Pharmacological inhibition of histamine N-methyltransferase extends wakefulness and suppresses cataplexy in a mouse model of narcolepsy
Fumito Naganuma, Birkan Girgin, Anne Bernadette S Agu, Kyosuke Hirano, Tadaho Nakamura, Kazuhiko Yanai, Ramalingam Vetrivelan, Takatoshi Mochizuki, Masashi Yanagisawa, Takeo Yoshikawa
SLEEP, Oxford University Press (OUP), 2024年10月23日
研究論文（学術雑誌）, Abstract

Histamine, a neurotransmitter, plays a predominant role in maintaining wakefulness. Further, our previous studies showed that histamine N-methyltransferase (HNMT), a histamine-metabolising enzyme, is important for regulating brain histamine concentration. However, the effects of pharmacological HNMT inhibition on mouse behaviour, including the sleep-wake cycle and cataplexy, in a mouse model of narcolepsy have not yet been investigated. In the present study, we investigated the effects of metoprine, an HNMT inhibitor with high blood-brain barrier permeability, in wild-type (WT) and orexin-deficient (OxKO) narcoleptic mice. Metoprine increased brain histamine concentration in a time- and dose-dependent manner without affecting peripheral histamine concentrations. Behavioural tests showed that metoprine increased locomotor activity in both novel and familiar environments, but did not alter anxiety-like behaviour. Sleep analysis showed that metoprine increased wakefulness and decreased non-rapid eye movement (NREM) sleep through the activation of the histamine H1 receptor (H1R) in WT mice. In contrast, the reduction of rapid eye movement (REM) sleep by metoprine occurred independent of H1R. In OxKO mice, metoprine was found to prolong wakefulness and robustly suppress cataplexy. In addition, metoprine has a greater therapeutic effect on cataplexy than pitolisant, which induces histamine release in the brain, and has been approved for patients with narcolepsy. These data demonstrate that HNMT inhibition has a strong effect on wakefulness, demonstrating therapeutic potential against cataplexy in narcolepsy.

Regulation of wakefulness by neurotensin neurons in the lateral hypothalamus
Fumito Naganuma, Mudasir Khanday, Sathyajit Sai Bandaru, Whidul Hasan, Kyosuke Hirano, Takeo Yoshikawa, Ramalingam Vetrivelan
Experimental Neurology, 115035, 115035, Elsevier BV, 2024年10月
研究論文（学術雑誌）

The impact of pitolisant, an H3 receptor antagonist/inverse agonist, on perirhinal cortex activity in individual neuron and neuronal population levels.
Kyosuke Hirano, Yoshikazu Morishita, Masabumi Minami, Hiroshi Nomura
Scientific reports, 12, 1, 7015, 7015, 2022年05月12日, ［国際誌］
英語, 研究論文（学術雑誌）, Histamine is a neurotransmitter that modulates neuronal activity and regulates various brain functions. Histamine H3 receptor (H3R) antagonists/inverse agonists enhance its release in most brain regions, including the cerebral cortex, which improves learning and memory and exerts an antiepileptic effect. However, the mechanism underlying the effect of H3R antagonists/inverse agonists on cortical neuronal activity in vivo remains unclear. Here, we show the mechanism by which pitolisant, an H3R antagonist/inverse agonist, influenced perirhinal cortex (PRh) activity in individual neuron and neuronal population levels. We monitored neuronal activity in the PRh of freely moving mice using in vivo Ca2+ imaging through a miniaturized one-photon microscope. Pitolisant increased the activity of some PRh neurons while decreasing the activity of others without affecting the mean neuronal activity across neurons. Moreover, it increases neuron pairs with synchronous activity in excitatory-responsive neuronal populations. Furthermore, machine learning analysis revealed that pitolisant altered the neuronal population activity. The changes in the population activity were dependent on the neurons that were excited and inhibited by pitolisant treatment. These findings indicate that pitolisant influences the activity of a subset of PRh neurons by increasing the synchronous activity and modifying the population activity.

【時間の神経科学-時を生み出すこころと脳の仕組み】時間の心理学と神経科学 失われた記憶想起の回復　　　　　　　　　　　　　　　
平野 匡佑, 野村 洋, Clinical Neuroscience, 41, 8, 1063, 1066, 2023年08月
(株)中外医学社, 日本語

ヒスタミンH3 受容体逆作動薬による嗅周皮質神経活動の調節作用　　　　　　　　　　　　　　　
平野匡佑, 久保絢女, 南雅文, 野村洋
第30回神経行動薬理若手研究者の集い, 2021年03月03日