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

30 Citations (Scopus)

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

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Orexin Receptors
Cataplexy
Narcolepsy
Wakefulness
Neurons
Body Temperature
Hypothalamus
Sleep
Pharmacology
Brain

Keywords

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

ASJC Scopus subject areas

  • General

Cite this

Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models. / Irukayama-Tomobe, Yoko; Ogawa, Yasuhiro; Tominaga, Hiromu; Ishikawa, Yukiko; Hosokawa, Naoto; Ambai, Shinobu; Kawabe, Yuki; Uchida, Shuntaro; Nakajima, Ryo; Saitoh, Tsuyoshi; Kanda, Takeshi; Vogt, Kaspar; Sakurai, Takeshi; Nagase, Hiroshi; Yanagisawa, Masashi.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 22, 30.05.2017, p. 5731-5736.

Research output: Contribution to journalArticle

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, vol. 114, no. 22, pp. 5731-5736. https://doi.org/10.1073/pnas.1700499114
Irukayama-Tomobe, Yoko ; Ogawa, Yasuhiro ; Tominaga, Hiromu ; Ishikawa, Yukiko ; Hosokawa, Naoto ; Ambai, Shinobu ; Kawabe, Yuki ; Uchida, Shuntaro ; Nakajima, Ryo ; Saitoh, Tsuyoshi ; Kanda, Takeshi ; Vogt, Kaspar ; Sakurai, Takeshi ; Nagase, Hiroshi ; Yanagisawa, Masashi. / Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 22. pp. 5731-5736.
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