title: Wake-promoting effects of ONO-4127Na, a prostaglandin DP1 receptor antagonist, in hypocretin/orexin deficient narcoleptic mice.
abstract: Prostaglandin (PG)D2 is an endogenous sleep substance, and a series of animal studies reported that PGD2 or PGD2 receptor (DP1) agonists promote sleep, while DP1 antagonists promote wakefulness. This suggests the possibility of use of PG DP1 antagonists as wake-promoting compounds. We therefore evaluated the wake-promoting effects of ONO-4127Na, a DP1 antagonist, in a mouse model of narcolepsy (i.e., orexin/ataxin-3 transgenic mice) and compared those to effects of modafinil. ONO-4127Na perfused in the basal forebrain (BF) area potently promoted wakefulness in both wild type and narcoleptic mice, and the wake-promoting effects of ONO-4127Na at 2.93 × 10(-4) M roughly corresponded to those of modafinil at 100 mg/kg (p.o.). The wake promoting effects of ONO-4127Na was observed both during light and dark periods, and much larger effects were seen during the light period when mice slept most of the time. ONO-4127Na, when perfused in the hypothalamic area, had no effects on sleep. We further demonstrated that wake-promoting effects of ONO-4127Na were abolished in DP1 KO mice, confirming that the wake-promoting effect of ONO-4127Na is mediated by blockade of the PG DP1 receptors located in the BF area. ONO-4127Na reduced DREM, an EEG/EMG assessment of behavioral cataplexy in narcoleptic mice, suggesting that ONO-4127Na is likely to have anticataplectic effects. DP1 antagonists may be a new class of compounds for the treatment of narcolepsy-cataplexy, and further studies are warranted.
authors.affiliation: Sleep and Circadian Neurobiology Laboratory, Stanford University, United States; Department of Neuropsychiatry, Akita University Graduate School of Medicine, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Sagawa
authors.affiliation: Sleep and Circadian Neurobiology Laboratory, Stanford University, United States; Department of Neuropsychiatry, Akita University Graduate School of Medicine, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Sato
authors.affiliation: Sleep and Circadian Neurobiology Laboratory, Stanford University, United States.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Sakai
authors.affiliation: Sleep and Circadian Neurobiology Laboratory, Stanford University, United States; Department of Integrative Physiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Chikahisa
authors.affiliation: Sleep and Circadian Neurobiology Laboratory, Stanford University, United States; Department of Otorhinolaryngology, Jikei University School of Medicine, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Chiba
authors.affiliation: Sleep and Circadian Neurobiology Laboratory, Stanford University, United States.
authors.forename: Takashi
authors.initials: T
authors.lastname: Maruyama
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: Junki
authors.initials: J
authors.lastname: Yamamoto
authors.affiliation: Sleep and Circadian Neurobiology Laboratory, Stanford University, United States. Electronic address: nishino@stanford.edu.
authors.forename: Seiji
authors.initials: S
authors.lastname: Nishino
mesh_terms: D000818:Animals; D000067699:Ataxin-3 / Q000172:deficiency* / Q000235:genetics; D001559:Benzhydryl Compounds / Q000494:pharmacology; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004569:Electroencephalography; D004576:Electromyography; D007031:Hypothalamus / Q000187:drug effects / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000077408:Modafinil; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009290:Narcolepsy / Q000188:drug therapy* / Q000503:physiopathology; D000068797:Orexins / Q000172:deficiency* / Q000235:genetics; D017440:Photoperiod; D016548:Prosencephalon / Q000187:drug effects / Q000503:physiopathology; D011448:Prostaglandin Antagonists / Q000494:pharmacology*; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012894:Sleep Stages / Q000187:drug effects / Q000502:physiology; D014851:Wakefulness / Q000187:drug effects / Q000502:physiology; D064690:Wakefulness-Promoting Agents / Q000494:pharmacology*
chemical_list: D001559:Benzhydryl Compounds; C000596233:Hcrt protein, mouse; D000068797:Orexins; D011448:Prostaglandin Antagonists; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D064690:Wakefulness-Promoting Agents; D000067699:Ataxin-3; C511594:Atxn3 protein, mouse; D000077408:Modafinil; C036293:prostaglandin D2 receptor
keywords: Hypocretin/orexin; Modafinil; Narcolepsy; Prostaglandin; Prostaglandin D2; Prostaglandin DP1 receptor antagonist