Adibhatla Rao Muralikrishna, Hatcher James F, Dempsey Robert J
Department of Neurological Surgery, Cardiovascular Research Center, University of Wisconsin, Madison, WI 53792, USA.
Antioxid Redox Signal. 2003 Oct;5(5):647-54. doi: 10.1089/152308603770310329.
Phospholipid degradation is an important promoter of neuronal death after transient cerebral ischemia. Phospholipid hydrolysis by phospholipase A2 (PLA2) 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 PLA2 activity in relationship to attenuating hydroxyl radical (OH*) generation and lipid peroxidation after transient forebrain ischemia in gerbil. High Ca2+ dependency (millimolar range) of PLA2 activity suggests that secretory PLA2 is the predominant isoform in membrane and mitochondria. Citicoline attenuated the increase in PLA2 activity in both membrane and mitochondrial fractions. In vitro, citicoline and its components choline and cytidine had no effect on the PLA2 activity. Thus, citicoline is not a "direct PLA2 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 PLA2.
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A2（PLA2）介导的磷脂水解会释放花生四烯酸。花生四烯酸代谢会导致活性氧、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产物，已针对中风进行了13项III期临床试验，目前正在评估其对阿尔茨海默病和帕金森病的治疗效果。在此，我们研究了胞磷胆碱对沙土鼠短暂性前脑缺血后PLA2活性的影响，及其与减轻羟自由基（OH*）生成和脂质过氧化的关系。PLA2活性对高Ca2+（毫摩尔范围）的依赖性表明，分泌型PLA2是膜和线粒体中的主要亚型。胞磷胆碱可减轻膜和线粒体组分中PLA2活性的增加。在体外，胞磷胆碱及其成分胆碱和胞苷对PLA2活性没有影响。因此，胞磷胆碱不是“直接的PLA2抑制剂”。胞磷胆碱还显著减轻了心磷脂的丢失以及花生四烯酸从磷脂酰胆碱和磷脂酰乙醇胺中的释放。短暂性脑缺血导致OH*和丙二醛大量形成，而胞磷胆碱显著减轻了它们的形成。这些结果表明，胞磷胆碱通过减弱对PLA2的刺激来提供神经保护作用。
