanai  JOURNAL OF PHARMACOLOGICAL SCIENCES  124-  127P  -127P  2014  [Not refereed][Not invited]
  
• Molecular mechanism of monoamine transport by primary human astrocytes

  Fumito Naganuma, Takeo Yoshikawa, Tadaho Nakamura, Tomomitsu Iida, Yamato Miura, Kazuhiko Yanai  JOURNAL OF PHARMACOLOGICAL SCIENCES  124-  74P  -74P  2014  [Not refereed][Not invited]
  
• 【アレルギー疾患と睡眠】ヒスタミンと睡眠との関わり ヒスタミン神経系の覚醒と睡眠

  三浦 大和, 飯田 智光, 長沼 史登, 中村 正帆, 吉川 雄朗, 谷内 一彦  Progress in Medicine  33-  (12)  2589  -2594  2013/12  [Not refereed][Not invited]
  
• ヒトアストロサイトーマ由来細胞株1321N1はPMATを介してモノアミンを取り込む

  長沼 史登, 吉川 雄朗, 飯田 智光, 谷内 一彦  日本臨床精神神経薬理学会・日本神経精神薬理学会合同年会プログラム・抄録集  23回・43回-  193  -193  2013/10  [Not refereed][Not invited]
  
• 睡眠剥奪ストレスに惹起される不安様行動は、ヒスタミン摂取により低減される

  長沼 史登, Mohsen Attayeb, 吉川 雄朗, 谷内 一彦  日本臨床精神神経薬理学会・日本神経精神薬理学会合同年会プログラム・抄録集  23回・43回-  248  -248  2013/10  [Not refereed][Not invited]
  
• The role of histamine receptors on glucagon secretion in atc1.6 cell

  Tadaho Nakamura, Takeo Yoshikawa, Fumito Naganuma, Ryuichi Harada, Attayb Mohsen, Kazuhiko Yanai  Inflammation Research  62-  (S1)  S40  -S40  2013/07  [Not refereed][Not invited]
  
• Histamine transport by mouse plasma membrane monoamine transporter and mouse organic cation transporter 3

  Fumito Naganuma, Takeo Yoshikawa, Tadaho Nakamura, Tomomitsu Iida, Ryuichi Harada, Attayb Mohsen, Kazuhiko Yanai  Inflammation Research  62-  (S1)  S32  -S32  2013/07  [Not refereed][Not invited]
  
• 低親和性モノアミントランスポーターの機能解析

  三浦大和, 吉川雄朗, 長沼史登, 中村正帆, 飯田智光, 谷内一彦  日本薬理学会北部会プログラム・抄録集  64th-  2013
• 花粉症治療の現状と今後の展望-免疫・薬理からみた-2 非鎮静性抗ヒスタミン薬の薬理学的特徴

  中村正帆, 長沼史登, 谷内一彦, 吉川雄朗  月刊アレルギーの臨床  (439)  2013
• ヒスタミンはヒスタミンH3受容体を介してミクログリアの機能を抑制する

  飯田智光, 飯田智光, 吉川雄朗, 根東明広, 長沼史登, 中村正帆, 三浦大和, 岩田錬, 谷内一彦, 谷内一彦  日本薬理学会北部会プログラム・抄録集  64th-  2013
• Molecular Mechanism of Histamine Clearance by Human Astrocytes

  Takeo Yoshikawa, Fumito Naganuma, Tomomitsu Iida, Tadaho Nakamura, Atsuko Kasajima, Hironobu Sasano, Kazuhiko Yanai  JOURNAL OF PHARMACOLOGICAL SCIENCES  121-  137P  -137P  2013  [Not refereed][Not invited]
  
• Plasma Membrane Monoamine Transporter (PMAT) has Important Roles in Monoamine Clearance in Astrocyte

  Fumito Naganuma, Takeo Yoshikawa, Tomomitsu Iida, Kazuhiko Yanai  JOURNAL OF PHARMACOLOGICAL SCIENCES  121-  74P  -74P  2013  [Not refereed][Not invited]
  
• ヒトアストロサイトーマ由来細胞株1321N1細胞におけるセロトニン取り込み機構の解明

  長沼 史登, 吉川 雄朗, 飯田 智光, 谷内 一彦  日本薬理学雑誌  141-  (1)  2P  -2P  2013/01  [Not refereed][Not invited]
  
• 小動物PET/CTを用いた抗ヒスタミン薬レボセチリジンの鎮静性評価

  飯田 智光, 船木 善仁, 石渡 喜一, 長沼 史登, 原田 龍一, 吉川 雄朗, 古本 祥三, 岩田 錬, 谷内 一彦  日本薬理学雑誌  141-  (1)  3P  -3P  2013/01  [Not refereed][Not invited]
  
• 非鎮静性抗ヒスタミン薬の薬理学的特徴

  中村正帆, 長沼史登, 谷内一彦, 吉川雄朗  アレルギーの臨床  33-  (1)  22  -26  2013  [Not refereed][Not invited]
   

  花粉症やアトピー性皮膚炎などのアレルギー性疾患ガイドラインで中枢移行性の少ない非鎮静性抗ヒスタミン薬が推奨されている。医師や薬剤師は鎮静性抗ヒスタミン薬の危険性を十分に患者などに啓蒙する義務があり、また処方する場合にはその鎮静作用の有無を十分に検討してから薬剤を選択することが重要である。できるかぎり非鎮静性抗ヒスタミン薬を第一選択薬とすべきである。なぜならその有効性Efficacyは抗ヒスタミン薬の間ではほぼ同じであるからである。本稿では非鎮静性抗ヒスタミン薬の薬理学的特徴について紹介する。(著者抄録)
• ヒスタミンの生理作用

  飯田智光, 三浦大和, 長沼史登, 中村正帆, 吉川雄朗, 谷内一彦  皮膚アレルギーフロンティア  11-  (2)  65  -70  2013  [Not refereed][Not invited]
   

  ヒスタミンは、1910年にDaleらによりその作用が見出されて以来、その生理作用について多くの研究が行われている。また、ヒスタミンH1、H2受容体拮抗薬を開発したDaniel Bovet、Sir James W.Blackが、それぞれ1957年、1988年にノーベル医学生理学賞を受賞し、創薬により人類に多大な貢献をしている。近年、遺伝子ノックアウトマウスがH1〜H4受容体、ヒスチジン脱炭酸酵素(HDC)で作製されており、さらにH1受容体のX線解析も最近になって報告されている。ヒスタミンはアレルギーの起因物質として考えると"悪玉"と考えられていたが、最近の研究からヒスタミンの生理作用は生体にとって有益であることが多いことが示されてきた。(著者抄録)
• 抗ヒスタミン薬達人の処方箋 RX

  長沼史登, 谷内一彦  30  -34  2013  [Not refereed][Not invited]
  
• ヒトアストロサイトーマ由来細胞株1321N1におけるセロトニン取り込み機構について

  長沼 史登, 吉川 雄朗, 飯田 智光, 谷内 一彦  日本臨床精神神経薬理学会・日本神経精神薬理学会合同年会プログラム・抄録集  22回・42回-  165  -165  2012/10  [Not refereed][Not invited]
  
• HISTAMINE H-3 RECEPTOR REGULATES THE FUNCTIONS OF THE PANCREATIC beta-CELL

  T. Nakamura, T. Yoshikawa, N. Noguchi, F. Naganuma, R. Harada, A. Mohsen, K. Yanai  INFLAMMATION RESEARCH  61-  S83  -S83  2012/09  [Not refereed][Not invited]
  
