Protection against nerve agent-induced neuropathology, but not cardiac pathology, is associated with the anticonvulsant action of drug treatment.
Brain and cardiac tissue was examined for pathological changes from rats that survived 24 hrs following exposure to a convulsant dose of the nerve agent soman. The animals had been treated following varying durations of seizure activity (2.5 - 40 min) with a number of different compounds that did or did not terminate the seizure. Moderate to severe neuropathology was evident in virtually all animals (98%) in which drug treatment did not terminate seizures. All animals that experienced up to 10 min of seizure activity before drug treatment successfully terminated the seizure were free of neuropathology. There was an increasing frequency in the incidence of neuropathology in animals that experienced 20 (10%) or 40 min (79%) of seizure activity before drug treatment terminated the seizure, but the degree of neuropathology in these groups was significantly less than that observed in animals where seizure activity was not terminated. Cardiac lesions occurred at a much higher frequency (88%) than neuropathological changes (57%) and were not consistently associated with the anticonvulsant effectiveness. Early treatment (< or = 10 min) with anticholinergic drugs, however, was associated with protection from cardiac damage. The results strongly support the hypothesis that nerve agent-induced brain damage is linked to epileptiform activity. The minimal amount of seizure activity necessary for irreversible neural damage to become evident under these conditions is approximately 20 min, and the process accelerates greatly after this minimal time has elapsed. Successful termination of seizure activity, regardless of the type of drug used, protected either totally or relatively against brain damage depending upon how long the seizure had progressed. The mechanisms responsible for cardiac lesion formation occur more rapidly and may have a cholinergic component.
McDonough
J H
JH
Biochemical Pharmacology Branch, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5425, USA.
Dochterman
L W
LW
Smith
C D
CD
Shih
T M
TM
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001285:Atropine / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D003975:Diazepam / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D008297:Male; D009206:Myocardium / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012601:Scopolamine / Q000494:pharmacology; D012640:Seizures / Q000139:chemically induced* / Q000517:prevention & control; D012999:Soman / Q000633:toxicity*; D013997:Time Factors
D000927:Anticonvulsants; D018696:Neuroprotective Agents; D001285:Atropine; D012999:Soman; D012601:Scopolamine; D003975:Diazepam