Cerebroprotective actions of hydrogen sulfide in the epileptic brain in newborn pigs

Background Neonatal epileptic seizures cause postictal dysregulation of cerebral blood flow. Hydrogen sulfide (H 2 S), a mediator with vasodilator and antioxidant properties, is produced in the brain by astrocyte cystathionine β-synthase (CBS). This study investigated whether H 2 S improves the cerebral vascular outcome of seizures. Methods Epileptic seizures were induced in newborn pigs using bicuculline. The effects of the CBS inhibitor aminooxyacetate (AOA) and the H 2 S donor NaHS on cerebral vascular outcome of seizures were examined in live pigs, cerebral endothelial cells, and cortical astrocytes. Results Brain H 2 S was elevated during seizures. AOA blocked H 2 S and reduced functional hyperemia in the epileptic brain. The endothelium- and astrocyte-dependent vasodilation of pial arterioles was impaired 48 h after seizures suggesting cerebral vascular dysfunction. Systemic NaHS elevated brain H 2 S and blocked reactive oxygen species in the epileptic brain and in primary endothelial cells and astrocytes during inflammatory and excitotoxic conditions. Postictal cerebrovascular dysfunction was exaggerated in H 2 S-inhibited pigs and minimized in NaHS-treated pigs. Conclusions H 2 S elevation in the epileptic brain via activation of CBS contributes to functional hyperemia and exhibits cerebroprotective properties. The H 2 S donor NaHS enhances brain antioxidant defense and provides a therapeutic approach for preventing adverse cerebral vascular outcome of neonatal epileptic seizures. Impact Epileptic seizures in neonates lead to prolonged postictal cerebral vascular dysregulation. The role of hydrogen sulfide (H 2 S), a mediator with vasodilator and antioxidant properties, in the epileptic brain has been explored. Astrocytes are major sites of enzymatic H 2 S production in the epileptic brain. Postictal cerebral vascular dysfunction is exaggerated when astrocyte H 2 S production is pharmacologically inhibited during seizures. Postictal cerebral vascular dysfunction is minimized when the brain H 2 S is elevated by systemic administration of NaHS during seizures. NaHS provides a therapeutic approach for improving cerebrovascular outcome of epileptic seizures via a mechanism that involves the antioxidant potential of H 2 S.