A Comparison of the Neuroprotective and Reactivating Efficacy of a Novel Bispyridinium Oxime K870 with Commonly Used Pralidoxime and the Oxime HI-6 in Tabun-Poisoned Rats.

Jiří Kassa,Jana Hatlapatková,Jana Žďárová Karasová,Filip Caisberger,Jaroslav Pejchal,Vendula Hepnarová

doi:10.14712/18059694.2021.25

Jiří Kassa, Jana Hatlapatková + Show 4 more

Open Access

https://doi.org/10.14712/18059694.2021.25

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Abstract

The comparison of neuroprotective and central reactivating effects of the oxime K870 in combination with atropine with the efficacy of standard antidotal treatment in tabun-poisoned rats. The neuroprotective effects of antidotal treatment were determined in rats poisoned with tabun at a sublethal dose using a functional observational battery 2 h and 24 h after tabun administration, the tabun-induced brain damage was investigated by the histopathological evaluation and central reactivating effects of oximes was evaluated by the determination of acetylcholinesterase activity in the brain using a standard spectrophotometric method. The central reactivating efficacy of a newly developed oxime K870 roughly corresponds to the central reactivating efficacy of pralidoxime while the ability of the oxime HI-6 to reactivate tabun-inhibited acetylcholinesterase in the brain was negligible. The ability of the oxime K870 to decrease tabun-induced acute neurotoxicity was slightly higher than that of pralidoxime and similar to the oxime HI-6. These results roughly correspond to the histopathological evaluation of tabun-induced brain damage. The newly synthesized oxime K870 is not a suitable replacement for commonly used oximes in the antidotal treatment of acute tabun poisonings because its neuroprotective efficacy is only slightly higher or similar compared to studied currently used oximes.

Highlights

Nerve agents including tabun are highly toxic organophosphorus compounds that were developed and stockpiled for use as chemical warfare agents [1]
As some nerve agents including tabun penetrate through the blood-brain barrier (BBB), they can cause centrally mediated seizure activity that can rapidly progress to status epilepticus and contribute to profound brain damage [2,3,4]
While five non-treated tabun-poisoned rats, two tabun-poisoned rats treated with atropine alone and one tabun-poisoned rat treated with atropine and pralidoxime died before the evaluation of tabun-induced neurotoxicity by functional observational battery (FOB), all tabun-poisoned rats treated with atropine in combination with K870 or the oxime HI-6 survived till the end of experiment

Summary

Introduction

Nerve agents including tabun are highly toxic organophosphorus compounds that were developed and stockpiled for use as chemical warfare agents [1]. Their main toxic mechanism is based on their covalent binding to the active site of acetylcholinesterase (AChE, EC 3.1.1.7) resulting in AChE irreversible inhibition and development of cholinergic crisis. It differs from other highly toxic organophosphates by its chemical structure and by the fact that commonly used antidotes (atropine in combination with an oxime) are not able to sufficiently eliminate tabun-induced acute toxic effects. Its acute toxic effects are extraordinarily difficult to counteract because of the existence of a free electron pair located on amidic nitrogen that makes the nucleophilic attack of oximes almost impossible [5, 6]

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