Piermartiri Tetsade, Pan Hongna, Figueiredo Taiza H, Marini Ann M
Molecular and Cellular Biology Graduate School Program, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.
Department of Neurology and Program in Neuroscience, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.
Molecules. 2015 Nov 12;20(11):20355-80. doi: 10.3390/molecules201119698.
α-Linolenic acid (ALA) is a nutraceutical found in vegetable products such as flax and walnuts. The pleiotropic properties of ALA target endogenous neuroprotective and neurorestorative pathways in brain and involve the transcription factor nuclear factor kappa B (NF-κB), brain-derived neurotrophic factor (BDNF), a major neuroprotective protein in brain, and downstream signaling pathways likely mediated via activation of TrkB, the cognate receptor of BDNF. In this review, we discuss possible mechanisms of ALA efficacy against the highly toxic OP nerve agent soman. Organophosphate (OP) nerve agents are highly toxic chemical warfare agents and a threat to military and civilian populations. Once considered only for battlefield use, these agents are now used by terrorists to inflict mass casualties. OP nerve agents inhibit the critical enzyme acetylcholinesterase (AChE) that rapidly leads to a cholinergic crisis involving multiple organs. Status epilepticus results from the excessive accumulation of synaptic acetylcholine which in turn leads to the overactivation of muscarinic receptors; prolonged seizures cause the neuropathology and long-term consequences in survivors. Current countermeasures mitigate symptoms and signs as well as reduce brain damage, but must be given within minutes after exposure to OP nerve agents supporting interest in newer and more effective therapies. The pleiotropic properties of ALA result in a coordinated molecular and cellular program to restore neuronal networks and improve cognitive function in soman-exposed animals. Collectively, ALA should be brought to the clinic to treat the long-term consequences of nerve agents in survivors. ALA may be an effective therapy for other acute and chronic neurodegenerative disorders.
α-亚麻酸（ALA）是一种存在于亚麻和核桃等植物产品中的营养保健品。ALA的多效性作用于大脑中的内源性神经保护和神经修复途径，涉及转录因子核因子κB（NF-κB）、脑源性神经营养因子（BDNF，大脑中的一种主要神经保护蛋白）以及可能通过BDNF的同源受体TrkB激活介导的下游信号通路。在本综述中，我们讨论了ALA对抗剧毒有机磷神经毒剂梭曼的可能作用机制。有机磷（OP）神经毒剂是剧毒化学战剂，对军事和平民人口构成威胁。这些毒剂曾经仅被认为用于战场，现在被恐怖分子用来造成大规模人员伤亡。OP神经毒剂抑制关键酶乙酰胆碱酯酶（AChE），这会迅速导致涉及多个器官的胆碱能危机。癫痫持续状态是由突触乙酰胆碱过度积累导致的，进而导致毒蕈碱受体过度激活；长时间的癫痫发作会导致幸存者出现神经病理学变化和长期后果。目前的对策可减轻症状和体征，并减少脑损伤，但必须在接触OP神经毒剂后几分钟内给予，这激发了人们对更新、更有效疗法的兴趣。ALA的多效性导致了一个协调的分子和细胞程序，以恢复梭曼暴露动物的神经网络并改善认知功能。总体而言，应将ALA引入临床，以治疗幸存者中神经毒剂造成的长期后果。ALA可能是治疗其他急性和慢性神经退行性疾病的有效疗法。
