Neuropharmacological mechanisms of nerve agent-induced seizure and neuropathology.
This paper proposes a three phase "model" of the neuropharmacological processes responsible for the seizures and neuropathology produced by nerve agent intoxication. Initiation and early expression of the seizures are cholinergic phenomenon; anticholinergics readily terminate seizures at this stage and no neuropathology is evident. However, if not checked, a transition phase occurs during which the neuronal excitation of the seizure per se perturbs other neurotransmitter systems: excitatory amino acid (EAA) levels increase reinforcing the seizure activity; control with anticholinergics becomes less effective; mild neuropathology is occasionally observed. With prolonged epileptiform activity the seizure enters a predominantly non-cholinergic phase: it becomes refractory to some anticholinergics; benzodiazepines and N-methyl-D-aspartate (NMDA) antagonists remain effective as anticonvulsants, but require anticholinergic co-administration; mild neuropathology is evident in multiple brain regions. Excessive influx of calcium due to repeated seizure-induced depolarization and prolonged stimulation of NMDA receptors is proposed as the ultimate cause of neuropathology. The model and data indicate that rapid and aggressive management of seizures is essential to prevent neuropathology from nerve agent exposure.
McDonough
J H
JH
Pharmacology Division, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5425, USA.
Shih
T M
TM
D000818:Animals; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D006801:Humans; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D012640:Seizures / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology
D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors