Singh Naveen, Golime RamaRao, Kumar Abdhesh, Roy Tuhin
Biomedical Verification Division, Defence Research and Development Establishment (DRDE), Jhansi Road, Gwalior, M.P, India.
Department of Epidemiology and Public Health, Central University of Tamil Nadu, Thiruvarur, India.
Mol Neurobiol. 2025 Jan;62(1):461-474. doi: 10.1007/s12035-024-04294-2. Epub 2024 Jun 13.
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). 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 (2XLD) 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.
急性接触神经毒剂可在数分钟内致人死亡，或产生多种神经毒性作用及随后的脑损伤，并可能导致长期不良后果。近期在叙利亚平民中滥用神经毒剂、日本恐怖袭击期间、英国和马来西亚的个人暗杀事件表明，神经毒剂对世界人口构成潜在威胁。现有的神经毒剂解毒剂提供的保护并不完全，尤其是治疗延迟时。为了开发有效的药物，阐明神经毒剂诱发多种神经功能障碍的潜在机制是有益的。本研究旨在探讨神经毒剂毒性作用期间神经炎症的分子基础，重点关注炎性小体相关蛋白和神经退行性变。在大鼠中，单次皮下注射梭曼（90 μg/kg）后，海马体、梨状皮质和杏仁核区域的含NOD样受体家族pyrin结构域蛋白3（NLRP3）和胶质纤维酸性蛋白（GFAP）免疫反应水平显著升高。蛋白质免疫印迹分析表明，神经炎症指标蛋白高迁移率族蛋白B1（HMGB1）和诱导型一氧化氮合酶（iNOS）水平显著升高。不同大鼠脑区中出现的氟玉红C染色的变性神经元表明神经毒剂毒性作用期间存在神经退行性变。加兰他敏（3 mg/kg，-30分钟）预处理，随后阿托品（10 mg/kg，肌肉注射）和咪达唑仑（5 mg/kg，肌肉注射）后处理，可完全保护动物免受超致死剂量梭曼（2倍半数致死剂量）诱导的死亡，并减少神经炎症和神经退行性变。结果表明，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应对神经毒剂意外/故意释放的急救人员的有效治疗选择。
