Phospholipase A2, hydroxyl radicals, and lipid peroxidation in transient cerebral ischemia.
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.
Department of Neurological Surgery, Cardiovascular Research Center, University of Wisconsin, Madison, WI 53792, USA. adibhatl@neurosurg.wisc.edu
Rao Muralikrishna
RM
Adibhatla
James F
JF
Hatcher
Robert J
RJ
Dempsey
D000818:Animals; D016718:Arachidonic Acid / Q000032:analysis; D002118:Calcium / Q000378:metabolism; D002308:Cardiolipins / Q000032:analysis; D002462:Cell Membrane / Q000201:enzymology; D002851:Chromatography, High Pressure Liquid; D003566:Cytidine Diphosphate Choline / Q000494:pharmacology*; D005841:Gentisates / Q000032:analysis; D005849:Gerbillinae; D006624:Hippocampus / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D062385:Hydroxybenzoates / Q000032:analysis; D017665:Hydroxyl Radical / Q000378:metabolism*; D007425:Intracellular Membranes / Q000201:enzymology; D002546:Ischemic Attack, Transient / Q000503:physiopathology*; D015227:Lipid Peroxidation / Q000502:physiology*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology; D008954:Models, Biological; D010713:Phosphatidylcholines / Q000032:analysis; D010714:Phosphatidylethanolamines / Q000032:analysis; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D020156:Salicylic Acid / Q000032:analysis / Q000494:pharmacology
D002308:Cardiolipins; D005841:Gentisates; D062385:Hydroxybenzoates; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D016718:Arachidonic Acid; D017665:Hydroxyl Radical; C483858:phosphatidylethanolamine; D008315:Malondialdehyde; D003566:Cytidine Diphosphate Choline; C009135:2,3-dihydroxybenzoic acid; D010741:Phospholipases A; D054467:Phospholipases A2; D020156:Salicylic Acid; D002118:Calcium; C010925:2,5-dihydroxybenzoic acid