†Department of Anatomy, National University of Singapore, Singapore 119260, Singapore.
‡Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, Ohio 43210, United States.
ACS Chem Neurosci. 2015 Jun 17;6(6):814-31. doi: 10.1021/acschemneuro.5b00073. Epub 2015 May 1.
Phospholipases A2 (PLA2) are a diverse group of enzymes that hydrolyze membrane phospholipids into arachidonic acid and lysophospholipids. Arachidonic acid is metabolized to eicosanoids (prostaglandins, leukotrienes, thromboxanes), and lysophospholipids are converted to platelet-activating factors. These lipid mediators play critical roles in the initiation, maintenance, and modulation of neuroinflammation and oxidative stress. Neurological disorders including excitotoxicity; traumatic nerve and brain injury; cerebral ischemia; Alzheimer's disease; Parkinson's disease; multiple sclerosis; experimental allergic encephalitis; pain; depression; bipolar disorder; schizophrenia; and autism are characterized by oxidative stress, inflammatory reactions, alterations in phospholipid metabolism, accumulation of lipid peroxides, and increased activities of brain phospholipase A2 isoforms. Several old and new synthetic inhibitors of PLA2, including fatty acid trifluoromethyl ketones; methyl arachidonyl fluorophosphonate; bromoenol lactone; indole-based inhibitors; pyrrolidine-based inhibitors; amide inhibitors, 2-oxoamides; 1,3-disubstituted propan-2-ones and polyfluoroalkyl ketones as well as phytochemical based PLA2 inhibitors including curcumin, Ginkgo biloba and Centella asiatica extracts have been discovered and used for the treatment of neurological disorders in cell culture and animal model systems. The purpose of this review is to summarize information on selective and potent synthetic inhibitors of PLA2 as well as several PLA2 inhibitors from plants, for treatment of oxidative stress and neuroinflammation associated with the pathogenesis of neurological disorders.
磷脂酶 A2（PLA2）是一组具有多种功能的酶，能够水解膜磷脂生成花生四烯酸和溶血磷脂。花生四烯酸进一步代谢为类二十烷酸（前列腺素、白三烯、血栓素），而溶血磷脂则转化为血小板激活因子。这些脂质介质在神经炎症和氧化应激的启动、维持和调节中起着关键作用。包括兴奋性毒性；创伤性神经和脑损伤；脑缺血；阿尔茨海默病；帕金森病；多发性硬化症；实验性变态反应性脑脊髓炎；疼痛；抑郁；双相情感障碍；精神分裂症；自闭症在内的多种神经疾病的特点是氧化应激、炎症反应、磷脂代谢改变、脂质过氧化物积累以及脑磷脂酶 A2 同工酶活性增加。几种新老合成 PLA2 抑制剂，包括脂肪酸三氟甲基酮；甲基花生四烯酸氟膦酸酯；溴烯醇内酯；吲哚基抑制剂；吡咯烷基抑制剂；酰胺抑制剂，2-氧代酰胺；1,3-二取代丙-2-酮和多氟烷基酮以及基于植物的 PLA2 抑制剂，包括姜黄素、银杏叶和积雪草提取物，已被发现并用于治疗细胞培养和动物模型系统中的神经疾病。本综述的目的是总结选择性和有效的 PLA2 合成抑制剂以及几种来自植物的 PLA2 抑制剂的信息，用于治疗与神经疾病发病机制相关的氧化应激和神经炎症。
