Objective: Despite decades of epilepsy research, 30% of focal epilepsies remain resistant to antiseizure drugs, with effective drug development impeded by lack of understanding on how seizures are initiated. Here, we report the mechanism of seizure onset relevant to most seizures that are characteristic of focal epilepsies. Methods: Electric and metabolic network parameters were measured using several seizure models in mouse hippocampal slices and acutely induced seizures in rats in vivo to determine metabolic events occurring at seizure onset. Results: We show that seizure onset is associated with a rapid release of H 2 O 2 resulting from N-methyl-D-aspartate (NMDA) receptor-mediated activation of nicotinamide adenine dinucleotide phosphate oxidase (NOX). NOX blockade prevented the fast H 2 O 2 release as well as the direct current shift and seizurelike event induction in slices. Similarly, intracerebroventricular injection of NOX antagonists prevented acutely induced seizures in rats. Interpretation: Our results show that seizures are initiated by NMDA receptor-mediated NOX-induced oxidative stress and can be arrested by NOX inhibition. We introduce a novel use for blood-brain barrier-permeable NOX inhibitor with a significant potential to become the first seizure-specific medication. Thus, targeting NOX may provide a breakthrough treatment for focal epilepsies. ANN NEUROL 2019;85:907-920 A major goal of contemporary epilepsy research is the View this article online at wileyonlinelibrary.com.

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