Osaka Bioscience Institute, Suita, Osaka 565, Japan
n the late 1970s, we reported that prostaglandin (PG) D2 and E2 are the major PGs in the CNS of rats and other mammals including humans. PGD2 had long been considered as a minor and biologically inactive prostanoid. In 1983, we found that when PGD2 was infused into the third ventricle of a rat during the night, both SWS and REM sleep increased significantly. The effect was specific for PGD2 and dose-dependent. Most importantly, sleep induced by PGD2 was indistinguishable from physiological sleep as judged by EEG, EMG, locomotor activities, brain temperature, heart rate, and general behavior of the rat. Subsequently the specific activity of PGD synthase(PGDS) in the rat brain as well as the level of PGD2 in the CSF of rat was shown to exhibit circadian fluctuation in parallel with the sleep/wake cycle. We then purified PGDS from human and rat brains, and found that inorganic quadrivalent selenium compounds are potent, specific, non-competitive, and reversible inhibitors of brain PGDS. When selenium chloride was infused into the third ventricle of a rat during the day, both SWS and REM sleep were inhibited time- and dose-dependently and in about 2 hours from the start of infusion, both SWS and REMS were almost completely inhibited indicating that PGDS is the key enzyme in sleep-regulation. In situ hybridization, immunohistochemical staining and direct determination of enzyme activity reveal that PGDS is mainly, if not exclusively, present in the membrane system surrounding the brain, namely arachnoid membrane and choroid plexus, and that it is secreted into the CSF to become b-trace. These results indicate that PGDS and PGD2 thus produced circulate in the ventricular system, subarachnoid space and extracellular space in the brain system. PGD2, then, interacts with receptors on the ventro-medial surface of the rostral basal forebrain to initiate the signal to make the brain sleep. Preliminary evidence suggests that the sleep inducing signal initiated by PGD2 is then transmitted into the brain parenchyma by adenosine through adenosine A2a receptor.
