CENTRAL MAMMALIAN NEURONS NORMALLY RESISTANT TO GLUTAMATE TOXICITY ARE MADE SENSITIVE BY ELEVATED EXTRACELLULAR CA-2+ - TOXICITY IS BLOCKED BY THE N-METHYL-D-ASPARTATE ANTAGONIST MK-801
CENTRAL MAMMALIAN NEURONS NORMALLY RESISTANT TO GLUTAMATE TOXICITY ARE MADE SENSITIVE BY ELEVATED EXTRACELLULAR CA-2+ - TOXICITY IS BLOCKED BY THE N-METHYL-D-ASPARTATE ANTAGONIST MK-801
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DOI：
10.1073/pnas.85.17.6556
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发表时间：
1988-09-01
影响因子：
11.1
通讯作者：
LIPTON, SA
中科院分区：
文献类型：
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作者：
HAHN, JS;AIZENMAN, E;LIPTON, SA
人们普遍认为，一种类似于N-甲基-D-天冬氨酸的谷氨酸样毒素可能是严重神经损伤后神经细胞死亡的原因，包括中风、癫痫和退行性疾病，如亨廷顿病、阿尔茨海默氏病和关岛发现的肌萎缩侧索硬化症-帕金森病-痴呆症综合征。关于这些疾病的一个令人费解的事实是，每种疾病所特有的特定神经元组的脆弱性不同。我们在此报告，在正常培养条件下，已确定的中枢神经元群体（大鼠视网膜神经节细胞）对毫摩尔浓度的谷氨酸的神经毒性作用具有抵抗力。膜片钳实验表明，这种电阻与对 N-甲基-D-天冬氨酸的非常小的离子电流响应有关。然而，通过增加细胞外 Ca2+ 浓度来改变离子环境，会导致该群体中谷氨酸诱导的细胞死亡显着增加。在这些条件下，Mg2+或氨基酸拮抗剂MK-801[(+)-5-甲基-10，11-二氢-5H-二苯并-(α，γ)-环庚烯-5-10-亚胺马来酸盐]，N-甲基-D-天冬氨酸受体偶联离子通道的阻断剂，完全消除谷氨酸的致死作用。这些发现强烈表明，Ca2+ 通过 N-甲基-D-天冬氨酸激活通道进入是造成此类神经元死亡的原因，并提出了可能在临床上用于治疗各种神经系统疾病的策略。
It is widely held that a glutamate-like toxin that resembles N-methyl-D-aspartate may be responsible for the death of nerve cells seen after severe neurological insults including stroke, seizures, and degenerative disorders, such as Huntington disease, Alzheimer disease, and the amyotrophic lateral sclerosis-parkinsonism-dementia complex found on Guam. One puzzling fact about these maladies is the differential vulnerability of specific groups of neurons peculiar to each condition. We report here that an identified population of central neurons, rat retinal ganglion cells, are resistant to the neurotoxic effects of millimolar concentrations of glutamate under otherwise normal culture conditions. Patch-clamp experiments show that this resistance is associated with a very small ionic current response to N-methyl-D-aspartate. Varying the ionic milieu by increasing the extracellular Ca2+ concentration, however, results in a striking increase in glutamate-induced cell death in this population. Under these conditions, Mg2+ or the amino acid antagonist MK-801 [(+)-5-methyl-10, 11-dihydro-5H-dibenzo-(.alpha., .gamma.)-cyclohepten-5-10-imine maleate], blockers of N-methyl-D-aspartate receptor-coupled ion channels, completely abrogate the lethal effects of glutamate. These findings strongly suggest that Ca2+ entry through N-methyl-D-aspartate-activated channels is responsible for this type of neuronal death and suggest strategies that may be clinically useful in the treatment of various neurological disorders.