Pharmacological inhibition of histamine N-methyltransferase extends wakefulness and suppresses cataplexy in a mouse model of narcolepsy

Naganuma, Fumito; Girgin, Birkan; Agu, Anne Bernadette S.; Hirano, Kyosuke; Nakamura, Tadaho; Yanai, Kazuhiko; Vetrivelan, Ramalingam; Mochizuki, Takatoshi; Yanagisawa, Masashi; Yoshikawa, Takeo

Pharmacological inhibition of histamine N-methyltransferase extends wakefulness and suppresses cataplexy in a mouse model of narcolepsy

Naganuma, Fumito; Girgin, Birkan; Agu, Anne Bernadette S. et al.

Sleep, 2024, 48(1), zsae244

Permalink : https://hdl.handle.net/2115/96191

このアイテムのアクセス数:79件（2026-08-18 03:12 集計）

閲覧可能ファイル

ファイル	フォーマット	サイズ	閲覧回数	説明
HUSCAP_Proof 20240913	pdf	3.76 MB	91

論文情報

ファイル出力 EndNote Basic出力 Mendeley出力

アクセス権	open access
URI	https://hdl.handle.net/2115/96191
タイトル	Pharmacological inhibition of histamine N-methyltransferase extends wakefulness and suppresses cataplexy in a mouse model of narcolepsy
著者	Naganuma, Fumito ; Girgin, Birkan ; Agu, Anne Bernadette S. ; Hirano, Kyosuke ; Nakamura, Tadaho ; Yanai, Kazuhiko ; Vetrivelan, Ramalingam ; Mochizuki, Takatoshi ; Yanagisawa, Masashi ; Yoshikawa, Takeo
e-Rad_Researcher 80780519 著者名 Naganuma, Fumito
著者名 Girgin, Birkan
著者名 Agu, Anne Bernadette S.
著者名 Hirano, Kyosuke
著者名 Nakamura, Tadaho
著者名 Yanai, Kazuhiko
著者名 Vetrivelan, Ramalingam
著者名 Mochizuki, Takatoshi
著者名 Yanagisawa, Masashi
e-Rad_Researcher 70506633 著者名 Yoshikawa, Takeo
言語	英語
キーワード	Histamine
	Histamine N-methyl transferase
	Metoprine
	Narcolepsy
	Wakefulness
発行日	2024-10-23
出版者	Oxford university press
収録物名	Sleep
巻(号)	48(1)
ページ	zsae244
抄録	Histamine, a neurotransmitter, plays a predominant role in maintaining wakefulness. Furthermore, our previous studies showed that histamine N-methyltransferase (HNMT), a histamine-metabolizing enzyme, is important for regulating brain histamine concentration. However, the effects of pharmacological HNMT inhibition on mouse behavior, 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. Behavioral tests showed that metoprine increased locomotor activity in both novel and familiar environments, but did not alter anxiety-like behavior. 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.
資源タイプ	学術雑誌論文
出版タイプ	Accepted Manuscript
権利情報	This is a pre-copyedited, author-produced version of an article accepted for publication in Sleep following peer review. The version of record Fumito Naganuma, Birkan Girgin, Anne Bernadette S Agu, Kyosuke Hirano, Tadaho Nakamura, Kazuhiko Yanai, Ramalingam Vetrivelan, Takatoshi Mochizuki, Masashi Yanagisawa, Takeo Yoshikawa, Pharmacological inhibition of histamine N-methyltransferase extends wakefulness and suppresses cataplexy in a mouse model of narcolepsy, Sleep, Volume 48, Issue 1, January 2025, zsae244 is available online at: https://doi.org/10.1093/sleep/zsae244
PISSN	0161-8105
EISSN	1550-9109
関連情報 (isVersionOf)	出版社版DOI https://doi.org/10.1093/sleep/zsae244