Neuroprotective interaction effects of NMDA and AMPA receptor antagonists in an in vitro model of cerebral ischemia
Neuroprotective interaction effects of NMDA and AMPA receptor antagonists in an in vitro model of cerebral ischemia
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NMDA 和 AMPA 受体拮抗剂在体外脑缺血模型中的神经保护相互作用
DOI：
10.1016/s0006-8993(98)01051-8
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发表时间：
1999
期刊：
影响因子：
2.9
通讯作者：
M. Bowlby
中科院分区：
文献类型：
--
作者：
Robert L. Arias;J. R. Tasse;M. Bowlby
采用急性大鼠海马脑片制备缺血离体模型。几种竞争性和非竞争性谷氨酸亚型选择性拮抗剂（CGS-19755，MK-801，YM 90 K和GYKI-52466）的神经保护浓度最初确定在缺氧增强激动剂诱导的兴奋性毒性实验。随后测试在这些研究中证明有效的浓度对缺血发作的有效性。缺血定义为暴露于无血糖培养基30分钟，同时缺氧5分钟，该方案是通过经验性确定各种低血糖和缺氧损伤对海马切片保持电生理活性能力的影响而得出的。暴露于这样的缺血发作导致大多数切片的活力丧失，这种效应强烈依赖于细胞外钙。AMPA拮抗剂单独应用在本发明的体外缺血模型中不产生神经保护作用，而NMDA拮抗剂单独应用具有适度的神经保护作用。与此相反，10 μM MK-801和300 μM GYKI-52466（分别为非竞争性NMDA和AMPA受体拮抗剂）的联合应用导致几乎完全的神经保护作用。这种保护是通过扣留细胞外钙，表明谷氨酸受体过度刺激的毒性作用，可以单独占钙流入。该组合治疗对海马切片存活率的作用是协同的，其大于单个化合物的作用的总和。结果表明，对急性缺血损伤的神经保护可能需要联合治疗方法。
An in vitro model of ischemia was developed and characterized using the acute rat hippocampal slice preparation. Neuroprotective concentrations of several competitive and noncompetitive glutamate subtype-selective antagonists (CGS-19755, MK-801, YM90K and GYKI-52466) were initially determined in anoxia-enhanced agonist-induced excitotoxicity experiments. Concentrations which proved to be effective in these studies were subsequently tested for their effectiveness against an ischemic episode. Ischemia was defined as a 30-min exposure to aglycemic media ending in 5 min of concurrent anoxia, a protocol which was arrived at by empirically determining the effect of various hypoglycemic and anoxic insults on the ability of hippocampal slices to retain their electrophysiological viability. Exposure to such an ischemic episode resulted in a loss of viability by most slices, an effect which was strongly dependent on extracellular calcium. AMPA antagonists applied alone produced no neuroprotective effect in the present model of in vitro ischemia, while NMDA antagonists applied alone had a modest neuroprotective effect. In contrast, the coapplication of 10 μM MK-801 and 300 μM GYKI-52466, noncompetitive NMDA and AMPA receptor antagonists, respectively, resulted in almost complete neuroprotection. This protection was comparable to that obtained by withholding extracellular calcium, indicating that the toxic effects of glutamate receptor overstimulation can be accounted for solely by calcium influx. The effect of this combination treatment on the survival rate of hippocampal slices was synergistic, that is greater than the sum of the effects of the individual compounds. The results indicate that neuroprotection against acute ischemic insults may require a combination therapy approach.
影响因子：
4.2
作者：
B. Siesjö;Ken-ichiro Katsura;Qi Zhao;J. Folbergrová;Kerstin Pahlmark;Peter Siesjö;Maj-lis Smith
通讯作者：
B. Siesjö;Ken-ichiro Katsura;Qi Zhao;J. Folbergrová;Kerstin Pahlmark;Peter Siesjö;Maj-lis Smith
拮抗谷氨酸神经毒性的方法。
DOI：
--
发表时间：
1990
期刊：
Cerebrovascular and brain metabolism reviews
影响因子：
--
作者：
Choi,DW
通讯作者：
Choi,DW