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 A2 (PLA2), PtdChospecific
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 PLA2 activity, secretory PLA2 (sPLA2)-IIA
mRNA and
protein levels, PtdCho-PLC activity, and PLD2
protein expression following reperfusion.
CDP-choline treatment significantly attenuated PLA2 activity, sPLA2-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 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, PtdCho-PLC, and
PLD and regulation of CCT collectively down-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 Ptd-Cho levels by differentially affecting sPLA2-IIA, PtdCho-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.