Effect of five acetylcholinesterase reactivators on tabun‐intoxicated rats: induction of oxidative stress versus reactivation efficacy

Abstract

Oxime reactivators HI-6, obidoxime, trimedoxime, K347 and K628 were investigated as drugs designed for treatment of tabun intoxication. The experiments were performed on rats in order to simulate real conditions. Rats were intoxicated with one LD(50 )of tabun and treated with atropine and mentioned reactivators. Activities of erythrocyte acetylcholinesterase (AChE), plasma butyrylcholinesterase (BChE) and brain AChE were measured as markers of reactivation efficacy. An estimation of low molecular weight antioxidant levels using cyclic voltammetry was the second examination parameter. The evaluation of cholinesterases activity showed good reactivation potency of blood AChE and plasma BChE by commercially available obidoxime and newly synthesized K347. The potency of oximes to reactivate brain AChE was lower due to the poor blood-brain barrier penetration of used compounds. Commercially available reactivator HI-6 and newly synthesized K628 caused oxidative stress measured by cyclic voltammetry as antioxidant level. The oxidative stress provoked by HI-6 and K628 was found to be significant on probability level P = 0.05. The others reactivators did not affect antioxidant levels.

Changes of rat plasma total low molecular weight antioxidant level after tabun exposure and consequent treatment by acetylcholinesterase reactivators

“…The antioxidative defence mechanism sharply increases and counteracts the impairment of oxidative balance as indicated by the important marker, malondialdehyde [9]. The total level of antioxidants can also be shifted when drugs reactivating inhibited AChE are administered [10]. This study was carried out as an attempt to estimate the effects of the currently available as well as some new AChE reactivators suitable for the treatment of intoxication by a highly toxic anticholinergic compound, namely tabun.…”

“…This study was carried out as an attempt to estimate the effects of the currently available as well as some new AChE reactivators suitable for the treatment of intoxication by a highly toxic anticholinergic compound, namely tabun. Following the important findings from our previous research [10], we have designed some new experiments based on equimolar rather than therapeutic doses. Though the effect of drugs suitable for reactivation of AChE inhibited by organophosphates or organophosphonates is generally known [5], this research is concerned with the understanding of oxidative stress modulation.…”

“…The activity of blood AChE was carried out by an adapted Ellman's method [10,12]. Blood was haemolysed in 0.02 M Tris buffer (pH 7.6) by mixing the blood with buffer in a ratio of 1:20.…”

“…The range of applied voltage was −0.1 to 1.1 V and the scan rate was adjusted to 50 mV/s. The antioxidants appeared as a wave in the anodic range [10,[14][15][16].…”

In vitro Screening of Oxime Reactivators on the Model of Paraoxon-inhibited Acetylcholinesterase-SAR Study

“…Atropine is used for binding to muscarinic acetylcholine receptors (AChR) with consequent neuronal transduction, therefore prevents from hyperstimulation with ACh and subsequent cholinergic crisis. 21 Diazepam is used for anticonvulsive treatment.…”