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.