engleski

Antidotal effects of bispyridinium para-oxime K203 on tabun-induced cholinesterase inhibition and oxidative stress in rats plasma

The widespread use of organophosphorous compounds (OP) as pesticides and the misuse of OP nerve agents in military conflicts or terrorist attacks emphasize the need for effective antidotal preparedness. The toxic symptomatology of OP is caused by irreversible inhibition of the serine-protease acetylcholinesterase (AChE), a vitally important enzyme that hydrolyses the neurotransmitter acetylcholin. Generally, anticholinergics such as atropine and AChE reactivators - oximes are used as first aid antidotes for OP intoxications. However, reactivation by oximes is not possible in all cases of OP poisoning, especially in the case of nerve agent tabun. Recent in vitro and in vivo studies on mice draw attention to oxime [(E)-1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide] (K203) as a very potent reactivator of tabun-inhibited AChE. In this study we used rats as experimental model to broaden our knowledge on antidotal potency of K203 as well as to examine impact of possible oxidative stress on OP toxicity and efficacy of applied therapy. Animals were injected subcutaneously with sublethal dose of tabun, and treated intraperitoneally 1min later with oxime K203 (5 or 25% of its LD50) alone or in combination with atropine. All animals were sacrificed after 0.5, 1, 6 and 24 h. Plasma samples were analyzed for cholinesterase (ChE) activity and levels of oxidative stress markers (the concentration of thiobarbituric reactive substances, TBARS, as a measure of lipid peroxidation and activity of an antioxidant enzyme superoxide dismutase, SOD). Either alone or in combination with atropine, K203 significantly increased ChE activity at 0.5 and 1 h, in respect to untreated rats poisoned with tabun. In addition, intraperitoneal administration of oxime alone as a control didn't disturb enzyme activity in plasma. Determined TBARS concentrations suggest that this acute treatments resulted with free radical-mediated lipid peroxidation. Considering SOD activity, a notable correlation exists between ChE depression and SOD elevation. Together with published data on K203's efficacy our results indicate the high potency of this oxime in counteracting tabun poisoning. Based on simultaneous measurements of TBARS and SOD we can conclude that the existence of oxidative stress have a role in OP toxicity.

bispyridinium para-oxime; tabun; rat; AChE

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