Citicoline decreases phospholipase A2 stimulation and hydroxyl radical generation in transient cerebral ischemia.
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.
Adibhatla
Rao Muralikrishna
RM
Department of Neurological Surgery, University of Wisconsin, Madison, Wisconsin 53792-3232, USA. adibhatl@neurosurg.wisc.edu
Hatcher
James F
JF
D000818:Animals; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D003566:Cytidine Diphosphate Choline / Q000494:pharmacology*; D005849:Gerbillinae; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D017665:Hydroxyl Radical / Q000378:metabolism; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D018697:Nootropic Agents / Q000494:pharmacology*; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2
D018696:Neuroprotective Agents; D018697:Nootropic Agents; D017665:Hydroxyl Radical; D003566:Cytidine Diphosphate Choline; D010741:Phospholipases A; D054467:Phospholipases A2; D002118:Calcium