Alcohol, phospholipase A2-associated neuroinflammation, and ω3 docosahexaenoic acid protection.
Alcohol, phospholipase A2-associated neuroinflammation, and ω3 docosahexaenoic acid protection.
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DOI：
10.1007/s12035-014-8690-0
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发表时间：
2014-08
影响因子：
5.1
通讯作者：
Neafsey EJ
中科院分区：
文献类型：
--
作者：
Collins MA;Tajuddin N;Moon KH;Kim HY;Nixon K;Neafsey EJ
长期滥用酒精（乙醇）会导致神经炎症和脑损伤，从而导致酒精性痴呆。阿尔伯特·孙（Albert Sun）博士是最早提出氧化应激是导致酒精中毒相关大脑退化的关键因素的人。事实上，在成年大鼠模型中，氧化应激已被证明对反复或间歇性“暴饮”酒精（乙醇）导致的海马和颞皮质神经损伤至关重要。尽管潜在的机制尚不确定，但我们在体内（成年雄性大鼠）和体外（大鼠器官型海马-内嗅皮质切片培养）的狂饮酒精实验中进行的免疫电泳和相关分析表明，磷脂酶A2 （PLA2）激活了神经炎症途径。结果进一步表明，伴随PLA2激活，狂饮酒精升高氧化应激加合物（“氧化足迹”），有趣的是，聚（adp -核糖）聚合酶-1 (PARP-1)，一种氧化应激反应性DNA修复酶，与称为parthanatos的非凋亡性神经元死亡过程相关。酒精处理也显著增加了水通道蛋白-4 (AQP4)，这是一种在星形胶质细胞中富集的水通道，当其增强时，可引发脑水肿和神经炎症。我们进一步发现，在脑片培养物中补充二十二碳六烯酸（DHA; 22:6 ω3）对酗酒神经毒性具有有效的保护作用，同时排除PLA2亚型、AQP4、PARP-1和氧化应激足迹的诱导变化。DHA的研究结果支持ω3“鱼油”补充剂在戒酒治疗中的建议。
Chronic alcohol (ethanol) abuse causes neuroinflammation and brain damage that can give rise to alcoholic dementia. Insightfully, Dr. Albert Sun was an early proponent of oxidative stress as a key factor in alcoholism-related brain deterioration. In fact, oxidative stress has proven to be critical to the hippocampal and temporal cortical neurodamage resulting from repetitive or intermittent “binge” alcohol (ethanol) exposure in adult rat models. Although the underlying mechanisms are not certain, our immunoelectrophoretic and related assays in binge alcohol experiments in vivo (adult male rats) and in vitro (rat organotypic hippocampal-entorhinal cortical slice cultures) have implicated phospholipase A2 (PLA2)-activated neuroinflammatory pathways. The results further indicated that concomitant with PLA2 activation, binge alcohol elevated oxidative stress adducts (“oxidative footprints”) and, interestingly, poly(ADP-ribose) polymerase-1 (PARP-1), an oxidative stress-responsive, DNA repair enzyme linked to a non-apoptotic neuronal death process termed parthanatos. Also significantly increased by the alcohol treatments was aquaporin-4 (AQP4), a water channel enriched in astrocytes that, when augmented, can trigger brain edema and neuroinflammation. We further have found that supplementation of brain slice cultures with docosahexaenoic acid (DHA; 22:6 ω3) exerted potent protection against binge alcohol neurotoxicity, while precluding induced changes in PLA2 isoforms, AQP4, PARP-1 and oxidative stress footprints. The DHA results lend support to recommendations of ω3 “fish oil” supplementation in alcoholism withdrawal therapies.