Inhibition of ischemia-induced glutamate release in rat striatum by dihydrokinate and an anion channel blocker.
Inhibition of ischemia-induced glutamate release in rat striatum by dihydrokinate and an anion channel blocker.
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DOI：
10.1161/01.str.30.2.433
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发表时间：
1999-02
期刊：
影响因子：
8.3
通讯作者：
Y. Seki;P. Feustel;R. Keller;B. Tranmer;H. Kimelberg
中科院分区：
文献类型：
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作者：
Y. Seki;P. Feustel;R. Keller;B. Tranmer;H. Kimelberg
背景和目的兴奋性氨基酸（EAA）受体的激活增加被认为是神经元损伤的主要原因。用微透析探针在大鼠纹状体两侧定位，研究缺血诱导EAA释放的可能来源和机制。方法氟烷麻醉大鼠，采用双侧颈总动脉阻断加控制性降压造成前脑缺血模型。在30分钟的缺血期间，在存在星形胶质细胞谷氨酸转运蛋白GLT-1的非转运阻断剂二氢激酶（DHK）或阴离子通道阻断剂4，4 '-二硝基芪-2，2'-二磺酸（DNDS）的情况下，通过透析探针单独或一起给药，测量谷氨酸和天冬氨酸的微透析液浓度。结果：在缺血期间，对照纹状体中谷氨酸和天冬氨酸浓度分别增加了44+/-13（平均值+/-SEM）倍和19+/-5倍基线，并在再灌注时恢复到基线值。DHK（1 mmol/L灌流液; n=8）显着减弱EAA增加相比，对照组（谷氨酸峰，9。6+/-1.7 vs.对照组，15.4+/-2.6 pmol/ microL）。10 mmol/L DHK同样降低EAA水平。DNDS（1 mmol/L; n=5）还抑制EAA峰值增加（谷氨酸峰值，5.8+/-1.1 vs对照，10.1+/-0.7 pmol/ microL）。在较高浓度下，DNDS（10 mmol/L; n=7）进一步减少谷氨酸和天冬氨酸的释放，并抑制缺血诱导的牛磺酸释放。1 mmol/L DHK和10 mmol/L DNDS（n=5）共同抑制83%的EAA释放（谷氨酸峰，2.7+/-0.7 vs对照，10.9+/-1.2 pmol/ microL）。结论：这些发现支持这一假设，即细胞肿胀诱导的EAAs释放和星形胶质细胞谷氨酸转运蛋白的逆转是缺血诱导的纹状体细胞外EAAs增加的贡献者，通过微透析测量。
BACKGROUND AND PURPOSE Increased activation of excitatory amino acid (EAA) receptors is considered a major cause of neuronal damage. Possible sources and mechanisms of ischemia-induced EAA release were investigated pharmacologically with microdialysis probes placed bilaterally in rat striatum. METHODS Forebrain ischemia was induced by bilateral carotid artery occlusion and controlled hypotension in halothane-anesthetized rats. During 30 minutes of ischemia, microdialysate concentrations of glutamate and aspartate were measured in the presence of a nontransportable blocker of the astrocytic glutamate transporter GLT-1, dihydrokinate (DHK), or an anion channel blocker, 4,4'-dinitrostilben-2,2'-disulfonic acid (DNDS), administered separately or together through the dialysis probe. RESULTS In control striata during ischemia, glutamate and aspartate concentrations increased 44+/-13 (mean+/-SEM) times and 19+/-5 times baseline, respectively, and returned to baseline values on reperfusion. DHK (1 mmol/L in perfusate; n=8) significantly attenuated EAA increases compared with control (glutamate peak, 9. 6+/-1.7 versus control, 15.4+/-2.6 pmol/ microL). EAA levels were similarly decreased by 10 mmol/L DHK. DNDS (1 mmol/L; n=5) also suppressed EAA peak increases (glutamate peak, 5.8+/-1.1 versus control, 10.1+/-0.7 pmol/ microL). At a higher concentration, DNDS (10 mmol/L; n=7) further reduced glutamate and aspartate release and also inhibited ischemia-induced taurine release. Together, 1 mmol/L DHK and 10 mmol/L DNDS (n=5) inhibited 83% of EAA release (glutamate peak, 2.7+/-0.7 versus control, 10.9+/-1.2 pmol/ microL). CONCLUSIONS These findings support the hypothesis that both cell swelling-induced release of EAAs and reversal of the astrocytic glutamate transporter are contributors to the ischemia-induced increases of extracellular EAAs in the striatum as measured by microdialysis.