• HUMAN ASTROCYTES TRANSPORT HISTAMINE THROUGH PLASMA MEMBRANE MONOAMINE TRANSPORTER

  T. Yoshikawa, F. Naganuma, T. Nakamura, T. Iida, R. Harada, A. Mohsen, K. Yanai  INFLAMMATION RESEARCH  61-  S58  -S58  2012/09  [Not refereed][Not invited]
  
• H3 receptor blockade increases locomotor activity in sleep-deprived wild type and H1 receptor knockout mice

  Attayeb Mohsen, Fumito Naganuma, Katsuhiko Shibuya, Tadaho Nakamura, Takeo Yoshikawa, Nobuyuki Okamura, Kazuhiko Yanai  JOURNAL OF PHARMACOLOGICAL SCIENCES  118-  151P  -151P  2012  [Not refereed][Not invited]
  
• In vivo evaluation of sedative properties of levocetirizine by small animal PET/CT

  Tomomitsu Iida, Yoshihito Funaki, Kiichi Ishiwata, Fumito Naganuma, Ryuichi Harada, Ren Iwata, Kazuhiko Yanai  JOURNAL OF PHARMACOLOGICAL SCIENCES  118-  252P  -252P  2012  [Not refereed][Not invited]
  
• Histamine H-3 Receptor Regulates the Functions of Pancreatic beta-cell

  Tadaho Nakamura, Takeo Yoshikawa, Naoya Noguchi, Fumito Naganuma, Ryuichi Harada, Attayeb Mohsen, Tomomitsu Iida, Atsuko Kasajima, Hironobu Sasano, Kazuhiko Yanai  JOURNAL OF PHARMACOLOGICAL SCIENCES  118-  74P  -74P  2012  [Not refereed][Not invited]
  
• A human astrocytoma-derived cell line transports dopamine through PMAT

  Fumito Naganuma, Takeo Yoshikawa, Tadaho Nakamura, Tomomitsu Iida, Kazuhiko Yanai  JOURNAL OF PHARMACOLOGICAL SCIENCES  118-  135P  -135P  2012  [Not refereed][Not invited]
  
• Predominant role of PMAT in histamine uptake by normal human astrocytes

  Takeo Yoshikawa, Fumito Naganuma, Tadaho Nakamura, Tomomitsu Iida, Kazuhiko Yanai  JOURNAL OF PHARMACOLOGICAL SCIENCES  118-  64P  -64P  2012  [Not refereed][Not invited]
  
• ヒトアストロサイトによるヒスタミン取り込み機構

  長沼 史登, 吉川 雄朗, 中村 正帆, 井筒 敏恵, 谷内 一彦  日本薬理学雑誌  139-  (1)  6P  -6P  2012/01  [Not refereed][Not invited]
  
• ヒトアストロサイトによるヒスタミン取り込み機構について(Important role of plasma membrane monoamine transporters in histamine uptake by human astrocytes)

  長沼 史登, 吉川 雄朗, 中村 正帆, 井筒 敏恵, 谷内 一彦  神経化学  50-  (2-3)  174  -174  2011/09  [Not refereed][Not invited]
  
• 膵β細胞に発現しているヒスタミン3型受容体はブドウ糖刺激インスリン分泌を抑制する

  中村 正帆, 吉川 雄朗, 大杉 真也, 長沼 史登, 野口 直哉, 谷内 一彦  日本生化学会大会プログラム・講演要旨集  84回-  4T15p  -15  2011/09  [Not refereed][Not invited]
  
• 第二世代抗ヒスタミン薬の薬理学的特徴 (日本医事新報)

  谷内一彦, 長沼史登  日本医事新報  (4547)  57  -59  2011/06  [Not refereed][Not invited]
  
• Histamine clearance in human astrocytoma derived cell lines

  Fumito Naganuma, Takeo Yoshikawa, Tadaho Nakamura, Toshie Idutsu, Kazuhiko Yanai  JOURNAL OF PHARMACOLOGICAL SCIENCES  115-  242P  -242P  2011  [Not refereed][Not invited]
  
• The deficiency of histamine H3 receptor increases the sensitivity of morphine-induced hyperlocomotion without affecting the reward in mice

  Dongying Zhang, Fumito Naganuma, Takeo Yoshikawa, Tadaho Nakamura, Attayeb Mohsen, Kazuhiko Yanai  JOURNAL OF PHARMACOLOGICAL SCIENCES  115-  69P  -69P  2011  [Not refereed][Not invited]
  
• The molecular mechanism of histamine uptake by human astrocytoma-derived cell line

  Fumito Naganuma, Takeo Yoshikawa, Tadaho Nakamura, Toshie Idutsu, Kazuhiko Yanai  NEUROSCIENCE RESEARCH  71-  E63  -E63  2011  [Not refereed][Not invited]
  
• Repeated exposures to the elevated zero maze increase anxiety in mice: gender difference

  Attayeb Mohsen, Tadaho Nakamura, Fumito Naganuma, Takeo Yoshikawa, Dongying Zhang, Nobuyuki Okamura, Kazuhiko Yanai  JOURNAL OF PHARMACOLOGICAL SCIENCES  115-  251P  -251P  2011  [Not refereed][Not invited]
  
• The acute blockade of histamine H3 receptors increases anxiogenic-like behaviors in mice

  Attayeb Mohsen, Fumito Naganuma, Tadaho Nakamura, Katsuhiko Shibuya, Takeo Yoshikawa, Nobuyuki Okamura, Kazuhiko Yanai  NEUROSCIENCE RESEARCH  71-  E198  -E198  2011  [Not refereed][Not invited]
  
• 内標準法によるヒスタミンと1-メチルヒスタミンの同時測定

  長沼史登, 井筒敏恵, 張冬頴, 中村正帆, 原田龍一, 吉川雄朗, 岡村信行, 谷内一彦  日本薬理学雑誌  137-  (1)  4P  -4P  2011/01  [Not refereed][Not invited]
  
• ヒスタミン受容体を理解する

  谷内一彦, 長沼史登, 中村正帆, 吉川雄朗  Dermatology Today  4-  4  -9  2011  [Not refereed][Not invited]
  
• ヒスタミン受容体とストレス脆弱性(Histamine receptors and stress vulnerability)

  谷内 一彦, 吉川 雄朗, 櫻井 映子, 及川 綾子, 長沼 史登, 岡村 信行  神経化学  49-  (2-3)  737  -737  2010/08  [Not refereed][Not invited]
  
• Histamine receptors and stress vulnerability

  Kazuhiko Yanai, Takeo Yoshikawa, Eiko Sakurai, Ayako Oikawa, Fumito Naganuma, Nobuyuki Okamura  NEUROSCIENCE RESEARCH  68-  E398  -E398  2010  [Not refereed][Not invited]
  

Books etc

• グッドマン・ギルマン薬理学書 13版

  長沼史登 (Joint translation第37章：脂質由来のオータコイド)
  廣川書店 2021/05

Presentations

• Evaluation of Therapeutic Potential for Histamine N-methyltransferase Inhibitior in Narcolepsy  [Not invited]

  Birkan Girgin, Fumito Naganuma, Anne Bernadette Agu, Tadaho Nakamura, Takatoshi Mochizuki, Takeo Yoshikawa

  Neuro2024
• ヒスタミン神経細胞不活性化によるセボフルラン誘発性不動化潜時の短縮  [Not invited]

  中村正帆, 杉山詩織, 若狭和彦, 川島美鈴, 長沼史登, 岡村信行

  日本麻酔科学会第71回学術集会
• Inhibition of histamine metabolizing enzyme in the brain reduces cataplexy in narcolepsy model mice

