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Carbon monoxide inhibits NADPH oxidase activation during seizures and prevents loss of postictal cerebral vascular function.

Prolonged seizures cause sustained neuronal injury and loss of cerebral blood flow regulation that may contribute to adverse neurological outcomes in neonates. Oxidative stress is potentially a key mechanism that initiates brain damage during seizures. In a newborn pig model of neonatal glutamatergic seizures, we investigated oxidative stress in the brain. Seizures lasting over 30 min increased the superoxide level in cerebral vessels and in the brain parenchyma. We hypothesize that NADPH oxidase is a source of superoxide during seizures. Apocynin, the NADPH oxidase inhibitor (20 mg/kg iv), inhibited superoxide elevation in response to seizures in cerebral microvessels and in the brain. Glutamate (0.05‐0.2mM) increased NADPH oxidase activity in cerebral microvascular endothelial cells 1.5‐2 fold. Carbon monoxide (CO, as CORM‐A1), reduced the basal enzyme activity and blocked the glutamate stimulation of NADPH oxidase. CORM‐A1 greatly reduced oxidative stress in ictal piglets and prevented sustained postictal loss of endothelial‐dependent cerebral blood flow regulation. Overall, these data suggest that NADPH oxidase is a major contributor to oxidative stress and cerebrovascular injury caused by seizures and glutamate. CO is a gaseous cytoprotective messenger molecule that preserves cerebrovascular integrity by inhibiting NADPH oxidase and preventing oxidative stress in response to seizures.