Protective action of the serine protease inhibitor N-tosyl-L-lysine chloromethyl ketone (TLCK) against acute soman poisoning.
Soman-poisoned rats display cholinergic crisis, a systemic mast cell degranulation characteristic of anaphylactic reactions and an excitotoxin-like sequential seizure and neuronal degeneration. The protection of guinea pigs from soman lethality by prophylactic administration of the serine protease inhibitor suramin suggests a possible proteolytic component in soman poisoning. The present study tested the effect of N-tosyl-L-lysine chloromethyl ketone (TLCK), an inhibitor of trypsin-like serine proteases, on soman-induced toxic signs (convulsions, righting reflex) and survival time. Nine control guinea pigs receiving 2 x LD(50) (56 microg kg(-1), s.c.) of soman immediately followed by a therapeutic dose of atropine sulfate (17.4 mg kg(-1) i.m.) experienced severe convulsions, and 8/9 lost the righting reflex. Six of these nine animals expired within 65 min; the three remaining animals survived 24 h to termination of the experiment. When a second group of animals were given TLCK (12 mg kg(-1), i.p.) 30 min prior to a 2 x LD(50) soman challenge and atropine-sulfate therapy, 5/9 experienced convulsions and only 3/9 lost the righting reflex. All nine animals survived beyond 4 h, with six surviving to 24 h. Compared with soman controls, prophylaxis with TLCK significantly prevented the loss of righting reflex (P = 0.05) and enhanced 4-h survival (P = 0.005). Although, convulsions were reduced and 24-h survival was improved in TLCK-treated animals, these results were not statistically significant. The protection from soman toxicity by chemically distinct protease inhibitors such as suramin and TLCK suggests a role for pathological proteolytic pathways in soman intoxication.
Cowan
F M
FM
Biochemical Pharmacology and Neurotoxicology Branches, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5400, USA.
Broomfield
C A
CA
Lenz
D E
DE
Shih
T M
TM
D000818:Animals; D001285:Atropine / Q000008:administration & dosage / Q000627:therapeutic use*; D002619:Chemical Warfare Agents / Q000506:poisoning; D002800:Cholinesterase Inhibitors / Q000506:poisoning*; D004347:Drug Interactions; D006168:Guinea Pigs; D007273:Injections, Intramuscular; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D007928:Lethal Dose 50; D008297:Male; D012018:Reflex / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D012999:Soman / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000506:poisoning / Q000633:toxicity; D013997:Time Factors; D014107:Tosyllysine Chloromethyl Ketone / Q000008:administration & dosage / Q000494:pharmacology*
D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D015842:Serine Proteinase Inhibitors; D014107:Tosyllysine Chloromethyl Ketone; D001285:Atropine; D012999:Soman