NOX1/NOX4 inhibitor setanaxib reduces brain oxidative stress and prevents cerebrovascular disease caused by epileptic seizures

Epileptic seizures cause brain oxidative stress which contributes to long-term cerebral vascular dysfunction and blood-brain barrier (BBB) damage leading to cerebrovascular disease and potential neurological deficits. Seeking new therapeutic interventions to reduce brain oxidative stress is crucial for preventing seizure-induced cerebrovascular and neurological complications. NADPH oxidase (NOX1-NOX5 isoforms) is a potent source of reactive oxygen species (ROS) in the brain. We tested the effects of setanaxib (GKT831), a first class selective inhibitor of NADPH oxidase isoforms NOX1/NOX4, on ROS generation in the neurovascular unit and on the cerebrovascular outcome of epileptic seizures in newborn pigs. Setanaxib (5-10 µM) exhibited strong antioxidant and cytoprotective effects in primary cerebral endothelial cells and astrocytes exposed to seizure-related excitatory and inflammatory pro-oxidants glutamate and TNF-alpha. Glutamatergic epileptic seizures were induced by bicuculline, and postictal cerebral vascular function and BBB permeability were evaluated 48 h after seizures in saline-control and setanaxib-treated pigs. Setanaxib (5 mg/kg i.p.) was administered 30 min before seizures (preventive protocol) or 10 min after bicuculline (therapeutic protocol). Postictal cerebral vascular function was evaluated 48 h after seizures by the responses of pial arterioles to endothelium- and astrocyte-dependent vasodilators bradykinin (BK), ADP, glutamate (Glu) and the glutamate receptor agonists NMDA and quisqualic acid (Quis). In the saline control post-epileptic pigs, the responses to all endothelium- and astrocyte-dependent dilators were greatly reduced compared to intact pigs. In contrast, in newborn pigs treated by setanaxib either before or during seizures, all postictal cerebral vascular responses were largely preserved. Furthermore, setanaxib administered preventively or therapeutically fully prevented BBB leakage detected by Evans Blue extravasation 48 h after seizures. In summary, setanaxib is a promising therapeutic agent to reduce brain oxidative stress and to prevent cerebrovascular disease and BBB disruption caused by epileptic seizures. Grant Support: R01NS105655, R01NS134659 (Parfenova) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.