Author: Sato, Masatoshi ; Maruyama, Takashi ; Chikahisa, Sachiko ; Yamamoto, Junki ; Sagawa, Yohei ; Chiba, Shintaro ; Nishino, Seiji ; Sakai, Noriaki

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.

01 Aug 2009·Nihon rinsho. Japanese journal of clinical medicine

[Molecular mechanisms of insomnia].

Article

Author: Urade, Yoshihiro

Prostaglandin (PG) D2 and adenosine are potent endogenous somnogens and their sleep-inducing mechanisms are well characterized. We examined the contribution of these somnogens to physiological sleep by the combination of pharmacological tools and gene-knockout (KO) mice. Complete insomnia was observed in wild-type mice after an intraperitoneal injection of SeCl4, an inhibitor of PGD synthase (PGDS), or caffeine, an antagonist of adenosine A2A receptors. The SeCl4-induced insomnia was not observed in PGDS- or DP1 receptor-KO mice and the caffeine-induced insomnia, in A(2A) receptor-KO mice. A DP1 antagonist, ONO-4127Na, reduced sleep of rats by 30% during infusion into the subarachnoid space of the basal forebrain. These results indicate that the PGD2/ adenosine system plays a critical role in the regulation of physiological sleep.

21 Nov 2006·Proceedings of the National Academy of SciencesQ1 · CROSS-FIELD

Lipocalin-type prostaglandin D synthase produces prostaglandin D ₂ involved in regulation of physiological sleep

Q1 · CROSS-FIELD

Article

Author: Xu, Xin-Hong ; Aritake, Kosuke ; Qu, Wei-Min ; Huang, Zhi-Li ; Eguchi, Naomi ; Narumiya, Shu ; Hayaishi, Osamu ; Urade, Yoshihiro ; Nambu, Fumio

Prostaglandin (PG) D 2 has been proposed to be essential for the initiation and maintenance of the physiological sleep of rats because intracerebroventricular administration of selenium tetrachloride (SeCl 4 ), a selective inhibitor of PGD synthase (PGDS), was shown to reduce promptly and effectively the amounts of sleep during the period of infusion. However, gene knockout (KO) mice of PGDS and prostaglandin D receptor (DP 1 R) showed essentially the same circadian profiles and daily amounts of sleep as wild-type (WT) mice, raising questions about the involvement of PGD 2 in regulating physiological sleep. Here we examined the effect of SeCl 4 on the sleep of WT and KO mice for PGDS and DP 1 R and that of a DP 1 R antagonist, ONO-4127Na, on the sleep of rats. The i.p. injection of SeCl 4 into WT mice decreased the PGD 2 content in the brain without affecting the amounts of PGE 2 and PGF 2α . It inhibited sleep dose-dependently and immediately after the administration during the light period when mice normally sleep, increasing the wake time; and the treatment with this compound resulted in a distinct sleep rebound during the following dark period. The SeCl 4 -induced insomnia was observed in hematopoietic PGDS KO mice but not at all in lipocalin-type PGDS KO, hematopoietic and lipocalin-type PGDS double KO or DP 1 R KO mice. Furthermore, the DP 1 R antagonist ONO-4127Na reduced sleep of rats by 30% during infusion into the subarachnoid space under the rostral basal forebrain at 200 pmol/min. These results clearly show that the lipocalin-type PGDS/PGD 2 /DP 1 R system plays pivotal roles in the regulation of physiological sleep.

100 Deals associated with ONO-4127

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Indication	Highest Phase	Country/Location	Organization	Date
Rhinitis, Allergic	Phase 3	GB	-	-
Rhinitis, Allergic	Phase 3	-	Ono Pharmaceutical Co., Ltd.	-
Sleep Initiation and Maintenance Disorders	Preclinical	JP	Ono Pharmaceutical Co., Ltd.	21 Nov 2006
Sleep Initiation and Maintenance Disorders	Preclinical	CN	Shanghai Medical College of Fudan University	21 Nov 2006
Sleep Initiation and Maintenance Disorders	Preclinical	JP	Osaka Bioscience Institute	21 Nov 2006

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