Neurobiology of organophosphate-induced seizures

Abstract

This review summarizes the efforts of our laboratories to develop a mechanism-based therapy for the treatment of organophosphate (OP) nerve agent-induced seizures. Organophosphate poisoning can occur during warfare and terrorist attacks and in the civilian sphere because of intentional or unintentional poisoning. Persons exposed to OPs experience seizures. We developed animal models of OP poisoning and then evaluated the effects of OP on excitatory α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated glutamatergic neurotransmission in the hippocampus using patch-clamp electrophysiology. Organophosphate agents enhance glutamatergic transmission by enhancing neurotransmitter release. M1 muscarinic receptors mediate this effect, at least in part. Muscarinic receptors exert this action by inhibiting specific KCNQ2/3 potassium channels, which mediate the M-current. Flupirtine, a drug that open channels, is effective against OP-induced seizures. This article is part of the Special Issue"Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".