Citicoline decreases phospholipase A2 stimulation and hydroxyl radical generation in transient cerebral ischemia

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Abstract
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 A2 (PLA2) activity in relation to the attenuation of hydroxyl radical (OH·) generation after transient forebrain ischemia of gerbil. PLA2 activity (requires mM Ca2+) 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 PLA2 activity, and thus citicoline as such is not a PLA2 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 PLA2 stimulation and decreases OH· generation after transient cerebral ischemia.