Cox J A, Lysko P G, Henneberry R C
Molecular Neurobiology Section, NINDS, Bethesda, MD 20892.
Brain Res. 1989 Oct 16;499(2):267-72. doi: 10.1016/0006-8993(89)90774-9.
Results of the present report show that cerebellar neurons in primary culture are resistant to glutamate concentrations as high as 5 mM in the presence of glucose and Mg2+, but sensitive to glutamate concentrations lower than 35 microM when the neurons are deprived of glucose. Glutamate toxicity is also potentiated when Mg2+ is removed but glucose and EDTA are present; in this case, higher concentrations of glutamate (1 mM) are required for full toxicity. Glucose concentrations as low as 50 microM are fully protective against the toxicity of 100 microM glutamate; pyruvate and, to a lesser extent, lactate are also protective. Significantly, increasing concentrations of extracellular Mg2+ are fully protective against the toxicity of 100 microM glutamate in the absence of glucose and against the toxicity of 1 mM glutamate in the presence of glucose and EDTA. We interpret these results as support for our hypothesis that the pivotal event in glutamate's transition to neurotoxin is relief of the Mg2+ block of the N-methyl-D-aspartate (NMDA) receptor channel, which is known to be voltage-dependent. Partial depolarization in response to depletion of high-energy phosphates relieves the voltage-dependent block enabling glutamate to stimulate an excessive ion influx which results in the death of the neuron by a mechanism which is not yet understood. We propose that this mechanism may be operative in the neuronal damage associated with a variety of neurodegenerative disorders.
本报告结果表明，在原代培养中，小脑神经元在有葡萄糖和Mg2+存在的情况下，对高达5 mM的谷氨酸浓度具有抗性，但当神经元缺乏葡萄糖时，对低于35 microM的谷氨酸浓度敏感。当去除Mg2+但存在葡萄糖和乙二胺四乙酸（EDTA）时，谷氨酸毒性也会增强；在这种情况下，需要更高浓度的谷氨酸（1 mM）才能产生完全毒性。低至50 microM的葡萄糖浓度对100 microM谷氨酸的毒性具有完全保护作用；丙酮酸以及程度稍低的乳酸也具有保护作用。值得注意的是，在没有葡萄糖的情况下，细胞外Mg2+浓度的增加对100 microM谷氨酸的毒性具有完全保护作用，在有葡萄糖和EDTA存在的情况下，对1 mM谷氨酸的毒性也具有完全保护作用。我们将这些结果解释为支持我们的假设，即谷氨酸向神经毒素转变的关键事件是N-甲基-D-天冬氨酸（NMDA）受体通道的Mg2+阻断解除，已知该阻断是电压依赖性的。对高能磷酸盐耗竭的部分去极化解除了电压依赖性阻断，使谷氨酸能够刺激过量的离子内流，从而通过一种尚未明了的机制导致神经元死亡。我们提出，这种机制可能在与多种神经退行性疾病相关的神经元损伤中起作用。
