Prostaglandin D synthase in the prenatal ovine brain and effects of its inhibition with selenium chloride on fetal sleep/wake activity in utero.

Brenda Lee, Jonathan J Hirst, David W Walker

Index: J. Neurosci. 22(13) , 5679-86, (2002)

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Abstract

It has been proposed that prostaglandin (PG) D(2) induces physiological sleep in mammals by acting on sleep centers located in the anterior hypothalamus. In fetal sheep, definitive rapid-eye-movement and non-rapid-eye-movement sleep states appear at approximately 125 d gestation (term is approximately 147 d). In adult animals, PGD synthase (PGDS) (functionally and structurally homologous to beta-trace protein) is secreted into CSF with a circadian pattern, with the highest concentrations present during sleep. In this study we show that PGDS/beta-trace protein is present in fetal sheep CSF at 125 and 135 d gestation but not at 90 d gestation. SeCl(4), a specific inhibitor of PGDS, was given to unanesthetized fetal sheep (130-140 d gestation) by intracerebroventricular infusion at a dose of 25, 100, 500, or 1000 pmol/min for 4 hr. Artificial CSF was infused in control experiments. Arousal behavior, defined as the presence of nuchal muscle electromyogram activity, electro-ocular activity, and breathing movements during low-amplitude electrocortical activity, increased from 3.8 +/- 1 min/hr to 6.6 +/- 0.5 and 7.0 +/- 0.3 min/hr at doses of 100 and 500 pmol/min, respectively (p < 0.05). SeCl(4) at 25 and 1000 pmol/min had no significant effect on arousal activity. Infusion of PGD(2) at 500 pmol/min intracerebroventricularly for 4 hr decreased the incidence of arousal from 3.8 +/- 0.5 min/hr to 0.7 +/- 0.3 min/hr (p < 0.05). When 500 pmol/min PGD(2) was infused immediately after a 4 hr infusion of SeCl(4) (500 pmol/min), the SeCl(4)-induced increase in arousal behavior was abolished. Together, the presence of PGDS/beta-trace protein in fetal CSF in late gestation and the effects of SeCl(4) in increasing the incidence of arousal-like behavior suggest that PGD(2) has a role in the induction and maintenance of prenatal sleep.