  Takeo Yoshikawa, Birkan Girgin, Anne Bernadette Agu, Tadaho Nakamura, Kazuhiko Yanai, Takatoshi Mochizuki, Shota Nagasawa, Yoshiharu Iwabuchi, Fumito Naganuma

  35th World Congress Collegium Internationale Neuro-Psychopharmacologicum  2024/05
• ヒスタミン代謝酵素阻害薬の薬理作用について  [Not invited]

  吉川雄朗, Birkan Girgin, Anne Bernadette Agu, 谷内一彦, 中村正帆, 長沼史登

  第24回日本ヒスタミン学会
• 扁桃体中心核ニューロテンシン神経細胞のREM睡眠制御における細胞活性と神経投射について  [Not invited]

  若狭和彦, 井上まり絵, 杉山詩織, 長沼史登, 中村正帆, 岡村信行

  第74回日本薬理学会北部会  2023/09
• ヒスタミン神経細胞の抑制はセボフルランの意識消失作用に影響するか  [Not invited]

  杉山詩織, 若狭和彦, 長沼史登, 中村正帆, 岡村信行

  第74回日本薬理学会北部会  2023/09
• ヒスタミン代謝酵素阻害薬のナルコレプシー治療に対する有効性の検討  [Not invited]

  長沼史登, Girgin Birkan, Bernadette S Agu Anne, 中村正帆, 谷内一彦, 吉川雄朗

  第45回日本睡眠学会・第30回日本時間生物学会学術大会合同大会  2023/09
• 睡眠覚醒に関わるニューロテンシン神経系の役割について

  長沼史登, 中村正帆, Vetrivelan Ramalingam, 吉川雄朗

  第36回北海道薬物作用談話会  2023/08
• 睡眠における扁桃体中心核ニューロテンシン神経細胞の役割について  [Not invited]

  中村正帆, 長沼史登, 吉川雄朗, 岡村信行

  第7回黒潮カンファレンス  2023/07
• ナルコレプシー治療におけるヒスタミン代謝酵素阻害薬の重要性について  [Not invited]

  吉川雄朗, 長沼史登, Gargin Birkan, 谷内一彦, 中村正帆

  第7回黒潮カンファレンス
• Neurotensinergic neurons in the lateral hypothalamus are important for physiological sleep-wake cycle  [Not invited]

  長沼史登, 中村正帆, Vetrivelan Ramalingam, 吉川雄朗, 岡村信行

  第96回日本薬理学会年会  2022/12
• Assessment of learning achievement using self-assessment rubric in the role-play for pharmacological education  [Not invited]

  中村正帆, 木村武司, 長沼史登, 吉川雄朗, 岡村信行, 柳田俊彦

  第96回日本薬理学会年会  2022/12
• ヒスタミン代謝酵素阻害剤メトプリンの行動薬理学的検討  [Not invited]

  吉川雄朗, 長沼史登, 長谷茜音, 谷内一彦, 中村正帆

  第73回日本薬理学会北部会  2022/09
• In vivo evaluation of novel near-infrared fluorescence probe THK565 for imaging amyloid β and tau protein deposits in Alzheimer's mouse model

  長沼史登, 村田大樹, 井上まり絵, 原田龍一, 工藤幸司, 中村正帆, 岡村信行

  第95回日本薬理学会年会  2022/03
• Leaning outcomes of the online role-play for pharmacological education: comparison between players and audiences

  中村正帆, 長沼史登, 岡村信行, 柳田俊彦

  第95回日本薬理学会年会  2022/03
• Important tole of neuronal histamine N-methyltransferase in brain function

  吉川雄朗, 小松由梨香, 松澤健介, 大塚里奈, 長沼史登, 中村正帆, 谷内一彦

  第95回日本薬理学会年会  2022/03
• 経口ヒスチジン摂取は脳内ヒスタミン神経系を活性化させることで記憶能を向上させる  [Not invited]

  盧優慈, 中村正帆, 長沼史登, 谷内一彦, 吉川雄朗

  第95回日本薬理学会年会  2022/03
• ヒスタミン神経細胞特異的な活性変化が攻撃行動と睡眠覚醒サイクルに及ぼす影響

  中村正帆, 長沼史登, 黒柳浩志, 田中聖人, 吉川雄朗, 谷内一彦, 岡村信行

  第23回日本ヒスタミン学会  2022/01
• 脳内ヒスタミン代謝酵素の機能解析

  吉川雄朗, 小松由梨香, 松澤健介, 大塚里奈, 長沼史登, 中村正帆, 谷内一彦

  第23回日本ヒスタミン学会  2022/01
• 中脳水道周辺灰白質へ投射するヒスタミン神経は神経因性疼痛を緩和する

  長沼史登、梅煜、松澤拓郎、中村正帆、岡村信行、谷内一彦、吉川雄朗

  第23回日本ヒスタミン学会  2022/01
• 吸入麻酔薬がニューロテンシン神経細胞の神経活動に及ぼす影響の検討

  長沼 史登, 中村 正帆, Vetrivelan Ramalingam, 岡村 信行

  第72回日本薬理学会北部会  2021/09
• 脳内アミロイド・タウを生体画像化するための近赤外線蛍光プローブTHK565の性能評価

  村田 大樹, 井上 まり絵, 長沼 史登, 中村 正帆, 工藤 幸司, 岡村 信行

  第72回日本薬理学会北部会  2021/09
• ヒスタミン神経細胞の化学遺伝学的抑制はマウス活動期の覚醒量を減らす

  黒柳 浩志, 田中 聖人, 長沼 史登, 中村 正帆, 岡村 信行

  第94回日本薬理学会年会  2021/03
• アストロサイトに発現するヒスタミン代謝酵素は自発行動量と覚醒状態を制御する

  大塚 里奈, 長沼 史登, 佐藤 夕季, 高橋 佑奈, 谷内 一彦, 吉川 雄朗

  第94回日本薬理学会年会  2021/03
• Histamine activation of periaqueductal grey matter and somatosensory cortex exerts an antinociceptive effect in mechanical allodynia

  梅 煜, 吉川 雄朗, 長沼 史登, 谷内 一彦

  第94回日本薬理学会年会  2021/03
• ニューロテンシン神経細胞特異的活性化はセボフルラン麻酔からの覚醒を促進する

  中村正帆, 長沼史登, 岡村信行

  日本麻酔科学会第67回学術集会  2020/11
• アストロサイトによる脳内ヒスタミン系制御の重要性について

  大塚里奈, 吉川雄朗, 長沼史登, 佐藤夕季, 高橋佑奈, 谷内一彦

  第71回日本薬理学会北部会  2020/09
• Histaminergic activation of periaqueductal grey matter and somatosensory cortex relieves mechanical allodynia in nerve-injury model mice.

