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.