Cytidine-5'-diphosphocholine affects CTP-phosphocholine cytidylyltransferase and lyso-phosphatidylcholine after transient brain ischemia.
Cytidine-5'-diphosphocholine (CDP-choline, also referred as citicoline), the key intermediate in phosphatidylcholine (PtdCho) synthesis, provided significant benefit in experimental central nervous system (CNS) injury including cerebral ischemia. CDP-choline is synthesized by CTP:phosphocholine cytidylyltransferase (CCT), the key rate-limiting enzyme in PtdCho synthesis. Phospholipase A(2) (PLA(2)) hydrolyzes PtdCho to produce free fatty acids and lyso-PtdCho, an inhibitor of CCT. We investigated the status of CCT and lyso-PtdCho after 10-min transient brain ischemia in gerbils with reperfusion up to 2 days. Ischemia with no reperfusion resulted in loss of CCT activity in cytosol (408 +/- 8 pmol/min/mg protein compared to sham 695 +/- 45; P < 0.01) and membrane (383 +/- 61 compared to sham 532 +/- 54; P < 0.05). CCT activity remained low over 24-hr reperfusion, and returned to sham levels at Day 2 in membrane but remained low in cytosol. CDP-choline significantly increased CCT activity in cytosol at 1 hr reperfusion (saline, 339 +/- 35 compared to CDP-choline, 430 +/- 70; P < 0.05) and in membrane at 6 hr (saline, 381 +/- 32 compared to CDP-choline, 489 +/- 50; P < 0.01) and 24 hr (saline, 417 +/- 24 compared to CDP-choline, 594 +/- 45; P < 0.01), but had no effect on CCT activity at Day 2. Lyso-PtdCho increased at 1-hr reperfusion (219 +/- 5 nmol/g tissue compared to sham, 92 +/- 8; P < 0.01), and remained elevated over 2 days. CDP-choline attenuated lyso-PtdCho levels at 1-hr reperfusion (162 +/- 21, P < 0.01 compared to saline). These data indicate that PtdCho synthesis is impaired after brain ischemia, and CDP-choline may increase PtdCho levels by attenuating the loss of CCT activity and lyso-PtdCho formation.
Adibhatla
Rao Muralikrishna
RM
Department of Neurological Surgery, University of Wisconsin, Madison, Wisconsin 53792-3232, USA. Adibhatl@neurosurg.wisc.edu
Hatcher
James F
JF
Dempsey
Robert J
RJ
D000704:Analysis of Variance; D000818:Animals; D019916:Choline-Phosphate Cytidylyltransferase / Q000187:drug effects / Q000378:metabolism*; D003566:Cytidine Diphosphate Choline / Q000378:metabolism / Q000494:pharmacology*; D025461:Feedback, Physiological; D005849:Gerbillinae; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology; D002546:Ischemic Attack, Transient / Q000201:enzymology*; D008244:Lysophosphatidylcholines / Q000378:metabolism*; D009474:Neurons / Q000201:enzymology; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000494:pharmacology
D008244:Lysophosphatidylcholines; D018696:Neuroprotective Agents; D003566:Cytidine Diphosphate Choline; D019916:Choline-Phosphate Cytidylyltransferase