Lipid alterations in transient forebrain ischemia: possible new mechanisms of CDP-choline neuroprotection.
We have previously demonstrated that cytidine 5'-diphosphocholine (CDP-choline or citicoline) attenuated arachidonic acid (ArAc) release and provided significant protection for the vulnerable hippocampal CA(1) neurons of the cornu ammonis after transient forebrain ischemia of gerbil. ArAc is released by the activation of phospholipases and the alteration of phosphatidylcholine (PtdCho) synthesis. Released ArAc is metabolized by cyclooxygenases/lipoxygenases to form eicosanoids and reactive oxygen species (ROS). ROS contribute to neurotoxicity through generation of lipid peroxides and the cytotoxic byproducts 4-hydroxynonenal and acrolein. ArAc can also stimulate sphingomyelinase to produce ceramide, a potent pro-apoptotic agent. In the present study, we examined the changes and effect of CDP-choline on ceramide and phospholipids including PtdCho, phosphatidylethanolamine (PtdEtn), phosphatidylinositol (PtdIns), phosphatidylserine (PtdSer), sphingomyelin, and cardiolipin (an exclusive inner mitochondrial membrane lipid essential for electron transport) following ischemia/1-day reperfusion. Our studies indicated significant decreases in total PtdCho, PtdIns, PtdSer, sphingomyelin, and cardiolipin and loss of ArAc from PtdEtn in gerbil hippocampus after 10-min forebrain ischemia/1-day reperfusion. CDP-choline (500 mg/kg i.p. immediately after ischemia and at 3-h reperfusion) significantly restored the PtdCho, sphingomyelin, and cardiolipin levels as well as the ArAc content of PtdCho and PtdEtn but did not affect PtdIns and PtdSer. These data suggest multiple beneficial effects of CDP-choline: (1) stabilizing the cell membrane by restoring PtdCho and sphingomyelin (prominent components of outer cell membrane), (2) attenuating the release of ArAc and limiting its oxidative metabolism, and (3) restoring cardiolipin levels.
Rao
A M
AM
Department of Neurological Surgery, University of Wisconsin, Madison, Wisconsin 53792-3232, USA. adibhatl@neurosurg.wisc.edu
Hatcher
J F
JF
Dempsey
R J
RJ
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002308:Cardiolipins / Q000378:metabolism; D002518:Ceramides / Q000378:metabolism; D003566:Cytidine Diphosphate Choline / Q000378:metabolism* / Q000494:pharmacology; D005849:Gerbillinae; D002546:Ischemic Attack, Transient / Q000378:metabolism*; D008297:Male; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology; D010713:Phosphatidylcholines / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D010718:Phosphatidylserines / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D016548:Prosencephalon / Q000098:blood supply / Q000378:metabolism*; D015424:Reperfusion; D013109:Sphingomyelins / Q000378:metabolism
D002308:Cardiolipins; D002518:Ceramides; D018696:Neuroprotective Agents; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D010716:Phosphatidylinositols; D010718:Phosphatidylserines; D010743:Phospholipids; D013109:Sphingomyelins; D016718:Arachidonic Acid; D003566:Cytidine Diphosphate Choline