Adibhatla Rao Muralikrishna, Hatcher James F
Department of Neurological Surgery, University of Wisconsin, Madison, Wisconsin 53792-3232, USA.
J Neurosci Res. 2003 Aug 1;73(3):308-15. doi: 10.1002/jnr.10672.
Neuroprotection by citicoline (CDP-choline) in transient cerebral ischemia has been demonstrated previously. Citicoline has undergone several Phase III clinical trials for stroke, and is being evaluated for treatment of Alzheimer's and Parkinson's diseases. Phospholipid degradation and generation of reactive oxygen species (ROS) are major factors causing neuronal injury in CNS trauma and neurodegenerative diseases. Oxidative metabolism of arachidonic acid (released by the action of phospholipases) contributes to ROS generation. We examined the effect of citicoline on phospholipase A(2) (PLA(2)) activity in relation to the attenuation of hydroxyl radical (OH.) generation after transient forebrain ischemia of gerbil. PLA(2) activity (requires mM Ca(2+)) increased significantly (P < 0.05) in both membrane (50.2 +/- 2.2 pmol/min/mg protein compared to sham 35.9 +/- 3.2) and mitochondrial fractions (77.0 +/- 1.2 pmol/min/mg protein compared to sham 33.9 +/- 1.2) after cerebral ischemia and 2 hr reperfusion in gerbil, which was significantly attenuated (P < 0.01) by citicoline (membrane, 39.9. +/- 2.2 and mitochondria, 41.9 +/- 3.2 pmol/min/mg protein). In vitro, citicoline and its components cytidine and choline had no effect on PLA(2) activity, and thus citicoline as such is not a PLA(2) inhibitor. Ischemia/reperfusion resulted in significant OH. generation (P < 0.01) and citicoline significantly (P < 0.01) attenuated their formation (expressed as 2,3-dihydroxybenzoic acid/salicylate ratio; ischemia/24 hr reperfusion, 6.30 +/- 0.23; sham, 2.56 +/- 0.27; ischemia/24 hr reperfusion + citicoline, 4.85 +/- 0.35). These results suggest that citicoline affects PLA(2) stimulation and decreases OH. generation after transient cerebral ischemia.
此前已证实胞磷胆碱（CDP - 胆碱）对短暂性脑缺血具有神经保护作用。胞磷胆碱已针对中风进行了多项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。磷脂降解和活性氧（ROS）生成是导致中枢神经系统创伤和神经退行性疾病中神经元损伤的主要因素。花生四烯酸的氧化代谢（由磷脂酶作用释放）有助于ROS生成。我们研究了胞磷胆碱对沙土鼠短暂性前脑缺血后羟基自由基（OH·）生成减少相关的磷脂酶A2（PLA2）活性的影响。沙土鼠脑缺血及2小时再灌注后，膜组分（与假手术组35.9±3.2相比，为50.2±2.2 pmol/min/mg蛋白）和线粒体组分（与假手术组33.9±1.2相比，为77.0±1.2 pmol/min/mg蛋白）中的PLA2活性（需要毫摩尔浓度的Ca2 +）均显著增加（P < 0.05），而胞磷胆碱可显著减弱这种增加（P < 0.01）（膜组分，39.9±2.2；线粒体，41.9±3.2 pmol/min/mg蛋白）。在体外，胞磷胆碱及其成分胞嘧啶和胆碱对PLA2活性无影响，因此胞磷胆碱本身不是PLA2抑制剂。缺血/再灌注导致显著的OH·生成（P < 0.01），而胞磷胆碱可显著（P < 0.01）减弱其形成（以2,3 - 二羟基苯甲酸/水杨酸比率表示；缺血/24小时再灌注，6.30±0.23；假手术组，2.56±0.27；缺血/24小时再灌注 + 胞磷胆碱，4.85±0.35）。这些结果表明，胞磷胆碱影响PLA2的激活并减少短暂性脑缺血后的OH·生成。
