Interaction of PGHS-2 and glutamatergic mechanisms controlling the ovine fetal hypothalamus-pituitary-adrenal axis

Abstract

Prostaglandins, generated within the fetal brain, are integral components of the mechanism controlling the fetal hypothalamus-pituitary-adrenal (HPA) axis. Previous studies in this laboratory demonstrated that prostaglandin G/H synthase isozyme 2 (PGHS-2) inhibition reduces the fetal HPA axis response to cerebral hypoperfusion, blocks the preparturient rise in fetal plasma ACTH concentration, and delays parturition. We also discovered that blockade of N-methyl-d-aspartate (NMDA) receptors reduces the fetal ACTH response to cerebral hypoperfusion. The present study was designed to test the hypothesis that PGHS-2 action and the downstream effect of HPA axis stimulation are stimulated by NMDA-mediated glutamatergic neurotransmission. Chronically catheterized late-gestation fetal sheep (n = 8) were injected with NMDA (1 mg iv). All responded with increases in fetal plasma ACTH and cortisol concentrations. Pretreatment with resveratrol (100 mg iv, n = 5), a specific inhibitor of PGHS-1, did not alter the magnitude of the HPA axis response to NMDA. Pretreatment with nimesulide (10 mg iv, n = 6), a specific inhibitor of PGHS-2, significantly reduced the HPA axis response to NMDA. To further explore this interaction, we injected NMDA in six chronically catheterized fetal sheep that were chronically infused with nimesulide (n = 6) at a rate of 1 mg/day into the lateral cerebral ventricle for 5-7 days. In this group, there was no significant ACTH response to NMDA. Finally, we tested whether the HPA axis response to prostaglandin E(2) (PGE(2)) is mediated by NMDA receptors. Seven chronically catheterized late-gestation fetal sheep were injected with 100 ng of PGE(2), which significantly increased fetal plasma ACTH and cortisol concentrations. Pretreatment with ketamine (10 mg iv), an NMDA antagonist, did not alter the ACTH or cortisol response to PGE(2). We conclude that generation of prostanoids via the action of PGHS-2 in the fetal brain augments the fetal HPA axis response to NMDA-mediated glutamatergic stimulation.

Neuroprotective Effect of Resveratrol Against Glutamate-Induced Excitotoxicity

“…Res also inhibited NMDA-induced neuronal death, intracellular calcium increase and reactive oxygen species generation in rat cortical neurons, confirming the neuroprotective effect of Res [11,28]. However, other studies have shown that pretreatment with Res did not alter the magnitude of the hypothalamus-pituitary-adrenal axis response to NMDA [29]. Furthermore, some studies have shown that treating neurons with Res did not protect them from Glu/NMDA-induced depletion of nicotinamide adenine dinucleotide (NAD+), an important energy substrate and cofactor in multiple metabolic reactions, and death [30].…”

Ketamine Attenuates the ACTH Response to Hypoxia in Late-Gestation Ovine Fetus

“…We know, from previous results in this laboratory, that NMDA stimulates fetal ACTH secretion [20]. However, it is also known that the fetal ACTH response to hypoxia is dependent on the carotid chemoreflex [10, 21, 22], and that at least one report in the literature suggests that ketamine modulates fetal ovine cardiovascular responses to chemoreceptor stimulation [16].…”

Ketamine modulates fetal hemodynamic and endocrine responses to umbilical cord occlusion

“…), partially inhibits the fetal ACTH response to hypoxic hypoxia (Chang and Wood ), and almost completely inhibits the fetal ACTH response to brachiocephalic artery occlusion (a model of brain and carotid body ischemic hypoxia) (Powers and Wood ). Furthermore, we have demonstrated that intravenous injection of NMDA stimulates fetal ACTH secretion, and that the effect is partially dependent on prostaglandin biosynthesis (Knutson and Wood ). Boekkooi et al.…”

“…We have reported that ketamine, a clinically useful drug that blocks N-methyl-D-aspartate (NMDA) receptors (Mishra et al 2001), partially inhibits the fetal ACTH response to hypoxic hypoxia (Chang and Wood 2015), and almost completely inhibits the fetal ACTH response to brachiocephalic artery occlusion (a model of brain and carotid body ischemic hypoxia) (Powers and Wood 2007). Furthermore, we have demonstrated that intravenous injection of NMDA stimulates fetal ACTH secretion, and that the effect is partially dependent on prostaglandin biosynthesis (Knutson and Wood 2010). Boekkooi et al (1995) reported that ketamine interrupts the chemoreflex control of the heart rate in the late-gestation fetal sheep.…”