BACKGROUND

Neonatal epileptic seizures cause postictal dysregulation of cerebral blood flow. Hydrogen sulfide (HS), a mediator with vasodilator and antioxidant properties, is produced in the brain by astrocyte cystathionine β-synthase (CBS). This study investigated whether HS 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 HS donor NaHS on cerebral vascular outcome of seizures were examined in live pigs, cerebral endothelial cells, and cortical astrocytes.

RESULTS

Brain HS was elevated during seizures. AOA blocked HS 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 HS 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 HS-inhibited pigs and minimized in NaHS-treated pigs.

CONCLUSIONS

HS elevation in the epileptic brain via activation of CBS contributes to functional hyperemia and exhibits cerebroprotective properties. The HS 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 (HS), a mediator with vasodilator and antioxidant properties, in the epileptic brain has been explored. Astrocytes are major sites of enzymatic HS production in the epileptic brain. Postictal cerebral vascular dysfunction is exaggerated when astrocyte HS production is pharmacologically inhibited during seizures. Postictal cerebral vascular dysfunction is minimized when the brain HS 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 HS.