Organophosphate (OP) pesticides and nerve agents are responsible for suicidal and accidental poisonings. The acute toxicity of nerve agents leads to progressive inhibition of the enzyme acetylcholinesterase (AChE) by phosphylation of serine residue at the active site of gorge. The recent massive destruction of Syrian civilians by nerve gas sarin, has again renewed the research attention of global science fraternity towards nerve agents, their mode of action and most prominently their therapeutic treatment. This review is principally focused on nerve agent intoxication. The common approach to deal with OP-intoxication is, application of antimuscarinic drug (atropine), anticonvulsant drug (diazepam) and clinically used oximes (pralidoxime, trimedoxime, obidoxime and asoxime). However, the existing therapeutic approach is arguable and has several failings to cure all kinds of nerve agent poisonings. Considering this issue, numerous oximes have been synthesized and screened through various in-vitro and in-vivo studies in last decade to overcome the downsides. At present, only a few oximes (bis pyridinum-oximes) exhibit sound efficacy against selective OPs. In spite of extensive efforts, till date no oxime is available as a universal antidote against all the classes of OPs. This review is centered on the recent developments and structural modification of AChE reactivators against nerve agent toxicity. In particular, a deeper look has been taken into chemical modifications of the reactivators by incorporation of different structural moieties targeted towards the increased reactivation affinity and improved blood brain barrier (BBB) penetration.
Neuroprotection from nerve agent such as soman-induced neural damage is a major challenge for existing drugs. Nerve agent exposure can cause many neural effects in survivors arising mainly due to acetylcholinesterase (AChE) inhibition or death within minutes. Unraveling the mechanisms underlying the nerve agent-induced multiple neurological effects is useful to develop better and safe drugs. The present study aimed to understand the molecular response during soman exposure and to evaluate the neuroprotective efficacy of galantamine on nerve agent-induced neurotoxic changes. mRNA expression studies using quantitative real-time PCR revealed significant changes in S-100β, Gfap, c-fos, and Bdnf in the hippocampus and piriform cortex after soman (90 μg/kg, s.c) exposure. Immunoblot analysis showed acute soman exposure significantly increased the protein levels of neuroglial markers (S100-β and GFAP); c-Fos and protein oxidation in discrete rat brain areas indicate their role in nerve agent-induced neurotoxicity. Induction of BDNF levels during soman exposure may indicate the recovery mechanisms activation. AChE was inhibited in the blood and brain up to 82% after soman exposure. Antidotal treatment with galantamine alone (3 mg/kg) and galantamine plus atropine (10 mg/kg) has protected animals from nerve agent-induced intoxication, death, and soman-inhibited AChE up to 45% in the blood and brain. Animal received galantamine displayed increased levels of neuroprotective genes (nAChRα-7, Bcl-2, and Bdnf) in the brain suggest the neuroprotective value of galantamine. Neuroglial changes, c-Fos, and protein oxidation levels significantly reduced after galantamine and galantamine plus atropine treatment indicate their potential antidotal value in nerve agent treatment.
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