![]() Rats that received antidotal treatment after soman exposure were protected from mortality and showed reduction in the soman induced expression of c-Fos, Bax and Calpain and necrosis. ![]() This therapeutic regime also reduced the soman induced Bax, Calpain expression levels to near control levels in the different brain regions studied, except a mild induction of c-Fos expression in the hippocampus. Soman increased the expression of neuronal proteins including c-Fos, Bax and Calpain levels in the hippocampus, cerebral cortex and cerebellum regions of the brain. Fluoro-Jade B (FJ-B) staining of neurodegenerative neurons showed that soman induced significant necrotic neuronal cell death, which was reduced by this antidotal treatment. HI-6 treatment reactivated soman inhibited plasma and RBC cholinesterase up to 40%. Therapeutic regime consisting of HI-6 (50 mg/kg, i.m), atropine (10 mg/kg, i.m) and midazolam (5 mg/kg, i.m) protected animals against soman (2 × LD 50, s.c) lethality completely at 2 h and 80% at 24 h. In the present study, we intend to study the efficacy of antidotes comprising of HI-6 (1-methoxy]-methyl]-2- pyridinium dichloride), atropine and midazolam on soman induced neurodegeneration and the expression of c-Fos, Calpain, and Bax levels in discrete rat brain areas. ![]() The biochemical changes that occur following nerve agent exposure needs to be elucidated to understand the mechanisms behind their long term neurological effects and to design better therapeutic drugs to block their multiple neurotoxic effects. Acute nerve agent exposure can cause rapid death or leads to multiple and long term neurological effects. ![]() All rights reserved.Recent alleged attacks with nerve agent sarin on civilians in Syria indicate their potential threat to both civilian and military population. The oxime acts as antidote against physostigmine and pyridostigmine poisoning by reactivating AChE in the brain and diaphragm, respectively.Īcetylcholinesterase Anticholinergic Oxime Physostigmine Pyridostigmine Rat.Ĭopyright © 2018 Elsevier B.V. As a consequence, increasing doses of atropine and their combination with hexamethonium assure excellent protection against physostigmine toxicity, while the best protection against pyridostigmine is provided by a strictly peripherally acting antinicotinic d-tubocurarine and bispyridinium oxime HI-6. Mechanism of physostigmine-induced lethal effect is predominantly central and it involves inhibition of brain AChE, while pyridostigmine produces the same effect exclusively outside the central nervous system, by inhibiting AChE in the respiratory muscles. Oxime HI-6 50 mg/kg reactivated acetylcholinesterase (AChE) in brain inhibited by physostigmine and in diaphragm inhibited by pyridostigmine. Atropine and hexamethonium produced better protection in physostigmine-poisoned rats, while d-tubocurarine and HI-6 were more efficacious in pyridostigmine-intoxicated animals. Biochemical experiments consisted in measuring of the cholinesterase activities in brain, whole blood and diaphragm in rats 5, 15, 30, 60, 120 and 240 min after poisoning with 0.8 LD 50 of physostigmine or pyridostigmine.Īll the tested antidotes assured some degree of protection against the two carbamates. Atropine (5, 10 and 20 mg/kg), hexamethonium (5, 10 and 20 mg/kg), d-tubocurarine (0.005, 0.010 and 0.020 mg/kg) and oxime HI-6 (25, 50 and 100 mg/kg) were used as monotherapies and in dual combinations, where atropine was the obligatory antidote. ![]() Median lethal dose (LD 50) in animals treated with antidotes were compared to the ones in saline-treated rats and protective ratios (PRs) were calculated. Carbamates were injected subcutaneously (sc) and antidotes intramuscularly (im). The goal of this experimental study was to ascertain the life-preserving potential of anticholinergics atropine, hexamethonium and d-tubocurarine, oxime HI-6 and their combinations in rats poisoned with physostigmine or pyridostigmine.Įxperiments were performed in Wistar rats. Use of these medicinal carbamates, but also of carbamate insecticides, created need for research into the potential and mechanisms of action of several antidotes against carbamate poisonings, including anticholinergics and oximes. Physostigmine and its analogues neostigmine, pyridostigmine and rivastigmine are carbamates nowadays used in many indications, including antidotal effects against antimuscarinic poisonings, reversal of competitive neuromuscular block, myasthenia gravis, Alzheimer's disease and prophylaxis against nerve agent intoxications. ![]()
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