Department of Anesthesiology, University of Virginia Health System, 1 Hospital Drive, Charlottesville, VA 22908, USA.
J Cereb Blood Flow Metab. 2011 May;31(5):1283-92. doi: 10.1038/jcbfm.2010.222. Epub 2010 Dec 8.
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.
兴奋性氨基酸转运体（EAATs）在生理条件下将谷氨酸转运到细胞内。兴奋性氨基酸转运体 3（EAAT3）是主要的神经元 EAAT，也摄取半胱氨酸，这是合成谷胱甘肽的限速底物。因此，我们假设 EAAT3有助于提供脑缺血耐受。在 CD-1 小鼠基因背景下的雄性 8 周龄 EAAT3 敲除小鼠和野生型 CD-1 小鼠接受右侧大脑中动脉闭塞 90 分钟。评估它们的脑梗死体积、神经功能以及脑内谷胱甘肽、硝基酪氨酸和 4-羟基-2-壬烯醛（HNE）的水平。EAAT3 敲除小鼠的脑梗死体积大于野生型小鼠，神经功能缺损评分和运动协调功能更差，无论这些神经预后参数是在脑缺血后 24 小时还是 4 周评估。EAAT3 敲除小鼠的缺血半影区皮质和非缺血大脑皮质中的 HNE 水平高于野生型小鼠。EAAT3 敲除小鼠的缺血和非缺血皮质中的谷胱甘肽水平倾向于低于野生型小鼠。我们的结果表明，EAAT3 在局灶性脑缺血后限制缺血性脑损伤中很重要。这种作用可能涉及减轻脑氧化应激。
