ナルコレプシーの病因と治療薬の開発

Development of a Therapeutic Drug for Narcolepsy

ナルコレプシーは，日中の強い眠気やカタプレキシーなどを主症状とする睡眠障害で，根本的な治療法はいまだみつかっていない。筆者らの所属する機構で創出されたオレキシン2型受容体作動薬YNT-185は，カタプレキシーを抑制する効果があるだけでなく，覚醒時間の延長を促し，ナルコレプシー治療薬としてのオレキシン2型作動薬の有効性が示された。さらに過剰な眠気を伴う他の睡眠障害を改善する創薬にもつながることが期待される。

Abstract

Narcolepsy-cataplexy is a debilitating disorder characterized by excessive daytime sleepiness and cataplexy, a bilateral loss of muscle tone triggered by positive emotions. The disease is caused by the loss of orexin-producing neurons in the hypothalamus. Currently, only symptom-oriented therapies are available for narcolepsy. We have recently discovered a potent, non-peptide orexin type-2 receptor (OX2R) agonist, YNT-185. We show that peripheral administration of YNT-185 significantly ameliorated the narcolepsy symptoms in a mouse model for narcolepsy. No desensitization was observed after repeated administration of YNT-185 with respect to the suppression of cataplexy-like episodes. These results provide a proof -of-concept for mechanistic therapy for narcolepsy-cataplexy using OX2R agonists. Additionally, YNT-185 promoted wakefulness in wild-type mice, suggesting that orexin receptor agonists may be useful for the treatment of excessive daytime sleepiness due to other conditions, such as sleepiness accompanying depression and sleepiness due to side effects of medicines or jet lag/shift work.