Inhibition of sleep in rats by inorganic selenium compounds, inhibitors of prostaglandin D synthase.

Abstract

Prostaglandin (PG) D2 has been postulated to be an endogenous sleep-promoting factor in rats, and SeC14 and Na2SeO3 recently have been shown to inhibit the PGD synthase (prostaglandin-H2 D-isomerase, EC 5.3.99.2) activity of rat brain. The effect of these selenium compounds on sleep-wake activities was examined in freely moving rats along with their effects on brain temperature, food and water intake, and behavior. Test substances were administered for 6 hr into the third ventricle of rats, using a microdialysis technique. SeC4, time-and dose-dependently, inhibited sleep at perfusion rates of 60 pmol/0.2 jcl per min and higher, and the inhibition was almost complete at rates >200 pmol/0.2 gIl per min. The effect was reversible and was followed by a rebound. Na2SeO3 exhibited similar effects, but Na2SO3 did not show any effect on sleep. Simultaneous administration of dithiothreitol eliminated the sleep-inhibiting effects of these selenium compounds. These findings indicate that the decrease in sleep is due to inhibition of the PGD synthase activity in the brain by SeCL4 as-well as Na2SeO3. During the inhibition of sleep, the rats in general showed an activation of behavior with moderate elevation of brain temperature and a detectable increase in food and water intake, suggesting that the sleep-inhibited state of the rats was similar to the physiological state of wakefulness and that the inhibitory effect was not due to the general toxicity of selenium.Prostaglandins (PGs) D2 and E2, which are the major PGs in the brain of mammals, have been postulated to be endogenous factors for regulating sleep-wake activities in the rat and monkey (1, 2)-the former promoting sleep (3, 4) and the latter augmenting wakefulness (5-7). Naito et al. (8) reported the effects of intracerebroventricularly and systemically administered cyclooxygenase inhibitors such as indomethacin and diclofenac sodium on the sleep-wake activities of rats. However, these inhibitors are not specific for PG0)2 but prevent the synthesis of PGH2 from arachidonate, which in turn affects the consequent production of various eicosanoids, including PGD2 and E2. The rat brain PGD synthase (prostaglandin-H2 D-isomerase, EC 5.3.99.2) was purified to homogeneity and characterized by Urade et al. (9,10). More recently, Islam et al. (11) demonstrated in an in vitro study that inorganic quadrivalent selenocompounds, such as SeCL4 and Na2SeO3, inhibited the activity of the rat brain PGD synthase whereas other enzymes in the arachidonate cascade were not affected. Therefore, these selenocompounds may serve as useful probes for elucidating the role of endogenous PGD2 in the physiological sleep-wake regulation.In the present study, the effects of selenocompounds on sleep-wake activities, brain temperature, food and water intake, and behavior were examined in freely moving rats by administration of these compounds into the third ventricle via a microdialysis probe. The results obtained add further support to the hypothesis that PGD2 is involved in the promotion ...

Prostaglandin D synthase gene is involved in the regulation of non-rapid eye movement sleep

“…Infusion of selective inhibitors of PGDS, e.g., tetravalent selenium compounds, reversibly, timeand dose-dependently inhibited both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep during the daytime (13). These observations clearly showed that PGDS plays a crucial role in the regulation of physiological sleep.…”

“…Previously, the relationship between PGD 2 and sleep was examined mainly pharmacologically by administration of exogenous PGD 2 into the brain and inhibition of PGDS in vivo by selenium compounds (3,4,10,13) or under certain pathological conditions as reported in some sleep disorders (14,15).…”

Adenosine in the tuberomammillary nucleus inhibits the histaminergic system via A 1 receptors and promotes non-rapid eye movement sleep

“…PGD 2 -induced sleep was indistinguishable from natural physiological sleep as judged by several electrophysiological and behavioral criteria (5). Subsequent studies have shown that PGD 2 is involved in both circadian (6,7) and homeostatic regulation of sleep (8). Further studies on the molecular mechanisms of sleep-wake regulation by PGD 2 demonstrated that PGD 2 is produced by the action of lipocalin-type PGD synthase dominantly expressed in the leptomeninges (9), binds with PGD receptors (DPRs) exclusively localized in the arachnoid membrane of the basal forebrain (BF) (10), and promotes sleep through adenosine acting at adenosine A 2A receptors (A 2A R's) (11), followed by activation of sleep-active neurons in the ventrolateral preoptic (VLPO) area (12,13).…”

Promotion of sleep mediated by the A2a-adenosine receptor and possible involvement of this receptor in the sleep induced by prostaglandin D2 in rats.

“…Statistics was performed by use of paired t test, with each animal serving as its own control. Details of the scoring method of sleep-wake stages and the experimental equipments were described previously (2,15,16 (Fig. 1B), SWS showed a tendency to decrease during the first 3 hr of the infusion, but it then increased during the last 1-2 hr.…”