Glutamate neurotoxicity in vitro: antagonist pharmacology and intracellular calcium concentrations
Glutamate neurotoxicity in vitro: antagonist pharmacology and intracellular calcium concentrations
复制标题
DOI：
10.1523/jneurosci.10-01-00283.1990
复制
发表时间：
1990-01
期刊：
影响因子：
--
通讯作者：
R. Michaels;S. Rothman
中科院分区：
文献类型：
--
作者：
R. Michaels;S. Rothman
现在有令人信服的证据表明，兴奋性氨基酸谷氨酸（GLU）在细胞外空间的过度积累对中枢哺乳动物神经元是有毒的。然而，不同GLU受体在产生这种毒性中的作用尚未充分确定。也没有足够的信息，细胞内游离钙浓度与最终兴奋毒性死亡的相关性。我们使用培养的大鼠海马神经元来解决这些问题。大约75%的神经元在20分钟的GLU暴露后死亡。有效的红藻氨酸/使君子酸受体拮抗剂6-氰基-7-硝基喹喔啉-2，3-二酮没有显著改善GLU毒性，而选择性非竞争性N-甲基-D-天冬氨酸（NMDA）拮抗剂甲基-10，11-二氢-5-H-二苯并环庚烯-5，10-亚胺（MK-801）阻断GLU毒性至少2小时。有趣的是，红藻氨酸对海马神经元非常有毒，但MK-801可明显减弱这种毒性。这些结果表明，GLU的主要毒性是由NMDA受体介导的，并且在某些条件下红藻氨酸毒性反映了NMDA通道的非特异性开放。在这些神经元中的细胞内钙浓度在年底暴露于GLU和红藻氨酸（在存在和不存在不同的拮抗剂）相关性较差，最终的生存。限制钙升高的拮抗剂在预防死亡方面仍然无效。这些结果证实了早期的观察，强调的重要性，NMDA受体介导的葡萄糖毒性。然而，它们表明毒性与神经元钙浓度之间的关系可能非常复杂。这些实验的一个意外发现是，MK- 801与GLU的竞争性拮抗剂不同，可升高细胞内钙。
There is now convincing evidence that excessive accumulation of the excitatory amino acid glutamate (GLU) in the extracellular space is toxic to central mammalian neurons. However, the role of different GLU receptors in producing this toxicity has not been adequately ascertained. There is also no adequate information about the correlation of free intracellular calcium concentration with eventual excitotoxic death. We have used cultured rat hippocampal neurons to address these issues. Approximately 75% of our neurons died after a 20- min GLU exposure. The potent kainate/quisqualate receptor antagonist 6- cyano-7-nitroquinoxaline-2,3-dione did not significantly ameliorate the GLU toxicity, while the selective noncompetitive N-methyl-D-aspartate (NMDA) antagonist methyl-10,11-dihydro-5-H-dibenzocyclohepten-5,10- imine (MK-801) blocked the GLU toxicity for periods of at least 2 hr. Interestingly, kainate was very toxic to the hippocampal neurons, but this toxicity was markedly attenuated by MK-801. These results suggest that the major toxicity of GLU is mediated by NMDA receptors and that under some conditions kainate toxicity reflects nonspecific opening of NMDA channels. The intracellular calcium concentrations in these neurons at the end of exposure to GLU and kainate (in the presence and absence of different antagonists) correlated poorly with eventual survival. Antagonists that limited the rise in calcium were still ineffective in preventing death. These results confirm earlier observations that stressed the importance of NMDA receptors in mediating GLU toxicity. However, they indicate that the relationship between toxicity and neuronal calcium concentration may be very complicated. An unexpected finding of these experiments was that MK- 801, unlike competitive antagonists of GLU, elevated intracellular calcium.