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

Abstract

Neonatal epileptic seizures cause postictal dysregulation of cerebral blood flow. Hydrogen sulfide (H₂S), a mediator with vasodilator and antioxidant properties, is produced in the brain by astrocyte cystathionine β-synthase (CBS). This study investigated whether H₂S improves the cerebral vascular outcome of seizures. Epileptic seizures were induced in newborn pigs using bicuculline. The effects of the CBS inhibitor aminooxyacetate (AOA) and the H₂S donor NaHS on cerebral vascular outcome of seizures were examined in live pigs, cerebral endothelial cells, and cortical astrocytes. Brain H₂S was elevated during seizures. AOA blocked H₂S 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 H₂S 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 H₂S-inhibited pigs and minimized in NaHS-treated pigs. H₂S elevation in the epileptic brain via activation of CBS contributes to functional hyperemia and exhibits cerebroprotective properties. The H₂S donor NaHS enhances brain antioxidant defense and provides a therapeutic approach for preventing adverse cerebral vascular outcome of neonatal epileptic seizures. Epileptic seizures in neonates lead to prolonged postictal cerebral vascular dysregulation. The role of hydrogen sulfide (H₂S), a mediator with vasodilator and antioxidant properties, in the epileptic brain has been explored. Astrocytes are major sites of enzymatic H₂S production in the epileptic brain. Postictal cerebral vascular dysfunction is exaggerated when astrocyte H₂S production is pharmacologically inhibited during seizures. Postictal cerebral vascular dysfunction is minimized when the brain H₂S 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 H₂S.