  Mei Yu, Takeo Yoshikawa, Fumito Naganuma, Kazuhiko Yanai

  第71回日本薬理学会北部会  2020/09
• 神経細胞およびアストロサイト特異的ヒスタミンH1受容体欠損マウスの解析

  吉川 雄朗, Karpati Aniko, 長沼 史登, 松澤 拓郎, 谷内 一彦

  第93回日本薬理学会年会  2020/03
• 医学部学生に対してイオントラップの概念を理解するためのアスピリンを用いた薬物動態学実習

  佐藤岳哉, 斎藤将樹, 吉川雄朗, 長沼史登, 中村正帆, 岡村信行, 柳澤輝行, 谷内一彦

  第93回日本薬理学会年会  2020/03
• 成熟マウスにおける慢性ヒスタミン減少はうつ様行動と睡眠障害を惹起する

  山田 瑶, 吉川 雄朗, 長沼 史登, 谷内 一彦

  第93回日本薬理学会年会  2020/03
• メラニン凝集ホルモン神経細胞から放出されるグルタミン酸のREM睡眠における役割

  長沼史登, 中村正帆, Vetrivelan Ramalingam, 岡村信行

  第93回日本薬理学会年会  2020/03
• ヒスタミン神経細胞の薬理遺伝学的活性化が睡眠覚醒に及ぼす影響

  中村正帆, 長沼史登, 黒柳浩志, 田中聖人, 吉川雄朗, 谷内一彦, 岡村信行

  第22回日本ヒスタミン学会  2020/02
• ヒスタミン神経細胞の薬理遺伝学的活性化が睡眠覚醒に及ぼす影響

  中村正帆, 長沼史登, 黒柳浩志, 田中聖人, 吉川雄朗, 谷内一彦, 岡村信行

  第22回日本ヒスタミン学会  2020/02
• 成体マウス脳内の慢性的ヒスタミン減少は、うつ様行動の増加及び 自発行動量の減少を惹起する

  山田瑶, 吉川雄朗, 長沼史登, 谷内一彦

  第22回日本ヒスタミン学会  2020/02
• 成体マウス脳内のヒスタミン減少により、うつ様行動の増加、記憶能の低下、自発行 動量の減少が惹起される

  吉川雄朗, 長沼史登, 山田瑶, 吉川貴子, 大隅典子, 谷内一彦

  NPBPPP2020合同年会  2020
• Neurotensin in lateral hypothalamus

  Fumito Naganuma, Tadaho Nakamura, R Vetrivelan, Nobuyuki Okamura

  Novel Pain Therapeutics: from Basic Research to Clinical Translation and Rehabilitation  2019/10
• Behavioral changes related to increased brain histamine

  Tadaho Nakamura, Fumito Naganuma, Takeo Yoshikawa, Nobuyuki Okamura, Kazuhiko Yanai

  Novel Pain Therapeutics: from Basic Research to Clinical Translation and Rehabilitation.  2019/10
• 脳内ヒスタミン減少による成熟マウスでの行動変化について

  山田瑶, 吉川雄朗, 長沼史登, 谷内一彦

  第70回日本薬理学会北部会  2019/09
• 視床下部ニューロテンシン神経系が関与する新規覚醒機構

  長沼史登, 中村正帆, Vetrivelan Ramalingam, 岡村信行

  第21回応用薬理シンポジウム  2019/09
• 扁桃体ニューロテンシン神経細胞は REM 睡眠を調節する

  田中聖人, 黒柳浩志, 長沼史登, 中村正帆, 岡村信行

  第70回日本薬理学会北部会  2019/09
• 中枢ヒスタミン神経細胞の急性刺激はマウス攻撃行動を惹起する

  黒柳浩志, 田中聖人, 長沼史登, 中村正帆, 岡村 信行

  第70回日本薬理学会北部会  2019/09
• Histamine H1 receptors on astrocytes regulate aggressive behaviour, circadian rhythm, and wakefulness in mice

  Aniko Karpati, Takeo Yoshikawa, Fumito Naganuma, Kazuhiko Yanai

  Neuro2019  2019/07
• Neurotensinergic neurons in lateral hypothalamus have critical roles in wake promotion and hyperthermia

  長沼史登, 中村正帆, Vetrivelan Ramalingam, 岡村信行

  第42回日本神経科学大会  2019/07
• アデノ随伴ウイルスを用いた脳内ヒスタミン合成酵素の機能解析

  山田瑶, 吉川雄朗, 長沼史登, 谷内一彦

  第９２回日本薬理学会年会  2019/03
• メラニン凝集ホルモン神経は、ナルコレプシーモデルマウスにおけるREM睡眠の調節異常を引き起こす

  長沼史登, 中村正帆, Vetrivelan Ramalingam, 岡村信行

  第92回日本薬理学会年会  2019/03
• 経口デスロラタジンの脳内ヒスタミンH1受容体結合 陽電子放出断層撮影を用いたin vivoランダム割付二重盲検クロスオーバー臨床試験

  中村 正帆, 平岡 宏太良, 原田 龍一, 松澤 拓郎, 吉川 雄朗, 長沼 史登, 田代 学, 谷内 一彦, 岡村 信行

  臨床薬理 2019年11月 (一社)日本臨床薬理学会  2019
• 視床下部ニューロテンシン神経系が持つ新規覚醒機能

  長沼史登

  第57回脳神経科学コアセンターセミナー  2018/12
• 脳内ヒスタミン神経系の過剰な興奮はH2受容体を介してマウスの攻撃性を増加させる

  吉川雄朗, 飯田智光, 長沼史登, 中村正帆, 岡村信行, 谷内一彦

  第39回日本生物学的精神医学会・第47回日本神経精神薬理学会合同年会  2017/09
• 吸入麻酔薬の意識消失作用におけるヒスタミン受容体の役割

  民井亨, 中村正帆, 吉川雄朗, 長沼史登, 飯田智光, Karpati Aniko, 松澤拓郎, 北野陽菜, 山内正憲, 岡村信行, 谷内一彦

  第68回日本薬理学会北部会  2017/09
• THE EFFECT OF H3 RECEPTOR ANTAGONIST ON NEUROPATHIC PAIN

  T Nakamura, T Matsuzawa, M Mogilevskaya, A Mogi, T Yoshikawa, F Naganuma, N Okamura, K Yanai

  Histamine 2017  2017/05
• Histamine induced gliotransmitter release from cortical rat astrocytes

  Aniko Karpati, 吉川雄朗, 中村正帆, 長沼史登, 飯田智光, 谷内一彦

  第90回日本薬理学会年会  2017/03
• デスフルラン麻酔におけるヒスタミン受容体の役割

  民井亨, 中村正帆, 吉川雄朗, 長沼史登, 飯田智光, Karpati Aniko, 松澤拓郎, 北野陽奈, 岡村信行, 谷内一彦

  第90回日本薬理学会年会  2017/03
• Histamine promotes gliotransmitter release from astrocytes

  Karpati A, Yoshikawa T, Nakamura T, Naganuma F, Iida T, Yanai K

  Society for Neuroscience  2016/11
• Importance of Histamine Clearance for Brain Functions

  Yoshikawa T, Naganuma F, Nakamura T, Iida T, Karpati A, Mochizuki T, Yanai K

  Society for Neuroscience  2016/11
• Role of histamine neurons in isoflurane anesthesia.

  Tadaho Nakamura, Takeo Yoshikawa, Fumito Naganuma, Tomomitsu Iida, Aniko Karpati, Toru Tamii, Nobuyuki Okamura, Kazuiko Yanai

  第39回日本神経科学大会  2016/07
• Importance of histamine N-methyltransferase in brain functions

  Takeo Yoshikawa, Fumito Naganuma, Tadaho Nakamura, Takatoshi Mochizuki, Tomomitsu Iida, Aniko Karpati, Takuro Matsuzawa, Kazuhiko Yanai

  第39回日本神経科学大会  2016/07
• Astrocytes elevate glutamate release in response to histamine

  Anikó Kárpáti, Takeo Yoshikawa, Tadaho Nakamura, Fumito Naganuma, Tomomitsu Iida, Yamato Miura, Kazuhiko Yanai

  第39回日本神経科学大会  2016/07
• Histamine N-methyltransferase is important for the normal sleep-wake cycles and aggression through the regulation of brain histamine concentration.

