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Activation of NADPH oxidase is the primary trigger of epileptic seizures in rodent models
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International audience. Objective: Despite decades of epilepsy research, 30% of focal epilepsies remain resistant to anti-seizure 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 characteristic for 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 occuring at seizure onset.Results: We show that the seizure onset is associated with a rapid release of H 2 O 2 resulting from NMDA receptor-mediated activation of NADPH oxidase (NOX). NOX blockade prevented the fast H 2 O 2 release as well as the DC shift and seizure-like 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.
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