Journal Article

Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models

Sakurai, Takeshi, Tominaga, Hiromu, Ishikawa, Yukiko, Ogawa, Yasuhiro, Irukayama-Tomobe, Yoko, Yanagisawa, Masashi, Kanda, Takeshi, Nagase, Hiroshi, Hosokawa, Naoto, Ambai, Shinobu, Uchida, Shuntaro, Vogt, Kaspar, Nakajima, Ryo, Saitoh, Tsuyoshi, Kawabe, Yuki

2017

Overview

Narcolepsy-cataplexy is a debilitating disorder of sleep/wakefulness caused by a loss of orexin-producing neurons in the lateroposterior hypothalamus. Genetic or pharmacologic orexin replacement ameliorates symptoms in mouse models of narcolepsy-cataplexy. We have recently discovered a potent, nonpeptide OX2R-selective agonist, YNT-185. This study validates the pharmacological activity of this compound in OX2R-transfected cells and in OX2R-expressing neurons in brain slice preparations. Intraperitoneal, and intracerebroventricular, administration of YNT-185 suppressed cataplexy-like episodes in orexin knockout and orexin neuron-ablatedmice, but not in orexin receptor-deficient mice. Peripherally administered YNT- 185 also promotes wakefulness without affecting body temperature in wild-type mice. Further, there was no immediate rebound sleep after YNT-185 administration in active phase in wild-type and orexin-deficient mice. 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 a mechanistic therapy of narcolepsy-cataplexy by OX2R agonists.

• Publisher: National Academy of Sciences
• Subject: Animal models / Animals / Biological Sciences / Body temperature / Brain / Brain slice preparation / Cataplexy / Cataplexy - drug therapy / Cells / Desensitization / Disease Models, Animal / Hypothalamus / Hypothalamus - metabolism / Male / Mice / Mice, Inbred C57BL / Mice, Knockout / Narcolepsy / Narcolepsy - drug therapy / Neurons / Orexin Receptors - agonists / Orexin Receptors - genetics / Orexins / Orexins - genetics / Orexins - metabolism / Patch-Clamp Techniques / Peptides / Pharmacology / Rodents / Sleep / Sleep - drug effects / Sleep and wakefulness / Sleep disorders / Sleep Disorders, Circadian Rhythm - drug therapy / Wakefulness / Wakefulness - drug effects / Wakefulness-Promoting Agents - therapeutic use