Targeted over-expression of glutamate transporter 1 (GLT-1) reduces ischemic brain injury in a rat model of stroke.
Targeted over-expression of glutamate transporter 1 (GLT-1) reduces ischemic brain injury in a rat model of stroke.
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DOI：
10.1371/journal.pone.0022135
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Harvey BK;Airavaara M;Hinzman J;Wires EM;Chiocco MJ;Howard DB;Shen H;Gerhardt G;Hoffer BJ;Wang Y
在缺血性脑损伤发作后，释放兴奋性神经递质谷氨酸。谷氨酸的兴奋性毒性作用是中风发病机制的主要贡献者。本研究的目的是检查是否谷氨酸转运蛋白（GLT-1）的过度表达减少缺血性脑损伤的大鼠模型中风。我们产生了腺相关病毒（AAV）载体表达大鼠GLT-1的cDNA（AAV-GLT 1）。AAV-GLT 1的功能性表达通过在非中风大鼠脑中增加的谷氨酸清除率来证实，如通过体内电流分析法所测量的。在大脑中动脉闭塞（MCAo）60 min前3周将AAV-GLT 1注射到梗死的未来皮质区域中。分别在MCAo后1天和2天使用TUNEL和TTC染色评估组织损伤。在中风后2、8和14天进行行为测试。与AAV-GFP相比，接受AAV-GLT 1的动物在60分钟的MCAo期间显示出细胞外谷氨酸的持续时间和幅度的显著降低，这是通过微透析测量的。在AAV-GLT 1注射区域观察到脑梗死和DNA片段化的显著减少。与AAV-GFP组相比，接受AAV-GLT 1的动物显示出中风后行为恢复的显著改善。我们证明了谷氨酸转运体GLT-1的局灶性过表达显著减少了缺血诱导的谷氨酸溢出，减少了细胞死亡并改善了行为恢复。这些数据进一步支持谷氨酸在脑缺血性损伤的发病机制中的作用，并证明靶向基因递送以减少缺血诱导的谷氨酸溢出减少了中风引起的细胞和行为缺陷。
Following the onset of an ischemic brain injury, the excitatory neurotransmitter glutamate is released. The excitotoxic effects of glutamate are a major contributor to the pathogenesis of a stroke. The aim of this study was to examine if overexpression of a glutamate transporter (GLT-1) reduces ischemic brain injury in a rat model of stroke. We generated an adeno-associated viral (AAV) vector expressing the rat GLT-1 cDNA (AAV-GLT1). Functional expression of AAV-GLT1 was confirmed by increased glutamate clearance rate in non-stroke rat brain as measured by in vivo amperometry. AAV-GLT1 was injected into future cortical region of infarction 3 weeks prior to 60 min middle cerebral artery occlusion (MCAo). Tissue damage was assessed at one and two days after MCAo using TUNEL and TTC staining, respectively. Behavioral testing was performed at 2, 8 and 14 days post-stroke. Animals receiving AAV-GLT1, compared to AAV-GFP, showed significant decreases in the duration and magnitude of extracellular glutamate, measured by microdialysis, during the 60 minute MCAo. A significant reduction in brain infarction and DNA fragmentation was observed in the region of AAV-GLT1 injection. Animals that received AAV-GLT1 showed significant improvement in behavioral recovery following stroke compared to the AAV-GFP group. We demonstrate that focal overexpression of the glutamate transporter, GLT-1, significantly reduces ischemia-induced glutamate overflow, decreases cell death and improves behavioral recovery. These data further support the role of glutamate in the pathogenesis of ischemic damage in brain and demonstrate that targeted gene delivery to decrease the ischemia-induced glutamate overflow reduces the cellular and behavioral deficits caused by stroke.
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影响因子：
8.3
作者：
BEDERSON, JB;PITTS, LH;BARTKOWSKI, H
通讯作者：
BARTKOWSKI, H
DOI：
10.1196/annals.1300.023
发表时间：
2003-01-01
期刊：
GLUTAMATE AND DISORDERS OF COGNITION AND MOTIVATION
影响因子：
--
作者：
Baker, DA;McFarland, K;Kalivas, PW
通讯作者：
Kalivas, PW
影响因子：
4.7
作者：
BENVENISTE, H;DREJER, J;DIEMER, NH
通讯作者：
DIEMER, NH
影响因子：
46.9
作者：
Garber, Ken
通讯作者：
Garber, Ken
影响因子：
3
作者：
Lowery, Rebecca L.;Zhang, Yu;Majewska, Ania K.
通讯作者：
Majewska, Ania K.