PNAS 103:17949-17954, 2006

 Lipocalin-type prostaglandin D synthase produces prostaglandin D2 involved in regulation of physiological sleep

Prostaglandin (PG) D2 has been proposed to be essential for the initiation and maintenance of the physiological sleep of rats because intracerebroventricular administration of selenium tetrachloride (SeCl4), 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 (DP1R) showed essentially the same circadian profiles and daily amounts of sleep as wild-type (WT) mice, raising questions about the involvement of PGD2 in regulating physiological sleep. Here we examined the effect of SeCl4 on the sleep of WT and KO mice for PGDS and DP1R and that of a DP1R antagonist, ONO-4127Na, on the sleep of rats. The i.p. injection of SeCl4 into WT mice decreased the PGD2 content in the brain without affecting the amounts of PGE2 and PGF2α. 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 SeCl4-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 DP1R KO mice. Furthermore, the DP1R 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/PGD2/DP1R system plays pivotal roles in the regulation of physiological sleep.

 　＝＝＝

●SeCl4（PGD synthaseの阻害剤）を入れると、sleep↓

●DP1R antagonistのONO-4127Naを入れると、sleep↓

●しかし、DP1R-KOマウスでは、sleepの量もcircadianも差がない

●L-PGDS-KOマウスでも、sleepの量もcircadianも差がない

  (Ref.)

↓

●PGD2以外のalternative pathwayによるcompensationの問題/阻害剤のspecificityの問題

●DP1R-KOマウスでSeCl4を入れるとどうなる？

↓

●H-PGDS、L-PGDS、DP1R-KOマウスでSeCl4を入れたら、、L-PGDS、DP1R-KOマウスではsleep↓の効果が見えなくなった。ということは、acuteの効果はやはり見える。

●sleep↓の後のリバウンドは、L&H-PGDS-DKOにすると消える。

●いずれにしても、circadianはがっつり残る→睡眠ホメオスタシスと日内変動のメカニズムがどう絡み合うのか？？