Prostaglandin D2 and sleep/wake regulation

Prostaglandin (PG) D₂ is the most potent endogenous sleep-promoting substance. PGD₂ 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. PGD₂ 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 A₁ receptor-possessing arousal neurons. PGD₂ 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 PGD₂-adenosine system is crucial for the maintenance of physiological sleep.