  Fumito Naganuma, Takeo Yoshikawa, Tadaho Nakamura, Kazuhiko Yanai

  30th CINP world congress of neuropsychopharmacology  2016/07
• Electroencephalogram of H1KO mice under isoflurane anesthesia.

  Tadaho, Nakamura, Takeo Yoshikawa, Fumito Naganuma, Tomomitsu Iida, Aniko Karpati, Toru Tamii, Nobuyuki Okamura, Kazuiko Yanai

  European Histamine Research Society 45th annual meeting  2016/05
• Role of brain histamine in glutamate release from cultured astrocytes

  Aniko Karpati, 吉川雄朗, 中村正帆, 長沼史登, 飯田智光, 三浦大和, 谷内一彦

  第89回日本薬理学会年会  2016/03
• マウスにおけるヒスタミン神経系とイソフルラン麻酔の相互作用について

  中村正帆, 吉川雄朗, 長沼史登, 飯田智光, 三浦大和, Aniko Karpati, 望月貴年, 谷内一彦

  第89回日本薬理学会年会  2016/03
• Histamine N-methyltransferaseの欠損はマウスにおいて睡眠覚醒サイクル異常と高い攻撃性を引き起こす

  長沼史登, 吉川雄朗, 中村正帆, 堀米愛, 三浦大和, 矢内敦, 望月貴年, 谷内一彦

  第89回日本薬理学会年会  2016/03
• Role of histaminergic neuronal system in isoflurane anesthesia

  Tadaho Nakamura, Takeo Yoshikawa, Fumito Naganuma, Osamu Kobayashi, Miho Kaneko, Masanori Yamauchi, Kazuhiko Yanai

  Anesthesiology2015  2015/10
• Histamine N-methyltransferseノ欠損はマウスにおいて攻撃性を高め、睡眠サイクル異常を引き起こす

  長沼史登, 吉川雄朗, 堀米愛, 三浦大和, 中村正帆, 矢内敦, 望月貴年, 谷内一彦

  第37回日本生物学的精神医学会第45回日本精神神経薬理学会  2015/09
• 生体内ミクログリアにおける中枢ヒスタミン系の役割

  飯田智光, 吉川雄朗, 松澤拓郎, 長沼史登, 中村正帆, 三浦大和, 谷内一彦

  第66回日本薬理学会北部会  2015/09
• イソフルランの麻酔作用におけるヒスタミン神経系の役割

  中村正帆, 吉川雄朗, 長沼史登, 三浦大和, 飯田智光, 松澤拓郎, 堀米愛, Karpati Aniko, 谷内一彦

  第66回日本薬理学会北部会  2015/09
• Histamine N-methyltransferase deficiency induced the abnormal sleep-awake cycles and aggressive behavior in mice

  長沼史登, 吉川雄朗, 矢内敦, 堀米愛, 三浦大和, 中村正帆, 望月貴年, 谷内一彦

  第58回日本神経化学大会  2015/09
• ヒスタミン研究に残された解決されるべき課題：脳内ヒスタミンの分解系を中心に

  谷内一彦, 長沼史登, 中村正帆, 岡村信行, 吉川雄朗

  第19回活性アミンに関するワークショップ  2015/08
• マウス多基質性トランスポーターによるモノアミン輸送能の検討

  三浦大和, 吉川雄朗, 長沼史登, 中村正帆, 飯田智光, 谷内一彦

  第19回活性アミンに関するワークショップ  2015/08
• Mechanism of brain histamine clearance

  吉川雄朗, 長沼史登, 三浦大和, 矢内敦, 堀米愛, 中村正帆, 望月貴年, 谷内一彦

  第38回日本神経科学大会  2015/07
• Role of histamine in gliotransmitter release from astrocytes

  Aniko Karpati, Takeo Yoshikawa, Tadaho Nakamura, Fumito Naganuma, Tomomitsu Iida, Yamato Miura, Kazuhiko Yanai

  第38回日本神経科学大会  2015/07
• 脳内ヒスタミンのクリアランス機構について

  吉川雄朗, 長沼史登, 三浦大和, 矢内敦, 堀米愛, 中村正帆, 望月貴年, 谷内一彦

  日本生化学会東北支部第81回例会  2015/05
• Analysis of histamine N-methyltransferase deficient mice

  Naganuma F, Yoshikawa T, Nakamura T, Miura Y, Matsuzawa T, Yanai K

  European Histamine Research Society 44th annual meeting  2015/05
• H1-knocked out mouse had high sensitivity to isoflurane anesthesia

  Nakamura T, Yoshikawa T, Naganuma F, iida T, Miura Y, Yanai K

  European Histamine Research Society 44th annual meeting  2015/05
• Histamine N-methyltransferase ノックアウトマウスの解析

  長沼史登, 吉川雄朗, 三浦大和, 柳生彩乃, 中村正帆, 谷内一彦

  第88回日本薬理学年会  2015/03
• イソフルラン麻酔における神経ヒスタミンとヒスタミンH1受容体の役割

  中村正帆, 吉川雄朗, 長沼史登, 飯田智光, 三浦大和, 谷内一彦

  第88回日本薬理学年会  2015/03
• 骨格筋特異的Ext1欠損マウスの解析

  三浦大和, 吉川雄朗, 中村正帆, 長沼史登, 飯田智光, 谷内一彦

  第88回日本薬理学年会  2015/03
• Histamine N-methyltransferaseノックアウトマウスの行動解析

  長沼史登, 吉川雄朗, 中村正帆, 三浦大和, 堀米愛, 谷内一彦

  第24回神経行動薬理若手研究者の集い  2015/03
• 脳内ヒスタミン研究におけるマイクロダイアリシスの使用について

  吉川雄朗, 中村正帆, 長沼史登, 三浦大和, 谷内一彦

  第２５回マイクロダイアリシス研究会  2014/12
• マウスにおける低親和性トランスポーターの輸送能解析

  三浦大和, 吉川雄朗, 長沼史登, 中村正帆, 谷内一彦

  第18回日本ヒスタミン学会  2014/10
• Histamine N-methyl transferaseノックアウトマウスの解析

  長沼史登, 吉川雄朗, 三浦大和, 中村正帆, 谷内一彦

  第18回日本ヒスタミン学会  2014/10
• 低ヒスチジン食によりマウス脳内ヒスタミン含量が減少し、不安様行動が惹起される

  吉川雄朗, 中村正帆, 柴草哲朗, 杉田麻友, 長沼史登, 飯田智光, 三浦大和, モフセンアタイエブ, 原田龍一, 谷内一彦

  第18回日本ヒスタミン学会  2014/10
• ヒスタミン代謝酵素欠損マウスの解析

  吉川雄朗, 長沼史登, 三浦大和, 柳生彩乃, 谷内一彦

  第65回日本薬理学会北部会  2014/09
• The mechanism of monoamine transport by human astrocytes

  Fumito Naganuma, Takeo Yoshikawa, Tadaho Nakamura, Tomomitsu Iida, Yamato Miura, Kazuhiko Yanai

  17th world congress of basic & clinical pharmacology  2014/07
• The inhibitory effect of histamine in mouse primary microglia

  Iida T, Yoshikawa T, Asami Y, Naganuma F, Miura Y, Nakamura T, Mohsen A, Iwata R, Yanai K

  European histamine research society 43rd annual meeting  2014/05
• Analysis of mouse polyspecific transporters

  Miura Y, Yoshikawa T, Naganuma F, Nakamura T, Iida T, Harada R, Mohsen A, Yanai K

