Biochemistry-Vertox Division, DRDE, Jhansi road, Gwalior, M.P., India.
Process Technology Development Division, Defence Research and Development Establishment, Jhansi road, Gwalior, M.P., India.
Neurotox Res. 2018 May;33(4):738-748. doi: 10.1007/s12640-017-9815-9. Epub 2017 Sep 19.
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.
神经保护作用是治疗有机磷神经毒剂中毒的关键。有机磷神经毒剂接触人体后可导致多种神经毒性作用，主要与乙酰胆碱酯酶（AChE）抑制或快速死亡有关。阐明有机磷神经毒剂诱导的多种神经毒性作用的机制，有助于开发更好、更安全的药物。本研究旨在探讨沙林染毒后机体的分子反应，并评价加兰他敏对沙林诱导的神经毒性变化的神经保护作用。实时定量 PCR 结果显示，沙林（90μg/kg，皮下注射）染毒后，海马和梨状皮层中 S-100β、Gfap、c-fos 和 Bdnf 的 mRNA 表达显著改变。免疫印迹分析显示，急性沙林染毒可显著增加神经胶质标志物（S100-β 和 GFAP）的蛋白水平；c-Fos 和蛋白氧化在离散的大鼠脑区的表达，提示它们在神经毒剂诱导的神经毒性中的作用。沙林染毒过程中 BDNF 水平的升高可能表明其激活了恢复机制。染毒后 AChE 在血液和大脑中的抑制率高达 82%。单独给予加兰他敏（3mg/kg）和加兰他敏联合阿托品（10mg/kg）治疗，可防止动物因染毒、死亡以及沙林抑制 AChE 导致的中毒，血脑抑制率分别高达 45%。接受加兰他敏治疗的动物大脑中神经保护基因（nAChRα-7、Bcl-2 和 Bdnf）的水平升高，提示加兰他敏具有神经保护作用。加兰他敏和加兰他敏联合阿托品治疗后，神经胶质变化、c-Fos 和蛋白氧化水平显著降低，表明它们在神经毒剂治疗中有潜在的解毒作用。
