Insensitivity to glutamate neurotoxicity mediated by NMDA receptors in association with delayed mitochondrial membrane potential disruption in cultured rat cortical neurons
Insensitivity to glutamate neurotoxicity mediated by NMDA receptors in association with delayed mitochondrial membrane potential disruption in cultured rat cortical neurons
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DOI：
10.1111/j.1471-4159.2008.05270.x
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发表时间：
2008-06-01
影响因子：
4.7
通讯作者：
Yoneda, Yukio
中科院分区：
文献类型：
--
作者：
Kambe, Yuki;Nakamichi, Noritaka;Yoneda, Yukio
我们试图阐明机制的差异脆弱性谷氨酸（Glu）使用培养的神经元制备的胚胎大鼠大脑的离散结构。短暂暴露于Glu导致在10 μ M至1 mM下培养9或12天的海马神经元中线粒体活性显著降低，具有类似阿尔茨海默病的特征，而不显著影响皮质神经元中的线粒体活性。短暂暴露于谷氨酸也增加乳酸脱氢酶释放沿着的神经元标记蛋白在海马，但不是皮质，神经元免疫反应的细胞数量显着减少。皮质神经元对NMDA的细胞毒性也表现出类似的不敏感性，但对衣霉素、2，4-二硝基苯酚、过氧化氢或A23187的细胞毒性则不敏感。然而，NMDA是更有效地增加细胞内游离Ca 2+水平在皮层神经元比在海马神经元。神经保护性代谢型Glu受体拮抗剂未能显着影响对Glu的不敏感性，而NMDA更有效地破坏海马线粒体膜电位比皮层神经元。这些结果表明，皮层神经元将是不敏感的NMDA受体介导的凋亡神经毒性通过线粒体膜电位相关的机制，而不是细胞内游离Ca 2+水平，在大鼠脑。
We have attempted to elucidate mechanisms underlying differential vulnerability to glutamate (Glu) using cultured neurons prepared from discrete structures of embryonic rat brains. Brief exposure to Glu led to a significant decrease in the mitochondrial activity in hippocampal neurons cultured for 9 or 12 days at 10 mu M to 1 mM with an apoptosis-like profile, without markedly affecting that in cortical neurons. Brief exposure to Glu also increased lactate dehydrogenase release along with a marked decrease in the number of cells immunoreactive for a neuronal marker protein in hippocampal, but not cortical, neurons. Similar insensitivity was seen to the cytotoxicity by NMDA, but not to that by tunicamycin, 2,4-dinitrophenol, hydrogen peroxide or A23187, in cortical neurons. However, NMDA was more efficient in increasing intracellular free Ca2+ levels in cortical neurons than in hippocampal neurons. Antagonists for neuroprotective metabotropic Glu receptors failed to significantly affect the insensitivity to Glu, while NMDA was more effective in disrupting mitochondrial membrane potentials in hippocampal than cortical neurons. These results suggest that cortical neurons would be insensitive to the apoptotic neurotoxicity mediated by NMDA receptors through a mechanism related to mitochondrial membrane potentials, rather than intracellular free Ca2+ levels, in the rat brain.