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.
adibhatl@neurosurg.wisc.edu
Abstract
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.
