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

Adibhatla RM, Hatcher JF, Larsen EC, Chen X, Sun D, Tsao FH

Department of Neurological Surgery
University of Wisconsin
 Madison, WI 53792-3232
 J Biol Chem. 2006 Mar 10;281(10):6718-25.


Phosphatidylcholine is a major membrane phospholipid, and its loss is sufficient in itself to induce cell death.  Phosphatidylcholine homeostasis is regulated by the balance between hydrolysis and synthesis. Phosphatidylcholine is hydrolyzed by phospholipase A2 (PLA2), Phosphatidylcholine specific phospholipase C (Phosphatidylcholine -PLC), and phospholipase D (PLD). Phosphatidylcholine synthesis is rate-limited by CTP:phosphocholine cytidylyltransferase (CCT), which makes CDP-choline. The final step of Phosphatidylcholine synthesis is catalyzed by CDP-choline:1,2-diacylglycerol cholinephosphotransferase. Phosphatidylcholine synthesis in the brain is predominantly through the CDP-choline pathway.  Transient middle cerebral artery occlusion (tMCAO) significantly increased PLA2 activity, secretory PLA2 (sPLA2)-IIA mRNA and protein levels, Phosphatidylcholine-PLC activity, and PLD2 protein expression following reperfusion.  CDP-choline treatment significantly attenuated PLA2 activity, sPLA2-IIA mRNA and protein levels, and Phosphatidylcholine-PLC activity, but did not affect PLD2 protein expression.  tMCAO also resulted in loss of CCT activity and CCTalpha protein, which were partially restored by CDP-choline. No changes were observed in cytosolic PLA2 or calcium-independent PLA2 tMCAO. protein levels after Up-regulation of PLA2, phosphatidylcholine-PLC, and PLD and regulation of CCT collectively down-resulted in loss of phosphatidylcholine, 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 phosphatidylcholine levels by differentially affecting sPLA2-IIA, Phosphatidylcholine-PLC, and CCTalpha after transient focal cerebral ischemia.  A hypothetical scheme is proposed integrating results from this study and from other reports in the literature.

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