  European histamine research society 43rd annual meeting  2014/05
• マウス初代培養ミクログリアにおけるヒスタミンの役割

  飯田智光, 吉川雄朗, 浅見雄太, 中村正帆, 長沼史登, 原田龍一, 岩田錬, 谷内一彦

  第87回日本薬理学会年会  2014/03
• 膵ランゲルハンス島アルファ細胞におけるヒスタミンH3受容体の役割

  中村正帆, 吉川雄朗, 長沼史登, 飯田智光, 三浦大和, 谷内一彦

  第87回日本薬理学会年会  2014/03
• ヒトアストロサイトにおけるモノアミン取り込み機構の解明

  長沼史登, 吉川雄朗, 中村正帆, 飯田智光, 三浦大和, 谷内一彦

  第87回日本薬理学会年会  2014/03
• 食餌中に含まれるヒスチジンはヒスタミン神経系に必須である

  吉川雄朗, 柴草哲朗, 杉田麻友, モフセン・アタイエブ, 長沼史登, 谷内一彦

  第87回日本薬理学会年会  2014/03
• マウス多特異性トランスポーターの機能解析

  三浦大和, 吉川雄朗, 長沼史登, 中村正帆, モフセン・アタイエブ, 飯田智光, 谷内一彦

  第87回日本薬理学会年会  2014/03
• ヒトアストロサイトによるモノアミン取り込み機構

  長沼史登, 吉川雄朗, 飯田智光, 三浦大和, 谷内一彦

  第7回リトリート大学院生研究発表会  2014/01
• マウス初代培養ミクログリアにおけるヒスタミンの役割について

  飯田智光, 吉川雄朗, 長沼史登, 中村正帆, 三浦大和, 岩田錬, 谷内一彦

  第17回日本ヒスタミン学会  2013/11
• Plasma membrane monoamine transporter is important for monoamine uptake in a human astrocytoma-derived cell line, 1321N1 cells

  Naganuma F, Yoshikawa T, Nakamura T, Yanai K

  7th east asian consortium on biomedical engineering  2013/11
• The role of histamine receptors in pancreatic alpha-cells

  Nakamura T, Yoshikawa T, Naganuma F, Harada R, Yanai K

  7th east asian consortium on biomedical engineering  2013/11
• ヒトアストロサイトーマ由来細胞株1321N1はPMATを介してモノアミンを取り込む

  長沼史登, 吉川雄朗, 谷内一彦

  第23回日本臨床精神神経薬理学会・第43回日本神経精神薬理学会 合同大会  2013/10
• 睡眠剥奪ストレスに惹起される不安様行動は、ヒスタミン摂取により低減される

  長沼史登, Attayeb Mohsen, 吉川雄朗, 谷内一彦

  第23回日本臨床精神神経薬理学会・第43回日本神経精神薬理学会 合同大会  2013/10
• ヒスタミンはヒスタミンH3受容体を介してミクログリアの機能を抑制する

  飯田智光, 吉川雄朗, 根東明広, 長沼史登, 中村正帆, 三浦大和, 岩田錬, 谷内一彦

  第64回日本薬理学会北部会  2013/09
• 低親和性モノアミントランスポーターの機能解析

  三浦大和, 吉川雄朗, 長沼史登, 中村正帆, 飯田智光, 谷内一彦

  第64回日本薬理学会北部会  2013/09
• Histamine inhibits phagocytosis and morphological change in mouse primary microglia

  Tomomitsu Iida, Takeo Yoshikawa, Akihiro Kondo, Fumito Naganuma, Tadaho Nakamura, Ren Iwata, Kazuhiko Yanai

  NIH Tohoku University JSPS symposium  2013/05
• The role of histamine receptors on glucagon secretion in αTC1.6 cell

  T Nakamura, T, Yoshikawa, F Naganuma, R Harada, A Mohsen,K Yanai

  42nd European Histamine Research Society Annual Meeting  2013/05
• Histamine transport by mouse plasma membrane monoamine transporter and mouse organic cation transporter 3

  F Naganuma,T, Yoshikawa, T, Nakamura, T Iida, R Harada, A Mohsen, K Yanai

  42nd European Histamine Research Society Annual Meeting  2013/05
• Histamine Inhibited Phagocytosis of the Primary Mouse Microglia

  Tomomitsu Iida, Takeo Yoshikawa, Akihiro Kondo, FUmito Naganuma, Tadaho Nakamura, Attayeb Mohsen, Ren Iwata, Kazuhiko Yanai

  6th East Asian Pacific Student Workshop on Nano-Biomedical Engineering  2013/03
• Chronic Sleep Deprivation Impacts on Behaviors in Mice

  Attayeb Mohsen, Takeo Yoshikawa, Tadaho Nakamura, Fumito Naganuma, Tomomitsu Iida, Kazuhiko Yanai

  6th East Asian Pacific Student Workshop on Nano-Biomedical Engineering  2013/03
• アストロサイトにおけるモノアミン取り込みにはPMATが重要な役割を果たしている

  長沼史登, 吉川雄朗, 飯田智光, 谷内一彦

  第86回日本薬理学会年会  2013/03
• ヒトアストロサイトによるヒスタミン除去メカニズムの解明

  吉川雄朗, 長沼史登, 飯田智光, 中村正帆, 笠島敦子, 笹野公伸, 谷内一彦

  第86回日本薬理学会年会  2013/03
• Plasma membrane monoamine transporter (PMAT) is important for monoamine clearance by human astrocytoma-derived cell line.,1321N1 cells

  Fumito Naganuma, Takeo Yoshikawa, Tomomitsu Iida, kazuhiko Yanai

  The 21st Korea-Japan joint seminar on pharmacology  2012/10
• ヒトアストロサイトによるヒスタミン除去機構について

  吉川雄朗, 長沼史登, 飯田智光, 中村正帆, 笠島敦子, 笹野公伸, 谷内一彦

  第16回日本ヒスタミン学会  2012/10
• ヒトアストロサイトーマ由来細胞株1321N1におけるセロトニン取り込み機構について

  長沼史登, 吉川雄朗, 飯田智光, 谷内一彦

  第22回日本臨床精神神経薬理学会第42回日本神経精神薬理学会合同大会  2012/10
• Plasma membrane monoamine transporterはヒトアストロサイトにおけるドパミン不活化に重要である

  長沼史登, 吉川雄朗, 飯田智光, 中村正帆, 谷内一彦

  第35回日本神経科学大会  2012/09
• 小動物PET/CTを用いた抗ヒスタミン薬レボセチリジンの鎮静性評価

  飯田智光, 船木善仁, 石渡喜一, 長沼史登, 原田龍一, 吉川雄朗, 古本祥三, 岩田錬, 谷内一彦

  第63回日本薬理学会北部会  2012/09
• ヒトアストロサイトーマ由来細胞株1321N1細胞におけるセロトニン取り込み機構の解明

  長沼史登, 吉川雄朗, 飯田智光, 谷内一彦

  第63回日本薬理学会北部会  2012/09
• Mechanism of histamine clearance by primary human astrocytes

  T Yoshikawa, F Naganuma, T Iida, T Nakamura, K Yanai

  包括型脳科学研究推進支援ネットワーク 夏のワークショップ  2012/07
• ヒトアストロサイトによるヒスタミン不活化機構の解明

  長沼史登, 吉川雄朗, 中村正帆, 飯田智光, 谷内一彦

  第7回トランスポーター研究会年会  2012/06
• Human Astrocytes transport histamine through plasma membrane monoamine transporter

