Neurotrauma and Injury, Pain, Regeneration and Repair

Citicoline (CDP-choline) has undergone 13 phase III clinical stroke trials, 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, which is released by the action of phospholipases, contributes to ROS generation. Here, we examined the effect of citicoline on phospholipase A2 (PLA2) activity in relationship to attenuating the hydroxyl radical (OH) generation after transient forebrain ischemia of gerbil. A 10-min transient forebrain ischemia was induced by bilateral carotid artery occlusion in male Mongolian gerbils with reperfusion up to 24 h. Citicoline (500 mg/kg IP in saline) was given to gerbils at 0and 3-hr reperfusion. PLA2 activity in hippocampal membrane and mitochondrial fractions was determined. OH were determined by salicylate trapping and HPLC with electrochemical detection. The predominant form of PLA2 in gerbil hippocampus required millimolar Ca concentrations, characteristic of 14-kDa secretory PLA2. PLA2 activity increased in both membrane and mitochondrial fractions after transient cerebral ischemia in gerbil, which was significantly attenuated by citicoline treatment. In vitro, citicoline and its components cytidine and choline had no effect on PLA2 activity, and thus citicoline is not as such a PLA2 inhibitor. Ischemia/ reperfusion resulted in significant OH generation and citicoline significantly attenuated their formation. These results suggest that citicoline inhibits the stimulation of PLA2 and attenuates ROS formation after transient cerebral ischemia.