Increase in external glutamate and NMDA receptor activation contribute to H2O2-induced neuronal apoptosis
Increase in external glutamate and NMDA receptor activation contribute to H2O2-induced neuronal apoptosis
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DOI：
10.1046/j.1471-4159.1999.0731181.x
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发表时间：
1999-09-01
影响因子：
4.7
通讯作者：
Prémont, J
中科院分区：
文献类型：
--
作者：
Mailly, F;Marin, P;Prémont, J
本研究的目的是探讨细胞外谷氨酸和NMDA受体的刺激在短暂暴露于H2 O2诱导的培养的小鼠大脑皮层神经元的神经元死亡的作用。大多数的神经元损失后，短暂暴露于H2 O2的皮层神经元的结果从凋亡过程中涉及的二次刺激的NMDA受体，这发生在H2 O2冲洗。事实上，（a）NMDA受体拮抗剂强烈降低了H2 O2的神经毒性作用，（B）在不存在Mg 2+的情况下，H2 O2的神经毒性作用增强，（c）当在H2 O2暴露后随着延迟时间的增加而应用MK-801时，MK-801的保护作用逐渐减弱，（d）最后，H2 O2暴露后，细胞外谷氨酸浓度增加。H_2O_2引起的神经毒性主要是通过羟自由基的产生来介导的，这可能与（a）细胞外谷氨酸NMDA受体激活的延迟积累和（B）聚（ADP-核糖）聚合酶激活及相关的NAD含量降低有关。这两种机制的结合可能导致ATP消耗的增加和ATP合成的减少。由此导致的ATP含量的大幅下降可能最终导致神经元死亡。
The present study aims to investigate the role of extracellular glutamate and NMDA receptor stimulation in the neuronal death induced by a transient exposure to H2O2 of cultured neurons originating from mouse cerebral cortex. Most of the neuronal loss following a transient exposure to H2O2 of cortical neurons results from an apoptotic process involving a secondary stimulation of NMDA receptors, which occurs after H2O2 washout. Indeed, (a) the neurotoxic effect of H2O2 was strongly reduced by antagonists of NMDA receptors, (b) the neurotoxic effect of H2O2 was enhanced in the absence of Mg2+, (c) the protective effect of MK-801 progressively decayed when it was applied with increasing delay time after H2O2 exposure, and (d), finally, the extracellular concentration of glutamate was increased after H2O2 exposure. The major part of H2O2-induced neurotoxicity is mediated by the formation of hydroxyl radicals, which might be involved in (a) the delayed accumulation of extracellular glutamate acid NMDA receptor activation and (b) the poly(ADP-ribose) polymerase activation and the related NAD content decrease. The combination of these two mechanisms could lead to both an increase in ATP consumption and a decrease of ATP synthesis. The resulting large decrease in ATP content might be finally responsible for the neuronal death.