New PhysioNet Publication by A. Malkov et. al.

Activation of NADPH oxidase is the primary trigger of epileptic seizures in rodent models

A. Malkov, A. I. Ivanov,  A. Latyshkova, P. Bregestovski, M. Zilberter,Y. Zilberter

Annals of Neurology, 2019 (accepted)

Abstract

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 likely relevant for most seizures characteristic for focal epilepsies.

Methods

Electric and metabolic network parameters were measured in mouse hippocampal slices using several seizure models in hippocampal slices and acutely-induced seizures in-vivo to determine metabolic events occuring at seizure onset.

Results

We show that the seizure onset is associated with a rapid release of H2O2resulting from NMDA receptor-mediated activation of NADPH oxidase (NOX). NOX blockade prevented the fast H2O2release 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.

A. Concurrent combination of several events is required for seizure induction.

Spontaneous seizures are associated with fast release H2O2and glutamate as well as  tissue swelling. 

B. NOX inhibition reduces seizure activity in vivo.LFP recordings in hippocampus of anesthetized rats. Intracerebroventricular injection of 4-AP induced regular ictal discharges (red), that were suppressed by inhibition of NOX with GSK2795039. (Bb)Demonstrates long-lasting field recordings (gray) with the inserted black traces representing field recordings low-pass filtered at 1Hz, that shows clearlyultra-slow baseline deviations during seizure activity