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Lipid alterations in transient forebrain ischemia: possible new mechanisms of CDP-choline neuroprotection
A M Rao1, J F Hatcher, R J Dempsey
1Department of Neurological Surgery, University of Wisconsin, Madison, Wisconsin 53792-3232, USA. adibhatl@neurosurg.wisc.edu
Insights
Cytidine 5'-diphosphocholine (CDP-choline) protects brain cells after ischemia by restoring key phospholipids and reducing harmful arachidonic acid release. This treatment helps stabilize cell membranes and limits neurotoxic oxidative metabolism.
Area of Science:
- Neuroscience
- Biochemistry
- Cell Biology
Background:
- Transient forebrain ischemia causes neurotoxicity via arachidonic acid (ArAc) release and subsequent oxidative stress.
- Arachidonic acid metabolism generates reactive oxygen species (ROS) and pro-apoptotic agents like ceramide.
- CDP-choline demonstrated neuroprotective effects in previous studies involving ischemia.
Purpose of the Study:
- To investigate the impact of CDP-choline on phospholipid and ceramide levels post-ischemia.
- To determine CDP-choline's effect on arachidonic acid content in specific phospholipids.
- To elucidate the mechanisms underlying CDP-choline's neuroprotective action.
Main Methods:
- Gerbil model of transient forebrain ischemia followed by 1-day reperfusion.
- Analysis of phospholipid and ceramide profiles in hippocampal tissue.
- Quantification of arachidonic acid levels in various phospholipid fractions.
- Administration of CDP-choline post-ischemia and at reperfusion intervals.
Main Results:
- Ischemia/reperfusion significantly decreased phosphatidylcholine (PtdCho), phosphatidylinositol (PtdIns), phosphatidylserine (PtdSer), sphingomyelin, and cardiolipin levels.
- Arachidonic acid was depleted from phosphatidylethanolamine (PtdEtn) post-ischemia.
- CDP-choline treatment restored PtdCho, sphingomyelin, and cardiolipin levels.
- CDP-choline also restored arachidonic acid content in PtdCho and PtdEtn, but not PtdIns or PtdSer.
Conclusions:
- CDP-choline stabilizes cell membranes by restoring phosphatidylcholine and sphingomyelin.
- CDP-choline attenuates arachidonic acid release and limits its oxidative metabolism.
- CDP-choline restores cardiolipin levels, crucial for mitochondrial function.
Abstract:
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.