engleski

Effect of oxime K048 on AChE and BChE activity upon tabun poisoning in rats

Our recent in vitro and in vivo studies showed that the oxime 1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium) butane dibromide (K048) shows great promise as a reactivator of tabun-inhibited human erythrocyte acetylcholinesterase (AChE) and as an antidote for tabun poisoned mice. Encouraging results of our experiments prompted us to expand this study by new aims: (i) to establish K048 efficacy against AChE inhibition by tabun in rats ; (ii) to establish the levels of oxidative stress (lipid peroxidation) and to see whether there are any differences in this parameter upon tabun poisoning and applied treatments in rats. AChE and butyrylcholinesterase (BChE) activity was measured in rat plasma and brain after 0.5, 1, 6 and 24 h long oxime therapy. In view of the possible oxidative stress involved in OP poisoning, lipid peroxidation was measured in the same samples to determine the concentration of thiobarbituric reactive substances (TBARS). Significant reactivation potency of oxime K048 in rat plasma was noticed after 30 and 60 min long oxime therapy (oxime + atropine) when AChE activity was in the range of the control group (rats treated with saline only). Efficiency of K048 decreased after 6 h, probably due to the relatively short oxime circulation time in the blood. Interestingly, after 24 h AChE activities of both poisoned and treated rats were high (in the range of the control group). Unlike in plasma, no significant therapeutic effect of K048 was observed on cholinesterase activity in the rat brain, probably due to the limited penetration of the oxime through the blood brain barrier. Further, treatment with K048 did not preserve BChE activity in plasma or in brain, which is in agreement with the previous K048 in vitro study, showing limited BChE reactivation by K048. The plasma TBARS levels remained above the range of the control for most of the treatments. The levels of rat brain TBARS increased up to 24 h in all groups. According to the remaining AChE activity in the brain of approximately 30 % 24 h after tabun application, OP toxicity seems to be associated with tissue oxidative stress. However, to confirm this concept, a good strategy for further studies would be to measure simultaneously a number of biomarkers representing oxidative damage.

Cholinesterase; Inhibition; Reactivation; Nerve agent; Oxime; Oxidative stress

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