Metabotropic glutamate receptor 3 protects neurons from glucose-induced oxidative injury by increasing intracellular glutathione concentration
Metabotropic glutamate receptor 3 protects neurons from glucose-induced oxidative injury by increasing intracellular glutathione concentration
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DOI：
10.1111/j.1471-4159.2006.04373.x
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发表时间：
2007-04-01
影响因子：
4.7
通讯作者：
Russell, James W.
中科院分区：
文献类型：
--
作者：
Berent-Spillson, Alison;Russell, James W.
高葡萄糖浓度引起神经元中的氧化损伤和程序性细胞死亡，并可导致糖尿病性神经病变。激活3型代谢型谷氨酸受体（mGluR 3）可防止与雪旺细胞共培养的背根神经节神经元中葡萄糖诱导的氧化损伤。为了确定保护机制，在大鼠背根神经节神经元-雪旺细胞共培养物中进行研究。mGluR 3激动剂2 R，4 R-4-氨基吡咯烷-2，4-二羧酸酯阻止葡萄糖诱导的线粒体内膜去极化，活性氧积累和程序性细胞死亡，并增加谷胱甘肽（GSH）浓度在共培养的神经元和雪旺细胞，但不是在没有雪旺细胞培养的神经元。GSH合成抑制剂L-丁硫氨酸-亚砜亚胺处理的神经元的保护作用减弱，表明mGluR介导的保护作用需要GSH合成。GSH前体和GSH前体GSH-乙酯也保护神经元免受葡萄糖诱导的损伤，表明许旺细胞中的GSH合成以及反应前体向神经元的转运可能是mGluR介导的神经保护的基础。这些结果支持以下结论：激活胶质mGluR 3通过增加GSH抗氧化防御，增加自由基清除和稳定线粒体功能，保护神经元免受葡萄糖诱导的氧化损伤。
High glucose concentrations cause oxidative injury and programmed cell death in neurons, and can lead to diabetic neuropathy. Activating the type 3 metabotropic glutamate receptor (mGluR3) prevents glucose-induced oxidative injury in dorsal root ganglion neurons co-cultured with Schwann cells. To determine the mechanisms of protection, studies were performed in rat dorsal root ganglion neuron-Schwann cell co-cultures. The mGluR3 agonist 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate prevented glucose-induced inner mitochondrial membrane depolarization, reactive oxygen species accumulation, and programmed cell death, and increased glutathione (GSH) concentration in co-cultured neurons and Schwann cells, but not in neurons cultured without Schwann cells. Protection was diminished in neurons treated with the GSH synthesis inhibitor L-buthionine-sulfoximine, suggesting that mGluR-mediated protection requires GSH synthesis. GSH precursors and the GSH precursor GSH-ethyl ester also protected neurons from glucose-induced injury, indicating that GSH synthesis in Schwann cells, and transport of reaction precursors to neurons, may underlie mGluR-mediated neuroprotection. These results support the conclusions that activating glial mGluR3 protects neurons from glucose-induced oxidative injury by increasing free radical scavenging and stabilizing mitochondrial function, through increased GSH antioxidant defense.