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 degran ulation characteristic of anaphylactic reactions and an excitotoxin-like se quential seizure and neuronal degeneration. The protection of guinea pigs f rom soman lethality by prophylactic administration of the serine protease i nhibitor suramin suggests a possible proteolytic component in soman poisoni ng. The present study tested the effect of N-tosyl-L-lysine chloromethyl ke tone (TLCK), an inhibitor of trypsin-like serine proteases, on soman-induce d toxic signs (convulsions, righting reflex) and survival time. Nine contro l guinea pigs receiving 2 X LD50 (56 mug kg(-1), s.c.) of soman immediately followed by a therapeutic dose of atropine sulfate (17.4 mg kg(-1) i.m.) e xperienced severe convulsions, and 8/9 lost the righting reflex. Six of the se 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 LD50 soman challenge and atropine-sulfate therapy, 5/9 experienced convulsions and only 3/9 los t the righting reflex. All nine animals survived beyond 4 h, with six survi ving to 24 h. Compared with soman controls, prophylaxis with TLCK significa ntly prevented the loss of righting reflex (P = 0.05) and enhanced 4-h surv ival (P = 0.005). Although, convulsions were reduced and 24-h survival was improved in TLCK-treated animals, these results were not statistically sign ificant. The protection from soman toxicity by chemically distinct protease inhibitors such as suramin and TLCK suggests a role for pathological prote olytic pathways in soman intoxication. Published in 2001 by John Wiley & So ns, Ltd.