Phospholipase A2, hydroxyl radicals, and lipid peroxidation in transient cerebral ischemia
Phospholipase A2, hydroxyl radicals, and lipid peroxidation in transient cerebral ischemia
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DOI：
10.1089/152308603770310329
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发表时间：
2003-10-01
影响因子：
6.6
通讯作者：
Dempsey, RJ
中科院分区：
文献类型：
--
作者：
Adibhatla, RM;Hatcher, JF;Dempsey, RJ
磷脂降解是短暂性脑缺血后神经元死亡的重要促进因素。短暂性脑缺血后磷脂酶A（2）（PLA（2））水解磷脂释放花生四烯酸。花生四烯酸代谢导致活性氧、脂质过氧化物和有毒醛类（丙二醛、4-羟基壬烯醛和丙烯醛）的形成。胞磷胆碱（胞苷-5 '-二磷酸胆碱）是磷脂酰胆碱合成的中间体，已进行了13项治疗中风的III期临床试验，并正在评估其治疗阿尔茨海默病和帕金森病的效果。在这里，我们研究了胞二磷胆碱对PLA（2）活性的影响与衰减羟自由基（OH）的关系。沙土鼠短暂性前脑缺血后海马神经元的产生及脂质过氧化作用。PLA（2）活性的高Ca 2+依赖性（毫摩尔范围）表明分泌型PLA（2）是膜和线粒体中的主要亚型。胞二磷胆碱减弱膜和线粒体组分中PLA（2）活性的增加。在体外，胞磷胆碱及其组分胆碱和胞苷对PLA（2）活性无影响。因此，胞磷胆碱不是“直接PLA（2）抑制剂”。胞二磷胆碱还显著减弱了磷脂酰胆碱和磷脂酰乙醇胺释放心磷脂和花生四烯酸的损失。短暂性脑缺血导致OH的显著形成。丙二醛和胞二磷胆碱显著减弱它们的形成。这些结果表明，胞磷胆碱通过减弱PLA的刺激提供神经保护（2）。
Phospholipid degradation is an important promoter of neuronal death after transient cerebral ischemia. Phospholipid hydrolysis by phospholipase A(2) (PLA(2)) after transient cerebral ischemia releases arachidonic acid. Arachidonic acid metabolism results in formation of reactive oxygen species, lipid peroxides, and toxic aldehydes (malondialdehyde, 4-hydroxynonenal, and acrolein). Citicoline (cytidine-5'-diphosphocholine), an intermediate in phosphatidylcholine synthesis, has undergone 13 phase III clinical trials for stroke, and is being evaluated for treatment of Alzheimer's and Parkinson's diseases. Here we examined the effect of citicoline on PLA(2) activity in relationship to attenuating hydroxyl radical (OH.) generation and lipid peroxidation after transient forebrain ischemia in gerbil. High Ca2+ dependency (millimolar range) of PLA(2) activity suggests that secretory PLA(2) is the predominant isoform in membrane and mitochondria. Citicoline attenuated the increase in PLA(2) activity in both membrane and mitochondrial fractions. In vitro, citicoline and its components choline and cytidine had no effect on the PLA(2) activity. Thus, citicoline is not a "direct PLA(2) inhibitor." Citicoline also significantly attenuated loss of cardiolipin and arachidonic acid release from phosphatidylcholine and phosphatidylethanolamine. Transient cerebral ischemia resulted in significant formation of OH. and malondialdehyde, and citicoline significantly attenuated their formation. These results suggest that citicoline provides neuroprotection by attenuating the stimulation of PLA(2).