Abstract
The ability of newly developed oximes (K347, K628) to reduce tabun-induced acute neurotoxic signs and symptoms was compared with currently available oximes (obidoxime, HI-6) using a functional observational battery. The neuroprotective effects of the oximes studied (K347, K628, obidoxime, HI-6) combined with atropine on rats poisoned with tabun at a sublethal dose (220 microg/kg i.m.; 80% of LD50 value) were evaluated. Tabun-induced neurotoxicity was monitored by a functional observational battery and automatic measurement of motor activity at 24 hours following tabun challenge. The results indicate that all tested oximes combined with atropine enable tabun-poisoned rats to survive 24 hours following tabun challenge. Both newly developed oximes (K347, K628) combined with atropine are able to decrease tabun-induced neurotoxicity in the case of sublethal poisonings but they do not eliminate all tabun-induced acute neurotoxic signs and symptoms. Their ability to decrease the tabun-induced acute neurotoxicity is higher than that of the oxime HI-6 and it is slightly slower than the neuroprotective efficacy of obidoxime. As the neuroprotective potency of both newly developed oximes (K347, K628) is not as high as the potency of obidoxime, they are not a suitable replacement for obidoxime for the treatment of acute tabun poisonings.
Highlights
Organophosphorus nerve agents are considered to be the most dangerous chemical warfare agents
All tabun-poisoned rats survived till the end of experiment (24 hr following the intoxication) regardless of the type of oxime used
Non-treated tabun-poisoned rats survived for 24 hr after tabun challenge, too
Summary
Organophosphorus nerve agents are considered to be the most dangerous chemical warfare agents. Their acute toxic effects are based on the phosphonylation of acetylcholinesterase (AChE, EC 3.1.1.7), leading to the irreversible inhibition of its active site and subsequent overstimulation of postsynaptic cholinergic receptors due to the accumulation of the neurotransmitter acetylcholine in the synapses of the central and peripheral nervous systems [21, 22]. The standard antidotal treatment of nerve agent poisoning usually includes an anticholinergic agent to block the overstimulation of cholinergic receptors and an oxime to reactivate nerve agent-inhibited AChE [4, 29]. Some nerve agents were found to be resistant to standard antidotal treatment. One of the most resistant nerve agent is tabun (O-ethyl-N,N-dimethyl phosphoramidocyanidate), the deleterious effects of which are extraordinarily difficult to antagonize because of the changes in hydrogen bonding and the conformational changes of AChE-tabun complex prior to an aging process in the AChE active site [1, 6]
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