Neuroprotection afforded by prior citicoline administration in experimental brain ischemia:: effects on glutamate transport
Neuroprotection afforded by prior citicoline administration in experimental brain ischemia:: effects on glutamate transport
复制标题
DOI：
10.1016/j.nbd.2004.10.006
复制
发表时间：
2005-03-01
影响因子：
6.1
通讯作者：
Lizasoain, I
中科院分区：
文献类型：
--
作者：
Hurtado, O;Moro, MA;Lizasoain, I
背景和目的：胞苷-5‘-二磷胆碱(胞二磷胆碱或CDP-胆碱)是磷脂酰胆碱生物合成的中间体，在包括脑缺血在内的多种中枢神经系统损伤模型中显示出良好的作用。胞二磷胆碱是唯一已被证明对中到重度中风患者有效的神经保护剂。然而，胞二磷胆碱具有神经保护作用的确切机制还不完全清楚。本研究旨在利用脑缺血的体内和体外模型，探索胞磷胆碱的神经保护作用机制。方法：采用结扎颈总动脉和大脑中动脉的方法建立成年雄性Fischer大鼠局灶性脑缺血模型。阻断后每隔一定时间测定脑组织谷氨酸水平。然后处死动物，测量脑梗塞体积和脑内三磷酸腺苷水平。与体外缺血模型一样，分离或共培养的大鼠皮质神经元或星形胶质细胞暴露于缺氧-葡萄糖剥夺(OGD)或胞二磷胆碱(1-100微米)存在下。通过测定乳酸脱氢酶释放量来研究细胞活力。同时测定谷氨酸的释放和摄取，以及三磷酸腺苷水平。结果：胞二磷胆碱(0.5、1、2g/kg)ip。缺血前1h给予胞磷胆碱可使纹状体的梗塞面积缩小(分别为缺血前的18%、27%和42%，P<0.05)，这与胞二磷胆碱对缺血后谷氨酸浓度升高的抑制作用有关。胞二磷胆碱还可抑制缺血引起的皮质和纹状体ATP水平的下降。培养的大鼠皮质神经细胞与胞二磷胆碱(10和100微米)孵育可阻止OGD诱导的LDH和谷氨酸的释放，并导致OGD后ATP水平的恢复，证实了我们之前的结果。此外，胞二磷胆碱(100um)可增加培养的大鼠星形胶质细胞对谷氨酸的摄取和EAAT2谷氨酸转运体的膜表达。结论：我们的研究结果为胞磷胆碱的神经保护作用提供了新的机制，胞磷胆碱可协同减少脑缺血后谷氨酸的释放。(C)2004 Elsevier Inc.保留所有权利。
Background and purpose: Cytidine-5'-diphosphocholine (citicoline or CDP-choline), an intermediate in the biosynthesis of phosphatidylcholine, has shown beneficial effects in a number of CNS injury models including cerebral ischemia. Citicoline is the only neuroprotectant that has proved efficacy in patients with moderate to severe stroke. However, the precise mechanism by which citicoline is neuroprotective is not fully known. The present study was designed to search for mechanisms of citicoline neuroprotective properties using in vivo and in vitro models of brain ischemia. Methods: Focal brain ischemia was produced in male adult Fischer rats by occluding both the common carotid and middle cerebral arteries. Brain glutamate levels were determined at fixed intervals after occlusion. Animals were then sacrificed, and infarct volume and brain ATP levels were measured. As in vitro model of ischemia, rat cultured cortical neurones or astrocytes, isolated or in co-culture, were exposed to oxygen-glucose deprivation (OGD) either in the absence or in the presence of citicoline (1-100 muM). Viability was studied by measuring LDH release. Glutamate release and uptake, and ATP levels were also determined. Results: Citicoline (0.5, 1 and 2 g/kg i.p. administered I h before the occlusion) produced a reduction of the infarct size measured at striatum (18, 27 and 42% inhibition, respectively, n = 8, P < 0.05 vs. ischemia), effect that correlated with the inhibition caused by citicoline on ischemia-induced increase in glutamate concentrations after the onset of the ischemia. Citicoline also inhibited ischemia-induced decrease in cortical and striatal ATP levels. incubation of cultured rat cortical neurotics with citicoline (10 and 100 muM) prevented OGD-induced LDH and glutamate release and caused a recovery in ATP levels after OGD, confirming our previous results. In addition, citicoline (100 muM) caused an increase in glutamate uptake and in EAAT2 glutamate transporter membrane expression in cultured rat astrocytes. Conclusions: Our present findings show novel mechanisms for the neuroprotective effects of citicoline, which cooperate to decrease brain glutamate release after ischemia. (C) 2004 Elsevier Inc. All rights reserved.