Prostaglandin D Synthase in the Prenatal Ovine Brain and Effects of Its Inhibition with Selenium Chloride on Fetal Sleep/Wake ActivityIn Utero

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.

Novel method for in vivo hydroxyl radical measurement by microdialysis in fetal sheep brain in utero

“…Because salicylate inhibits cyclooxygenase activity, an important enzyme for prostaglandin production and a pathway with many physiological functions in both normal and disease conditions (33, 39), it has a significant limitation when prostaglandins are involved in responses to stress and trauma in the brain. This is almost certainly the case in the fetal and newborn brain, where prostaglandins are involved in the regulation of cerebral blood flow and neural activity that determine sleep and breathing activity (22). Furthermore, salicylate inhibits phospholipase C and interacts with several transition metal ions (5).…”

mRNA expression in mouse hypothalamus and basal forebrain during influenza infection: a novel model for sleep regulation

“…PGD2 is a major prostanoid in the mammalian brain as well as a major endogenous sleep-promoting substance in mice, rats, and monkeys and probably in humans (15). PGD2 promotes sleep via both the ventral rostral basal forebrain (24) and the anterior hypothalamus (22). Administration of inorganic selenium compounds modifies sleep, anesthesia, and hypothalamic phospholipid regulation in rats and mice (9,19,36).…”

Waking up too early – the consequences of preterm birth on sleep development

“…Evidence strongly suggests that the fetal brain is actively inhibited from initiating cortical arousal to an awake state, even in late gestation, through significant release of inhibitory neurotransmitters and modulators from the placenta as well as the fetal brain itself, such as steroids, adenosine and prostaglandin D2 (Lee et al . ; Hunter et al . ; Nguyen et al .…”