GYKI 52466 PROTECTS AGAINST NON-NMDA RECEPTOR-MEDIATED EXCITOTOXICITY IN PRIMARY RAT HIPPOCAMPAL CULTURES
GYKI 52466 PROTECTS AGAINST NON-NMDA RECEPTOR-MEDIATED EXCITOTOXICITY IN PRIMARY RAT HIPPOCAMPAL CULTURES
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DOI：
10.1016/0304-3940(93)90510-r
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发表时间：
1993-04-02
影响因子：
2.5
通讯作者：
ROBISON, PM
中科院分区：
文献类型：
--
作者：
MAY, PC;ROBISON, PM
谷氨酸兴奋毒性由n-甲基- d -天冬氨酸（NMDA）受体和非NMDA受体(α -氨基-3-羟基-5-甲基-异恶唑丙酸酯（AMPA)/kainate (KA)）两种机制介导，但缺乏特异性拮抗剂限制了AMPA/KA受体介导的兴奋毒性的表征。2,3-苯二氮卓类药物GYKI 52466是一种新发现的非竞争性AMPA/KA受体拮抗剂。我们研究了GYKI 52466在非nmda受体介导的兴奋性毒性的胚胎大鼠海马培养模型中的神经保护作用，KA作为AMPA/KA受体的激动剂。通过乳酸脱氢酶外排评估，用500 muM KA过夜可导致显著的神经元兴奋性毒性。GYKI 52466以剂量依赖的方式减弱KA的兴奋毒性，IC50为9ma。与竞争性拮抗剂（如各种喹草胺二酮）一起，GYKI 52466等非竞争性拮抗剂现在可用于剖析非nmda受体介导的兴奋毒性机制。
Glutamate excitotoxicity is mediated by both N-methyl-D-aspartate (NMDA)-receptor and non-NMDA receptor (alpha-amino-3-hydroxy-5-methyl-isoxazolepropionate (AMPA)/kainate (KA)) mechanisms but the lack of specific antagonists has limited the characterization of AMPA/KA receptor-mediated excitotoxicity. The 2,3-benzodiazepine GYKI 52466 is a newly described non-competitive AMPA/KA receptor antagonist. We have investigated the neuroprotective efficacy of GYKI 52466 in an embryonic rat hippocampal culture model of non-NMDA receptor-mediated excitotoxicity using KA as an agonist at the AMPA/KA receptor. Overnight treatment with 500 muM KA resulted in prominent neuronal excitotoxicity as assessed by lactate dehydrogenase efflux. GYKI 52466 attenuated KA excitotoxicity in a dose-dependent manner with an IC50 of 9 muM. Together with competitive antagonists (e.g., various quinoxalinediones), non-competitive antagonists like GYKI 52466 can now be used to dissect mechanisms of non-NMDA receptor mediated excitotoxicity.