Adibhatla Rao Muralikrishna, Hatcher James F, Dempsey Robert J
Department of Neurological Surgery, University of Wisconsin, Madison, Wisconsin 53792-3232, USA.
J Neurosci Res. 2004 May 1;76(3):390-6. doi: 10.1002/jnr.20078.
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.
胞苷-5'-二磷酸胆碱（CDP-胆碱，也称为胞磷胆碱）是磷脂酰胆碱（PtdCho）合成的关键中间体，在包括脑缺血在内的实验性中枢神经系统（CNS）损伤中具有显著益处。CDP-胆碱由CTP：磷酸胆碱胞苷转移酶（CCT）合成，CCT是PtdCho合成中的关键限速酶。磷脂酶A(2)（PLA(2)）水解PtdCho以产生游离脂肪酸和溶血磷脂酰胆碱，后者是CCT的抑制剂。我们研究了沙土鼠短暂性脑缺血10分钟并再灌注长达2天后CCT和溶血磷脂酰胆碱的状态。无再灌注的缺血导致胞质溶胶中CCT活性丧失（与假手术组相比，分别为408±8 pmol/分钟/毫克蛋白和695±45；P<0.01）以及膜中CCT活性丧失（与假手术组相比，分别为383±61和532±54；P<0.05）。在24小时再灌注期间CCT活性一直较低，在第2天膜中的CCT活性恢复到假手术水平，但胞质溶胶中的CCT活性仍较低。CDP-胆碱在再灌注1小时时显著增加胞质溶胶中的CCT活性（生理盐水组为339±35，CDP-胆碱组为430±70；P<0.05），在再灌注6小时（生理盐水组为381±32，CDP-胆碱组为489±50；P<0.01）和24小时（生理盐水组为417±24，CDP-胆碱组为594±45；P<0.01）时增加膜中的CCT活性，但在第2天对CCT活性无影响。溶血磷脂酰胆碱在再灌注1小时时增加（与假手术组相比，为219±5 nmol/克组织和92±8；P<0.01），并在2天内一直升高。CDP-胆碱在再灌注1小时时降低溶血磷脂酰胆碱水平（162±21，与生理盐水组相比P<0.01）。这些数据表明脑缺血后脑磷脂酰胆碱合成受损，CDP-胆碱可能通过减轻CCT活性丧失和溶血磷脂酰胆碱形成来增加磷脂酰胆碱水平。
