Protective action of the serine protease inhibitor N-tosyl-L-lysine chloromethyl ketone (TLCK) against acute soman poisoning

✍ Scribed by F. M. Cowan; C. A. Broomfield; D. E. Lenz; T.-M. Shih

• Publisher: John Wiley and Sons
• Year: 2001
• Tongue: English
• Weight: 78 KB
• Volume: 21
• Category: Article
• ISSN: 0260-437X
• DOI: 10.1002/jat.757

✦ Synopsis

Abstract

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 × LD~50~ (56 µg 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 × 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. Copyright © 2001 John Wiley & Sons, Ltd.