MEF2D Mediates the Neuroprotective Effect of Methylene Blue Against Glutamate-Induced Oxidative Damage in HT22 Hippocampal Cells
MEF2D Mediates the Neuroprotective Effect of Methylene Blue Against Glutamate-Induced Oxidative Damage in HT22 Hippocampal Cells
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MEF2D 介导亚甲蓝对 HT22 海马细胞中谷氨酸诱导的氧化损伤的神经保护作用
DOI：
10.1007/s12035-016-9818-1
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发表时间：
2017-04-01
影响因子：
5.1
通讯作者：
Pi, Rong-biao
中科院分区：
文献类型：
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作者：
Chen, Zi-wei;Liu, Anmin;Pi, Rong-biao
亚甲基蓝（MB）可以改善急性和慢性神经退行性疾病动物模型的行为，神经化学和神经病理学损伤，但其潜在机制尚不清楚。已知肌细胞增强因子2（MEF 2D）在几种模型中促进神经元存活，并且几种存活和死亡信号会聚于MEF 2D并调节其活性。在这里，我们研究了MEF 2D在MB对HT 22神经元细胞中谷氨酸诱导的毒性的神经保护作用中的作用。我们的结果表明，MB，事件在小于100 nM，提高了HT 22细胞暴露于2 mM谷氨酸的生存力。MB减轻线粒体损伤，并淬灭活性氧（ROS）由谷氨酸诱导。令人惊讶的是，50-200 nM的MB不影响Nrf 2/HO-1途径，这是一种重要的内源性抗氧化系统。进一步的研究表明，MB增加了MEF 2D的转录和翻译。此外，MB以MEF 2D依赖的方式上调线粒体NADH脱氢酶6（ND 6）的表达。MEF 2D的敲除消除了MB介导的ND 6增加和MB诱导的对谷氨酸诱导的毒性的神经保护。此外，我们发现MB促进小鼠海马和HT 22细胞中Akt功能活性，抑制GSK-3 β活性，并增加MEF 2D水平。这些发现首次证明MB保护HT 22神经元细胞免受谷氨酸诱导的细胞死亡，部分通过调节MEF 2D相关的存活途径。
Methylene blue (MB) can ameliorate behavioral, neurochemical, and neuropathological impairments in animal models of acute and chronic neurodegenerative disorders, but the underlying mechanism remains unclear. Myocyte enhancer factor 2 (MEF2D) is known to promote neuronal survival in several models, and several survival and death signals converge on MEF2D and regulate its activity. Here, we investigated the role of MEF2D in the neuroprotective effect of MB against glutamate-induced toxicity in HT22 neuronal cells. Our results showed that MB, event at less than 100 nM, improved the viability of HT22 cells exposed to 2 mM glutamate. MB attenuated the mitochondrial impairment and quenches the reactive oxygen species (ROS) induced by glutamate. Surprisingly, MB at 50-200 nM did not affect the Nrf2/HO-1 pathway, an important endogenous anti-oxidative system. Further study showed that MB increased the transcription and translation of MEF2D. In addition, MB upregulated the expression of mitochondrial NADH dehydrogenase 6 (ND6) in a MEF2D-dependent manner. Knockdown of MEF2D abolished both MB-medicated increase of ND6 and MB-induced neuroprotection against glutamate-induced toxicity. Moreover, we showed that MB promoted Akt function activity, suppressed GSK-3 beta activity, and increased MEF2D level in hippocampus of mice and HT22 cells. These findings for the first time demonstrate that MB protects HT22 neuronal cells against glutamate-induced cell death partially via the regulation of MEF2D-associated survival pathway.