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J. Biol. Chem., Vol. 281, Issue 10, 6718-6725, March 10, 2006

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CDP-choline Significantly Restores Phosphatidylcholine Levels by Differentially Affecting Phospholipase A₂ and CTP: Phosphocholine Cytidylyltransferase after Stroke^*

Rao Muralikrishna Adibhatla^¶1, James F. Hatcher^¶, Eric C. Larsen, Xinzhi Chen, Dandan Sun, and Francis H. C. Tsao

From the Department of Neurological Surgery and the Cardiovascular Research Center, University of Wisconsin, Madison, Wisconsin 53792-3232 and the ^¶Veterans Affairs Medical Center, Madison, Wisconsin 53705

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 CCT 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 CCT after transient focal cerebral ischemia. A hypothetical scheme is proposed integrating results from this study and from other reports in the literature.

Received for publication, November 10, 2005 , and in revised form, December 20, 2005.

^* This work was supported by NINDS Grant NS42008 from the National Institutes of Health and grants from the University of Wisconsin Medical School and Graduate School (to R. M. A.) and by laboratory resources provided by the William S. Middleton Veterans Affairs Hospital. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Neurological Surgery, H4-330, Clinical Science Center, 600 Highland Ave., University of Wisconsin, Madison, WI 53792-3232. Tel.: 608-263-1791; Fax: 608-263-1409; E-mail: adibhatl{at}neurosurg.wisc.edu.

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