Wake-promoting effects of ONO-4127Na, a prostaglandin DP1 receptor antagonist, in hypocretin/orexin deficient narcoleptic mice. 2016

Yohei Sagawa, and Masatoshi Sato, and Noriaki Sakai, and Sachiko Chikahisa, and Shintaro Chiba, and Takashi Maruyama, and Junki Yamamoto, and Seiji Nishino
Sleep and Circadian Neurobiology Laboratory, Stanford University, United States; Department of Neuropsychiatry, Akita University Graduate School of Medicine, Japan.

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.

UI MeSH Term Description Entries
D007031 Hypothalamus Ventral part of the DIENCEPHALON extending from the region of the OPTIC CHIASM to the caudal border of the MAMMILLARY BODIES and forming the inferior and lateral walls of the THIRD VENTRICLE. Lamina Terminalis,Preoptico-Hypothalamic Area,Area, Preoptico-Hypothalamic,Areas, Preoptico-Hypothalamic,Preoptico Hypothalamic Area,Preoptico-Hypothalamic Areas
D008810 Mice, Inbred C57BL One of the first INBRED MOUSE STRAINS to be sequenced. This strain is commonly used as genetic background for transgenic mouse models. Refractory to many tumors, this strain is also preferred model for studying role of genetic variations in development of diseases. Mice, C57BL,Mouse, C57BL,Mouse, Inbred C57BL,C57BL Mice,C57BL Mice, Inbred,C57BL Mouse,C57BL Mouse, Inbred,Inbred C57BL Mice,Inbred C57BL Mouse
D009043 Motor Activity Body movements of a human or an animal as a behavioral phenomenon. Activities, Motor,Activity, Motor,Motor Activities
D009290 Narcolepsy A condition characterized by recurrent episodes of daytime somnolence and lapses in consciousness (microsomnias) that may be associated with automatic behaviors and AMNESIA. CATAPLEXY; SLEEP PARALYSIS, and hypnagogic HALLUCINATIONS frequently accompany narcolepsy. The pathophysiology of this disorder includes sleep-onset rapid eye movement (REM) sleep, which normally follows stage III or IV sleep. (From Neurology 1998 Feb;50(2 Suppl 1):S2-S7) Gelineau Syndrome,Narcolepsy-Cataplexy Syndrome,Paroxysmal Sleep,Gelineau's Syndrome,Narcoleptic Syndrome,Gelineau's Syndromes,Gelineaus Syndrome,Narcolepsy Cataplexy Syndrome,Narcolepsy-Cataplexy Syndromes,Narcoleptic Syndromes,Sleep, Paroxysmal,Syndrome, Gelineau,Syndrome, Gelineau's,Syndrome, Narcolepsy-Cataplexy,Syndrome, Narcoleptic,Syndromes, Gelineau's,Syndromes, Narcolepsy-Cataplexy,Syndromes, Narcoleptic
D011448 Prostaglandin Antagonists Compounds that inhibit the action of prostaglandins. Prostaglandin Inhibitors,Antagonists, Prostaglandin,Inhibitors, Prostaglandin,Prostaglandin Antagonist,Prostaglandin Inhibitor,Antagonist, Prostaglandin,Inhibitor, Prostaglandin
D011971 Receptors, Immunologic Cell surface molecules on cells of the immune system that specifically bind surface molecules or messenger molecules and trigger changes in the behavior of cells. Although these receptors were first identified in the immune system, many have important functions elsewhere. Immunologic Receptors,Immunologic Receptor,Immunological Receptors,Receptor, Immunologic,Receptors, Immunological
D011982 Receptors, Prostaglandin Cell surface receptors that bind prostaglandins with high affinity and trigger intracellular changes which influence the behavior of cells. Prostaglandin receptor subtypes have been tentatively named according to their relative affinities for the endogenous prostaglandins. They include those which prefer prostaglandin D2 (DP receptors), prostaglandin E2 (EP1, EP2, and EP3 receptors), prostaglandin F2-alpha (FP receptors), and prostacyclin (IP receptors). Prostaglandin Receptors,Prostaglandin Receptor,Receptor, Prostaglandin,Receptors, Prostaglandins,Prostaglandins Receptors
D001831 Body Temperature The measure of the level of heat of a human or animal. Organ Temperature,Body Temperatures,Organ Temperatures,Temperature, Body,Temperature, Organ,Temperatures, Body,Temperatures, Organ
D004195 Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases. Animal Disease Model,Animal Disease Models,Disease Model, Animal
D004569 Electroencephalography Recording of electric currents developed in the brain by means of electrodes applied to the scalp, to the surface of the brain, or placed within the substance of the brain. EEG,Electroencephalogram,Electroencephalograms

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