Glutamate transporter type 3 knockout reduces brain tolerance to focal brain ischemia in mice
Glutamate transporter type 3 knockout reduces brain tolerance to focal brain ischemia in mice
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DOI：
10.1038/jcbfm.2010.222
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发表时间：
2011-05-01
影响因子：
6.3
通讯作者：
Zuo, Zhiyi
中科院分区：
文献类型：
--
作者：
Li, Liaoliao;Zuo, Zhiyi
兴奋性氨基酸转运蛋白（EAAT）在生理条件下将谷氨酸转运到细胞中。兴奋性氨基酸转运蛋白3（EAAT 3）是主要的神经元EAAT，也摄取半胱氨酸，半胱氨酸是谷胱甘肽合成的限速底物。因此，我们假设EAAT 3有助于提供脑缺血耐受。对CD-1小鼠基因背景的8周龄EAAT 3敲除雄性小鼠和野生型CD-1小鼠进行右侧大脑中动脉闭塞90分钟。评估其脑梗死体积、神经功能和脑内谷胱甘肽、硝基酪氨酸和4-羟基-2-壬烯醛（HNE）水平。与野生型小鼠相比，EAAT 3基因敲除小鼠的脑梗死体积更大，神经功能缺损评分和运动协调功能更差，无论这些神经功能结局参数是在脑缺血后24小时还是4周进行评估。EAAT 3基因敲除小鼠在缺血半暗带皮质和非缺血大脑皮质中的HNE水平高于野生型小鼠。EAAT 3基因敲除小鼠的缺血和非缺血皮质中的谷氨酸水平往往低于野生型小鼠。我们的研究结果表明，EAAT 3是重要的限制局灶性脑缺血后缺血性脑损伤。这种作用可能涉及减弱脑氧化应激。Journal of Cerebral Blood Flow & Metabolism（2011）31，1283-1292; doi：10.1038/jcbfm.2010.222; 2010年12月8日在线发表
Excitatory amino-acid transporters (EAATs) transport glutamate into cells under physiologic conditions. Excitatory amino-acid transporter type 3 (EAAT3) is the major neuronal EAAT and also uptakes cysteine, the rate-limiting substrate for synthesis of glutathione. Thus, we hypothesize that EAAT3 contributes to providing brain ischemic tolerance. Male 8-week-old EAAT3 knockout mice on CD-1 mouse gene background and wild-type CD-1 mice were subjected to right middle cerebral artery occlusion for 90 minutes. Their brain infarct volumes, neurologic functions, and brain levels of glutathione, nitrotyrosine, and 4-hydroxy-2-nonenal (HNE) were evaluated. The EAAT3 knockout mice had bigger brain infarct volumes and worse neurologic deficit scores and motor coordination functions than did wild-type mice, no matter whether these neurologic outcome parameters were evaluated at 24 hours or at 4 weeks after brain ischemia. The EAAT3 knockout mice contained higher levels of HNE in the ischemic penumbral cortex and in the nonischemic cerebral cortex than did wild-type mice. Glutathione levels in the ischemic and nonischemic cortices of EAAT3 knockout mice tended to be lower than those of wild-type mice. Our results suggest that EAAT3 is important in limiting ischemic brain injury after focal brain ischemia. This effect may involve attenuating brain oxidative stress. Journal of Cerebral Blood Flow & Metabolism(2011) 31, 1283-1292; doi:10.1038/jcbfm.2010.222; published online 8 December 2010