Abstract
The ability of two newly developed oximes (K727, K733) to reduce tabun-induced acute neurotoxic signs and symptoms was evaluated and compared with currently available trimedoxime in rats. The neuroprotective effects of the oximes studied combined with atropine on Wistar rats poisoned with tabun at a lethal dose (380 µg/kg i.m.; 90% of LD50 value) were evaluated. Tabun-induced neurotoxicity was monitored by the functional observational battery consisting of 38 measurements of sensory, motor and autonomic nervous functions at 2 hours following tabun challenge. All tested oximes combined with atropine enable tabun-poisoned rats to survive till the end of experiment. Both newly developed oximes (K727, K733) combined with atropine were able to decrease tabun-induced neurotoxicity in the case of lethal poisoning although they did not eliminate all tabun-induced acute neurotoxic signs and symptoms. The ability of both novel bispyridinium oximes to decrease tabun-induced acute neurotoxicity was slightly lower than that of trimedoxime. Therefore, the newly developed oximes are not suitable for the replacement of commonly used oximes such as trimedoxime in the treatment of acute tabun poisonings.
Highlights
Toxic organophosphorus compounds called nerve agents have been developed as chemical warfare agents
The inhibition of AChE after exposure to nerve agents leads to the accumulation of the neurotransmitter acetylcholine in the synaptic cleft and to subsequent overstimulation of both muscarinic and nicotinic cholinergic receptors that results in excitotoxicity, seizures, brain damage, long-term behavioral aberrations including cognitive deficits and other signs and symptoms of acute cholinergic crisis
While five non-treated tabun-poisoned rats died before the evaluation of tabun-induced neurotoxicity by functional observational battery (FOB), all tabun-poisoned rats treated with atropine in combination with an oxime survived till the end of experiment
Summary
Toxic organophosphorus compounds called nerve agents have been developed as chemical warfare agents. They exert their toxic effects primarily via irreversible inhibition of the enzyme acetylcholinesterase (AChE, EC 3.1.1.7) by phosphylation (phosphorylation or phosphonylation) of its active site serine in the central and peripheral nervous system. Anticholinergics are used for relieving muscarinic signs and symptoms whereas oximes are used for reactivation of nerve agent-inhibited AChE [2, 4, 5]. Currently available antidotal treatment is not able to sufficiently counteract acute toxic effects of nerve agents because of limited ability of oximes to reactivate nerve agent-inhibited AChE, especially in the case of acute poisoning with tabun, soman and cyclosarin [6,7,8]. Its deleterious effects are extraordinarily difficult to antagonize due to the changes in hydrogen bonding and conformational changes of AChE-tabun complex in the AChE active site that make the nucleophilic attack of oximes very difficult [9, 10]
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