Abstract：
Acute nerve agent exposure can kill a person within minutes or produce multiple neurotoxic effects and subsequent brain damage with potential long-term adverse outcomes. Recent abuse of nerve-agents on Syrian civilians, during Japan terrorist attacks, and personal assassinations in the UK, and Malaysia indicate their potential threat to world population. Existing nerve agent antidotes offer only incomplete protection especially, if the treatment is delayed. To develop the effective drugs, it is advantageous to elucidate the underlying mechanisms of nerve agent-induced multiple neurological impairments. This study aimed to investigate the molecular basis of neuroinflammation during nerve agent toxicity with focus on inflammasome-associated proteins and neurodegeneration. In rats, NOD-like receptor family pyrin domain containing 3 (NLRP3), and glial fibrillary acidic protein (GFAP) immunoreactivity levels were considerably increased in the hippocampus, piriform cortex, and amygdala areas after single subcutaneous soman exposure (90 µg/kg-1). Western analysis indicated a notable increase in the neuroinflammatory indicator proteins, high mobility group box 1 (HMGB1) and inducible nitric oxide synthase (iNOS) levels. The presence of fluorojade-C-stained degenerating neurons in distinct rat brain areas is indicating the neurodegeneration during nerve agent toxicity. Pre-treatment with galantamine (3 mg/kg, - 30 min) followed by post-treatment of atropine (10 mg/kg, i.m.) and midazolam (5 mg/kg, i.m.), has completely protected animals from death induced by supra-lethal dose of soman (2XLD50) and reduced the neuroinflammatory and neurodegenerative changes. Results highlight that this new prophylactic and therapeutic drug combination might be an effective treatment option for soldiers deployed in conflict areas and first responders dealing with accidental/deliberate release of nerve agents.
摘要：
急性神经毒剂暴露可在几分钟内杀死一个人，或产生多种神经毒性作用和随后的脑损伤，并有潜在的长期不良后果。最近对叙利亚平民滥用神经毒剂，在日本恐怖袭击期间，以及英国的个人暗杀，马来西亚表明了它们对世界人口的潜在威胁。现有的神经毒剂解毒剂只能提供不完全的保护，特别是，如果治疗延迟。为了开发有效的药物，这有利于阐明神经毒剂引起的多种神经损伤的潜在机制。本研究旨在探讨神经毒剂毒性过程中神经炎症的分子基础，重点是炎性小体相关蛋白和神经变性。在老鼠身上,NOD样受体家族pyrin结构域含3（NLRP3），神经胶质纤维酸性蛋白（GFAP）免疫反应性水平在海马中显著增加，梨状皮质,单次皮下梭曼暴露后的杏仁核区域（90µg/kg-1）。西方分析显示神经炎性指示蛋白显著增加，高迁移率族蛋白1(HMGB1)和诱导型一氧化氮合酶(iNOS)水平。在不同的大鼠大脑区域中存在荧光玉C染色的变性神经元，这表明神经毒剂毒性过程中存在神经变性。用加兰他敏预处理（3mg/kg，-30分钟），然后进行阿托品后处理（10mg/kg，i.m.）和咪达唑仑（5mg/kg，i.m.),完全保护动物免受超致死剂量的梭曼（2XLD50）诱导的死亡，并减少了神经炎症和神经退行性变化。结果强调，这种新的预防和治疗药物组合可能是部署在冲突地区的士兵和处理意外/故意释放神经毒剂的第一反应者的有效治疗选择。
