Prostaglandin D_2 and adenosine as endogenous somnogens

摘要

Prostaglandin D_2 (PGD_2) is the most potent endogenous sleep-promoting substance thus far reported. We have extensively studied its action mechanism at the molecular level. PCD_2 is produced by lipocalin-type PGD synthase, which is dominantly localized in the leptomeninges, choroid plexus, and oligodendrocytes in the brain; and it is secreted into the cerebrospinal fluid and stimulates DP, receptors localized in the arachnoid membrane of the ventral surface from the basal forebrain to the hypothalamus to increase the extracellular concentration of adenosine as a paracrine sleep-promoting molecule. Adenosine diffuses into the brain parenchyma, suppresses cholinergic arousal neurons in the basal forebrain via adenosine A_1 receptors, activates sleep-active neurons in the ventrolateral preoptic area via adenosine A_(2A) receptors, and concomitantly suppresses the histamin-ergic arousal center in the tuberomammillary nucleus through GABAergic and galaninergic inhibitory projections. Administration of an inhibitor of lipocalin-type PGD synthase (SeCU), an antagonist of DP, receptors (ONO-4127Na) or an antagonist of adenosine A_(2A) receptors (caffeine) results in sleep inhibition in rats and mice, indicating that the PGD_2-adenosine system is crucial for the maintenance of physiological sleep.