  T Yoshikawa, F Naganuma, T Nakamura, T Iida, R harada, A Mohsen, K Yanai

  41st Annual Meeting of the European Histamine Research Society  2012/05
• Histamine H3 receptor regulates the functions of pancreatic ß-cells

  T Nakamura, T Yoshikawa, N Noguchi, F Naganuma, R Harada, A Mohsen, K Yanai

  41st Annual Meeting of the European Histamine Research Society  2012/05
• ヒスタミン3型受容体による膵ß細胞機能の制御

  中村正帆, 吉川雄朗, 野口直哉, 長沼史登, 原田龍一, Attayeb Mohsen, 飯田智光, 笠島敦子, 笹野公伸, 谷内一彦

  第85回日本薬理学会年会  2012/03
• 正常ヒトアストロサイトによるヒスタミン取込はPMATを介して行われる

  吉川雄朗, 長沼史登, 中村正帆, 飯田智光, 谷内一彦

  第85回日本薬理学会年会  2012/03
• ヒトアストロサイトーマ由来細胞株はPMATを介してドパミンを取り込む

  長沼史登, 吉川雄朗, 中村正帆, 飯田智光, 谷内一彦

  第85回日本薬理学会年会  2012/03
• H3 receptor blockade increases locomotor activity in sleep-deprived wild type and H1 receptor knockout mice

  Attayeb Mohsen, 長沼史登, 渋谷勝彦, 中村正帆, 吉川雄朗, 岡村信行, 谷内一彦

  第85回日本薬理学会年会  2012/03
• Histamine H3 recptor regulates the functions of pancreatic ß-cells

  Tadaho Nakamura, Takeo Yoshikawa, Fumito Naganuma, Ryuichi Harada, Attayeb Mohsen, Masashi Saito, Kazuhiko Yanai

  NRF-JSPS Asian Science Seminar  2012/02
• ヒトアストロサイトによるヒスタミン取り込み機構

  長沼 史登, 吉川 雄朗, 中村 正帆, 井筒 敏恵, 谷内 一彦

  日本薬理学雑誌 2012年1月  2012/01
• Predominant role of PMAT in histamine uptake by normal human astrocytes

  Takeo Yoshikawa, Fumito Naganuma, Tadaho Nakamura, Tomomitsu Iida, Kazuhiko Yanai

  JOURNAL OF PHARMACOLOGICAL SCIENCES  2012
• A human astrocytoma-derived cell line transports dopamine through PMAT

  Fumito Naganuma, Takeo Yoshikawa, Tadaho Nakamura, Tomomitsu Iida, Kazuhiko Yanai

  JOURNAL OF PHARMACOLOGICAL SCIENCES  2012
• 正常ヒトアストロサイトによるヒスタミン取り込み機構の解明

  長沼史登, 吉川雄朗, 中村正帆, 井筒敏恵, 谷内一彦

  第15回日本ヒスタミン学会  2011/10
• Locomotor activity and antigenic-like behaviors are increased by histamine H3 receptors antagonist

  Attayeb, Mohsen, Fumito Naganuma, Tadaho Nakamura, Katsuhiko Shibuya, Takeo Yoshikawa, Nobuyuki Okamura, Kazuhiko Yanai

  第15回日本ヒスタミン学会  2011/10
• ヒトアストロサイトによるヒスタミン取り込み機構

  長沼史登, 吉川雄朗, 中村正帆, 井筒敏恵, 谷内一彦

  第62回日本薬理学会北部会  2011/09
• Histamine H3 receptors antagonists increase anziogenic-like behaviors and locomotor activity

  A Mohsen, F Naganuma, T Nakamura, T Yoshikawa, N Okamura, K Yanai

  第62回日本薬理学会北部会  2011/09
• Important role of plasma membrane monoamine transporters in histamine uptake by human astrocytes

  F Naganuma, T Yoshikawa, T Nakamura, T Idutsu, K Yanai

  第54回日本神経化学学会  2011/09
• 膵ß細胞に発現しているヒスタミン3型受容体はブドウ糖刺激インスリン分泌を抑制する

  中村正帆, 吉川雄朗, 大杉真也, 長沼史登, 野口直哉, 谷内一彦

  第84回日本生化学会大会  2011/09
• The mechanism of histamine uptake by human astrocytoma-derived cell line

  F Naganuma, T Yoshikawa, T Nakamura, T Idutsu, K Yanai

  第34回日本神経科学会年会  2011/09
• 膵β細胞に発現しているヒスタミン3型受容体はブドウ糖刺激インスリン分泌を抑制する

  中村 正帆, 吉川 雄朗, 大杉 真也, 長沼 史登, 野口 直哉, 谷内 一彦

  日本生化学会大会  2011/09
• ヒトアストロサイトによるヒスタミン取り込み機構について(Important role of plasma membrane monoamine transporters in histamine uptake by human astrocytes)

  長沼 史登, 吉川 雄朗, 中村 正帆, 井筒 敏恵, 谷内 一彦

  日本神経化学会  2011/09
• Repeated exposeres to the elevated zero maze increase anxiety in mice: gender difference

  Attayeb Mohsen, Tadaho Nakamura, Fumito Naganuma, Takeo Yoshikawa, Zhang Dongying, Nobuyuki Okamura, Kazuhiko Yanai

  第８４回日本薬理学会年会  2011/03
• The deficiency of histamine h3 receptor increases the sensitiviy of morphine-induced hyperlocomotion without affecting the reward in mice

  Dongying Zhang, Fumito Naganuma, Takeo Yoshikawa, Tadaho Nakamura, Attayeb Mofsen, Kazuhiko Yanai

  第８４回日本薬理学会年会  2011/03
• ヒトアストロサイトーマ由来細胞株におけるヒスタミン取り込み機構

  長沼史登, 吉川雄朗, 井筒敏恵, 中村正帆, 谷内一彦

  第８４回日本薬理学会年会  2011/03
• アストロサイトによるヒスタミン取り込み機構の解明

  長沼史登, 吉川雄朗, 中村正帆, 井筒敏恵, 谷内一彦

  第４回リトリート大学院生研究発表会  2011/01
• Repeated exposures to the elevated zero maze increase anxiety in mice: gender difference

  Attayeb Mohsen, Tadaho Nakamura, Fumito Naganuma, Takeo Yoshikawa, Dongying Zhang, Nobuyuki Okamura, Kazuhiko Yanai

  JOURNAL OF PHARMACOLOGICAL SCIENCES  2011
• The molecular mechanism of histamine uptake by human astrocytoma-derived cell line

  Fumito Naganuma, Takeo Yoshikawa, Tadaho Nakamura, Toshie Idutsu, Kazuhiko Yanai

  NEUROSCIENCE RESEARCH  2011
• The deficiency of histamine H3 receptor increases the sensitivity of morphine-induced hyperlocomotion without affecting the reward in mice

  The deficiency of histamine, receptor increases the sensitivity of morphine-induced hyperlocomotion without, affecting the reward in mice

  JOURNAL OF PHARMACOLOGICAL SCIENCES  2011
• Histamine clearance in human astrocytoma derived cell lines

  Fumito Naganuma, Takeo Yoshikawa, Tadaho Nakamura, Toshie Idutsu, Kazuhiko Yanai

  JOURNAL OF PHARMACOLOGICAL SCIENCES  2011
• Histamine-H3R-deficiency increased the sensitivity of morphine-induced hyperactivity but unaffected the rewarding response in in mice

