TY - JOUR
T1 - Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models
AU - Irukayama-Tomobe, Yoko
AU - Ogawa, Yasuhiro
AU - Tominaga, Hiromu
AU - Ishikawa, Yukiko
AU - Hosokawa, Naoto
AU - Ambai, Shinobu
AU - Kawabe, Yuki
AU - Uchida, Shuntaro
AU - Nakajima, Ryo
AU - Saitoh, Tsuyoshi
AU - Kanda, Takeshi
AU - Vogt, Kaspar
AU - Sakurai, Takeshi
AU - Nagase, Hiroshi
AU - Yanagisawa, Masashi
PY - 2017/5/30
Y1 - 2017/5/30
N2 - 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.
AB - 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.
KW - Electroencephalography
KW - Electromyography
KW - Excessive daytime sleepiness
KW - G protein-coupled receptors
KW - Neuropeptide
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U2 - 10.1073/pnas.1700499114
DO - 10.1073/pnas.1700499114
M3 - Article
C2 - 28507129
AN - SCOPUS:85020029560
SN - 0027-8424
VL - 114
SP - 5731
EP - 5736
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 22
ER -