NEUROPHARMACOLOGICAL MECHANISMS OF NERVE AGENT-INDUCED SEIZURE AND NEUROPATHOLOGY

This paper proposes a three phase ''model'' of the neuropharmacologica l processes responsible for the seizures and neuropathology produced b y nerve agent intoxication. Initiation and early expression of the sei zures are cholinergic phenomenon; anticholinergics readily terminate s eizures at this stage and no neuropathology is evident. However, if no t checked, a transition phase occurs during which the neuronal excitat ion of the seizure per se perturbs other neurotransmitter systems: exc itatory amino acid (EAA) levels increase reinforcing the seizure activ ity; control with anticholinergics becomes less effective; mild neurop athology is occasionally observed. With prolonged epileptiform activit y the seizure enters a predominantly non-cholinergic phase: it becomes refractory to some anticholinergics; benzodiazepines and N-methyl-D-a spartate (NMDA) antagonists remain effective as anticonvulsants, but r equire anticholinergic co-administration; mild neuropathology is evide nt in multiple brain regions. Excessive influx of calcium due to repea ted seizure-induced depolarization and prolonged stimulation of NMDA r eceptors is proposed as the ultimate cause of neuropathology. The mode l and data indicate that rapid and aggressive management of seizures i s essential to prevent neuropathology from nerve agent exposure. Publi shed by Elsevier Science Ltd.