Lipid Alterations in Transient Forebrain Ischemia

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Abstract
We have previously demonstrated that cytidine5′-diphosphocholine (CDP-choline or citicoline) attenuated arachidonicacid (ArAc) release and provided significant protection for the vulnerablehippocampal CA1 neurons of the cornu ammonis after transientforebrain ischemia of gerbil. ArAc is released by the activation ofphospholipases and the alteration of phosphatidylcholine (PtdCho) synthesis.Released ArAc is metabolized by cyclooxygenases/lipoxygenases to formeicosanoids and reactive oxygen species (ROS). ROS contribute to neurotoxicitythrough generation of lipid peroxides and the cytotoxic byproducts4-hydroxynonenal and acrolein. ArAc can also stimulate sphingomyelinase toproduce ceramide, a potent pro-apoptotic agent. In the present study, weexamined the changes and effect of CDP-choline on ceramide and phospholipidsincluding PtdCho, phosphatidylethanolamine (PtdEtn), phosphatidylinositol(PtdIns), phosphatidylserine (PtdSer), sphingomyelin, and cardiolipin (anexclusive inner mitochondrial membrane lipid essential for electron transport)following ischemia/1-day reperfusion. Our studies indicated significantdecreases in total PtdCho, PtdIns, PtdSer, sphingomyelin, and cardiolipin andloss of ArAc from PtdEtn in gerbil hippocampus after 10-min forebrainischemia/1-day reperfusion. CDP-choline (500 mg/kg i.p. immediately afterischemia and at 3-h reperfusion) significantly restored the PtdCho,sphingomyelin, and cardiolipin levels as well as the ArAc content of PtdChoand PtdEtn but did not affect PtdIns and PtdSer. These data suggest multiplebeneficial effects of CDP-choline: (1) stabilizing the cell membrane byrestoring PtdCho and sphingomyelin (prominent components of outer cellmembrane), (2) attenuating the release of ArAc and limiting its oxidativemetabolism, and (3) restoring cardiolipin levels.