Prostaglandin D2 and sleep/wake regulation

Prostaglandin (PG) D-2 is the most potent endogenous sleep-promoting substance. PGD(2) is produced by lipocalin-type PGD synthase localized in the leptomeninges, choroid plexus, and oligodendrocytes in the brain, and is secreted into the cerebrospinal fluid as a sleep hormone. PGD(2) stimulates DP1 receptors localized in the leptomeninges under the basal forebrain and the hypothalamus. As a consequence, adenosine is released as a paracrine sleep-promoting molecule to activate adenosine A(2A) receptor-expressing sleep-promoting neurons and to inhibit adenosine A(1) receptor-possessing arousal neurons. PGD(2) activates a center of non-rapid eye movement (NREM) sleep regulation in the ventrolateral preoptic area, probably mediated by adenosine signaling, which activation inhibits the histaminergic arousal center in the tuberomammillary nucleus via descending GABAergic and galaninergic projections. The administration of a lipocalin-type PGD synthase inhibitor (SeCl4), DP1 antagonist (ONO-4127Na) or adenosine A(2A) receptor antagonist (caffeine) suppresses both NREM and rapid eye movement (REM) sleep, indicating that the PGD(2)-adenosine system is crucial for the maintenance of physiological sleep. (C) 2011 Elsevier Ltd. All rights reserved.