  張冬穎, 吉川雄朗, 長沼史登, 中村正帆, 岡村信行, 加藤正人, 谷内一彦

  第61回日本薬理学会北部会  2010/09
• 内標準法によるヒスタミンと1-メチルヒスタミンの同時測定

  長沼史登, 井筒敏恵, 張冬穎, 中村正帆, 原田龍一, 吉川雄朗, 岡村信行, 谷内一彦

  第61回日本薬理学会北部会  2010/09
• Histamine receptors and stress vulnerability

  谷内一彦, 吉川雄朗, 櫻井映子, 及川綾子, 長沼史登, 岡村信行

  第33回日本神経化学大会  2010/09

Teaching Experience

PharmacologyPharmacology Tohoku Medical and Pharmaceutical University

Association Memberships

• THE JAPANESE SOCIETY OF NEUROPSYCHOPHARMACOLOGY   THE JAPANESE SOCIETY FOR NEUROCHEMISTRY   THE JAPAN NEUROSCIENCE SOCIETY   THE JAPANESE PHARMACOLOGICAL SOCIETY   北米神経科学会   

Research Projects

• 中枢神経系脆弱性と全身麻酔に関連した周術期認知機能障害の神経病理解析

  日本学術振興会：科学研究費助成事業

  Date (from‐to) : 2023/04 -2027/03 

  Author : 中村 正帆, 吉川 雄朗, 長沼 史登
• REM睡眠による異常タンパク質の排出増加はアルツハイマー病を治療できるか？

  日本学術振興会：科学研究費助成事業 基盤研究(C)

  Date (from‐to) : 2022/04 -2025/03 

  Author : 長沼 史登
• 吸入麻酔薬の意識消失作用におけるニューロテンシン神経系の役割

  日本学術振興会：科学研究費助成事業 基盤研究(C)

  Date (from‐to) : 2020/04 -2023/03 

  Author : 中村 正帆, 吉川 雄朗, 長沼 史登

   

  吸入麻酔薬がどのように作用し、意識を消失させるのか不明の点が多く残されている。ニューロテンシン神経系は覚醒に関連する神経核に広く投射しているので、吸入麻酔薬の意識消失作用を発揮する過程において、皮質下覚醒系を司る中心的な神経回路として重要な役割を果たしている可能性が考えられる。そこで本研究では吸入麻酔薬の意識消失作用におけるニューロテンシン神経系の役割を検証する。 まず視床下部ニューロテンシン神経細胞の分布と投射先を同定するため、ニューロテンシン神経細胞特異的に蛍光色素を発現させ、全脳にわたり薄切し免疫染色を行った。外側視床下部にニューロテンシン神経細胞が局在し、分界条床核 BNST, 腹側外側視索前野VLPO, 前脳基底部無名質SI, 腹外側中脳水道周囲灰白質vlPAG, 腕傍核PB, 青斑核LCなどの睡眠覚醒系に関与する脳領域に、多くの神経線維を投射していることが明らかになった。また吸入麻酔におけてニューロテンシン神経細胞の活性化がどのような影響を及ぼすかを検討するために、化学遺伝学的手法でマウスの視床下部ニューロテンシン神経細胞を特異的に活性化し、吸入全身麻酔から覚醒するまでの時間を測定した。その結果、ニューロテンシン神経細胞を特異的に活性化すると、全身麻酔からの回復が早くなった。一方、麻酔投与開始から体動が消失するまでの時間は差が無かったため、ニューロテンシン神経細胞は全身麻酔の導入には影響せず、回復期の覚醒に関与することが示唆された。次に、多様な神経線維投射のどれが覚醒に関与するか詳細に検討するため、神経投射先特異的な役割を検討した。神経線維投射先特異的な神経活性を制御するために光遺伝学的手法を用いるが、ベクターの極微量注入と光ファイバー埋め込みを実施し、予備的なデータが得られた。
• Importance of lateral hypothalamic neurotensinergic neurons in wake maintenance

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Early-Career Scientists

  Date (from‐to) : 2019/04 -2021/03 

  Author : Naganuma Fumito

   

  The optical stimulation of neurotensinergic neurons in lateral hypothalamus (Nts-LH) during NREM sleep strongly promoted arousal in mice. In addition, in vivo calcium imaging elucidated that neuronal activity of Nts-LH was high during wakefulness compared with during sleep. These results indicated that Nts-LH is important for wake maintenance.
• ヒスタミン神経系による攻撃性制御機構の解明

  日本学術振興会：科学研究費助成事業

  Date (from‐to) : 2018 -2020 

  Author : 吉川雄朗、長沼史登
• Functions of central histaminergic neurons in pathological model

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)

  Date (from‐to) : 2017/04 -2019/03 

  Author : NAGANUMA Fumito

   

  Microinjection of AAV-Cre into brain regions of Hnmt (a histamine-metabolizing enzyme)-flox mice increased histamine concentration in the injected regions. Increased histamine in hypothalamus increased locomotor activity, whereas that in amygdala increased aggression behaviors, respectively. On the other hand, in Hdc (histamine synthetase)-flox mice, microinjection of AAV-Cre into hypothalamus decreased brain histamine and induced the anxiety-like behaviors and suppressed locomotor activity and aggression behaviors. These results showed that histaminergic neurons were important for locomotor activity in hypothalamus and aggression behaviors in amygdala, suggesting that histaminergic neurons have a different role in various brain regions. In addition, this study could develop the new methods to study each functions of brain histamine depend on each brain regions.
• アストロサイトのＰＭＡＴを介した新規モノアミン取り込み機構について

  日本学術振興会：科学研究費助成事業 特別研究員奨励費

  Date (from‐to) : 2014/04 -2016/03 

  Author : 長沼 史登

   

  ニューロンに発現するモノアミントランスポーターは、シナプス間隙におけるモノアミン系神経伝達物質の濃度を調節し、神経活動の恒常性を維持する上で非常に重要な役割を持っている。事実、トランスポーターを標的とした薬剤は、精神疾患などの治療に広く用いられている。近年ニューロンだけでなく支持細胞であるアストロサイトがシナプス間隙におけるモノアミン系神経伝達物質の濃度調節に関与していることが分かってきたが、そのメカニズムは未だ不明なままであった。そのため、これらのメカニズムが明らかにすることで、更なる精神疾患の病態の解明や、新規治療標的の開発に繋がると考え、実験に着手した。まず、培養細胞を用いたin vitroの実験により、アストロサイトにおけるモノアミン取り込み能およびそのメカニズムを検討した。その結果、新規モノアミントランスポーターであるplasma membrane monoamine transporter (以下PMAT) が重要な役割を果たしていることが明らかとなった。次に、生体におけるPMATの役割を明らかにするため実験を行った。まず、マウスを用い、脳部位ごとにPMATの発現量を定量PCRにより検討を行った。その結果、ほとんどの脳部位において、セロトニントランスポーターや、ノルエピネフリントランスポーターに比べ、PMATが非常に多く発現していることが明らかとなった。次に、imipramineやdecynium22といった阻害剤を投与し、マイクロダイアリシス法で細胞外モノアミン量を測定したところ、薬物投与群は対照群に加え、優位に細胞外セロトニン、ノルエピネフリン、ヒスタミン量が増加していることが明らかとなった。以上の結果から、PMATは生体においても細胞外モノアミンの除去に重要な役割を果たしていることが示唆された。これに加え、本研究ではPMAT欠損マウスの作製を行った。マウスの作製は完了したが、表現型の解析については今後の課題である。
• 新規モノアミントランスポーターPMATの機能解析および阻害剤の開発

  Tohoku Univ. Division for International Advanced Research and Education：Ph.D. student

  Date (from‐to) : 2013/04 -2016/03 

  Author : Fumito Naganuma