CDP-choline significantly restores phosphatidylcholine levels by differentially affecting phospholipase A2 and CTP:: Phosphocholine cytidylyltransferase after stroke

Phosphatidylcholine (PtdCho) is a major membrane phospholipid, and its loss is sufficient in itself to induce cell death. PtdCho homeostasis is regulated by the balance between hydrolysis and synthesis. PtdCho is hydrolyzed by phospholipase A(2) (PLA(2)), PtdCho-specific phospholipase C (PtdCho-PLC), and phospholipase D (PLD). PtdCho synthesis is rate-limited by CTP: phosphocholine cytidylyltransferase (CCT), which makes CDP-choline. The final step of PtdCho synthesis is catalyzed by CDP-choline: 1,2-diacylglycerol cholinephosphotransferase. PtdCho synthesis in the brain is predominantly through the CDP-choline pathway. Transient middle cerebral artery occlusion (tMCAO) significantly increased PLA(2) activity, secretory PLA(2) (sPLA(2))-IIA mRNA and protein levels, PtdCho-PLC activity, and PLD2 protein expression following reperfusion. CDP-choline treatment significantly attenuated PLA(2) activity, sPLA(2)-IIA mRNA and protein levels, and PtdCho-PLC activity, but did not affect PLD2 protein expression. tMCAO also resulted in loss of CCT activity and CCT alpha protein, which were partially restored by CDP-choline. No changes were observed in cytosolic PLA(2) or calcium-independent PLA(2) protein levels after tMCAO. Up-regulation of PLA(2), PtdCho-PLC, and PLD and down-regulation of CCT collectively resulted in loss of PtdCho, which was significantly restored by CDP-choline treatment. CDP-choline treatment significantly attenuated the infarction volume by 55 +/- 5% after 1 h of tMCAO and 1 day of reperfusion. Taken together, these results suggest that CDP-choline significantly restores PtdCho levels by differentially affecting sPLA(2)-IIA, PtdCho-PLC, and CCT alpha after transient focal cerebral ischemia. A hypothetical scheme is proposed integrating results from this study and from other reports in the literature.