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

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

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

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 orexindeficient 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.

Original languageEnglish (US)
Pages (from-to)5731-5736
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number22
DOIs
StatePublished - May 30 2017

    Fingerprint

Keywords

  • Electroencephalography
  • Electromyography
  • Excessive daytime sleepiness
  • G protein-coupled receptors
  • Neuropeptide

ASJC Scopus subject areas

  • General

Cite this

Irukayama-Tomobe, Y., Ogawa, Y., Tominaga, H., Ishikawa, Y., Hosokawa, N., Ambai, S., Kawabe, Y., Uchida, S., Nakajima, R., Saitoh, T., Kanda, T., Vogt, K., Sakurai, T., Nagase, H., & Yanagisawa, M. (2017). Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models. Proceedings of the National Academy of Sciences of the United States of America, 114(22), 5731-5736. https://doi.org/10.1073/pnas.1700499114