The Na+/H+ Exchanger-1 Inhibitor Cariporide Prevents Glutamate-Induced Necrotic Neuronal Death by Inhibiting Mitochondrial Ca2+ Overload
The Na+/H+ Exchanger-1 Inhibitor Cariporide Prevents Glutamate-Induced Necrotic Neuronal Death by Inhibiting Mitochondrial Ca2+ Overload
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DOI：
10.1002/jnr.22818
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发表时间：
2012-04-01
影响因子：
4.2
通讯作者：
Jung, Yi-Sook
中科院分区：
文献类型：
--
作者：
Lee, Bo Kyung;Jung, Yi-Sook
在脑中，Na+/H+交换器-1（NHE-1）活化对缺血性损伤具有显著影响，并且在最近的研究中，已发现NHE-1抑制可保护神经元免受缺血性损伤。这种保护作用归因于防止细胞凋亡，但缺血后的神经元细胞死亡是坏死和凋亡细胞死亡的结果。在这里，我们评估了有效的NHE-1抑制剂cariporide在兴奋性毒性神经元死亡的体外模型中预防坏死细胞死亡的能力。发现Cariporide（100 nM）可减少谷氨酸诱导的坏死和凋亡神经元细胞死亡。谷氨酸暴露后，在培养的神经元细胞的胞质溶胶和线粒体中观察到两次Ca 2+浓度达到峰值，并且发现cariporide降低第二次Ca 2+浓度增加，但不是第一次。此外，谷氨酸介导的线粒体死亡途径，包括线粒体膜电位的损失和活性氧（ROS）的积累被发现由cariporide衰减。此外，cariporide有效地防止了暴露于谷氨酸后的坏死，并改善了与坏死细胞死亡有关的线粒体Ca 2+和ROS产生增加。这些结果表明，NHE-1参与坏死细胞死亡过程，其抑制提供了一种防止坏死和凋亡的手段。(C)2011 Wiley Periodicals，Inc.
In the brain, Na+/H+ exchanger-1 (NHE-1) activation has a significant impact on ischemic injury, and, in recent studies, NHE-1 inhibition has been found to protect neurons from ischemic injury. This protective effect has been ascribed to the prevention of apoptosis, but neuronal cell death following ischemia is a consequence of both necrotic and apoptotic cell death. Here, we evaluated the ability of the potent NHE-1 inhibitor cariporide to prevent necrotic cell death in an in vitro model of excitotoxic neuronal death. Cariporide (100 nM) was found to reduce both glutamate-induced necrotic and apoptotic neuronal cell death. Ca2+ concentrations were observed to peak twice in cytosol and mitochondria in cultured neuronal cells after glutamate exposure, and cariporide was found to reduce the second Ca2+ concentration increase, but not the first. Furthermore, glutamate-mediated mitochondrial death pathways involving loss of mitochondrial membrane potential and reactive oxygen species (ROS) accumulation were found to be attenuated by cariporide. In addition, cariporide effectively prevented necrosis following exposure to glutamate and ameliorated the mitochondrial Ca2+ and ROS production increases implicated in necrotic cell death. These results suggest that NHE-1 participates in the necrotic cell death process and that its inhibition offers a means of preventing both necrosis and apoptosis. (C) 2011 Wiley Periodicals, Inc.