Moriyama Hiroshi, Nomura Sadahiro, Imoto Hirochika, Oka Fumiaki, Maruta Yuichi, Mori Naomasa, Fujii Natsumi, Suzuki Michiyasu, Ishihara Hideyuki
Departments of Neurosurgery, Graduate School of Medicine, Yamaguchi University, Ube, Yamaguchi, Japan.
Epilepsy Center, Yamaguchi University Hospital, Ube, Yamaguchi, Japan.
Front Pharmacol. 2023 Mar 9;14:1138673. doi: 10.3389/fphar.2023.1138673. eCollection 2023.
Febrile seizures (FSs) are the most frequent type of seizures in infancy and childhood. Epileptiform discharges (EDs) on electroencephalogram at the time of first FS recurrence can increase the risk of epilepsy development. Therefore, inhibition of EDs is important. Recently, WS-3, a transient receptor potential melastatin 8 (TRPM8) agonist, reportedly suppressed penicillin G-induced cortical-focal EDs. However, the effects of TRPM8 agonists on FSs remain unknown. In this study, we aimed to clarify the effects of the TRPM8 agonist, and the absence of TRPM8 channels, on hyperthermia-induced FS by analyzing the fast ripple band. Hyperthermia (43°C for 30 min) induced by a heating pad caused FSs in postnatal day 7 wild-type (WT) and TRPM8 knockout (TRPM8KO) mice. FSs were defined as EDs occurring during behavioral seizures involving hindlimb clonus and loss of the righting reflex. Mice were injected with 1% dimethyl sulfoxide or 1 mM WS-3 20 min before the onset of hyperthermia, and electroencephalograms; movies; and rectal, brain and heating pad temperatures were recorded. In wild-type mice, WS-3 reduced the fast ripple amplitude in the first FS without changing rectal and brain temperature thresholds. In contrast, the anti-FS effect induced by the TRPM8 agonist was not observed in TRPM8KO mice and, compared with wild-type mice, TRPM8 deficiency lowered the rectal and brain temperature thresholds for FSs, exacerbated the fast ripple amplitude, and prolonged the duration of the initial FS induced by hyperthermia. Our findings suggest that TRPM8 agonists can be used to treat hyperthermia-induced FSs.
热性惊厥（FSs）是婴幼儿期最常见的惊厥类型。首次FS复发时脑电图上的癫痫样放电（EDs）会增加癫痫发生的风险。因此，抑制EDs很重要。最近，据报道，瞬时受体电位香草酸亚型8（TRPM8）激动剂WS-3可抑制青霉素G诱导的皮质局灶性EDs。然而，TRPM8激动剂对FSs的影响仍不清楚。在本研究中，我们旨在通过分析快波频段来阐明TRPM8激动剂以及TRPM8通道缺失对热诱导FSs的影响。加热垫诱导的热刺激（43°C，持续30分钟）可使出生后第7天的野生型（WT）和TRPM8基因敲除（TRPM8KO）小鼠发生FSs。FSs被定义为在涉及后肢阵挛和翻正反射丧失的行为性惊厥期间出现的EDs。在热刺激开始前20分钟，给小鼠注射1%二甲基亚砜或1 mM WS-3，并记录脑电图、视频以及直肠、脑和加热垫的温度。在野生型小鼠中，WS-3可降低首次FS时的快波幅度，而不改变直肠和脑的温度阈值。相比之下，在TRPM8KO小鼠中未观察到TRPM8激动剂诱导的抗FS效应，并且与野生型小鼠相比，TRPM8缺乏降低了FSs的直肠和脑温度阈值，加剧了快波幅度，并延长了热刺激诱导的初始FS的持续时间。我们的研究结果表明，TRPM8激动剂可用于治疗热诱导的FSs。
