Abstract
The highly toxic nature of tabun has been known for many years, but there are still serious limitations to antidotal therapy. In this study, we used rats as an experimental model to evaluate the efficiency of bispyridinium para-oxime K203 as therapy against tabun poisoning as well as to examine if induction of oxidative stress is linked to organophosphate toxicity. K203 showed high potency in counteracting tabun poisoning. Either alone or in combination with atropine, this oxime significantly increased cholinesterase activity at 0.5 and 1 h compared to untreated rats poisoned with tabun. Simultaneous measurements of markers of oxidative stress (lipid peroxidation and superoxide dismutase) showed that tabun poisoning, but also therapy (oxime alone or oxime plus atropine) applied immediately after tabun poisoning, could generate free radical species that may cause oxidative stress in rats.
Highlights
Organophosphorus (OP) compounds such as nerve agents and pesticides [paraoxon, chlorpyrifos, and tetraethyl pyrophosphate (TEPP)] constitute an extremely toxic group of compounds.[1]
Tabunphosphorylated AChE is resistant to reactivation due to low electrophilicity of the phosphoramidate conjugated to the AChE active site.[5]
In the Czech Republic, considerable efforts have been invested into the development of new reactivators to be used in cases of tabun poisoning
Summary
Organophosphorus (OP) compounds such as nerve agents (tabun, soman, sarin and VX) and pesticides [paraoxon, chlorpyrifos, and tetraethyl pyrophosphate (TEPP)] constitute an extremely toxic group of compounds.[1]. Inhibition by OP compounds is manifested through conjugation of a phosphorous group from OP to the catalytic serine residue at the active site of the enzyme.[2] AChE is a vitally important enzyme that hydrolyzes the neurotransmitter acetylcholine (ACh), which is involved in the numerous cholinergic pathways in both the central and peripheral nervous system. AChE reactivators are mono- or bis-quaternary pyridinium salts bearing in their molecule a functional oxime group able to reactivate inhibited AChE by displacing the phosphoryl residue from the active site and restoring the enzyme activity. Pralidoxime (2-PAM), TMB-4, obidoxime and HI-6 are the most commonly used oximes for the treatment of OP exposure. Reactivation by these oximes is not possible in all cases of OP poisoning, especially in the case of the nerve agent tabun.
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