Activation of Group II/III metabotropic glutamate receptors attenuates LPS‐induced astroglial neurotoxicity via promoting glutamate uptake
Activation of Group II/III metabotropic glutamate receptors attenuates LPS‐induced astroglial neurotoxicity via promoting glutamate uptake
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DOI：
10.1002/jnr.20897
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发表时间：
2006-08
影响因子：
4.2
通讯作者：
Fang Zhou;Hong-hong Yao;Jiayong Wu;Yan-jing Yang;Jian-hua Ding;Ji Zhang;G. Hu
中科院分区：
文献类型：
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作者：
Fang Zhou;Hong-hong Yao;Jiayong Wu;Yan-jing Yang;Jian-hua Ding;Ji Zhang;G. Hu
神经胶质细胞功能改变导致氧化应激和兴奋性毒性，可能导致神经退行性疾病中神经元死亡的开始或进展。我们报告星形胶质细胞组II和III代谢型谷氨酸受体（mGluR）对神经毒性的关键作用。分别用选择性激动剂DCG-IV或L-AP 4激活星形胶质细胞上的II或III组mGluR抑制星形胶质细胞脂多糖（LPS）条件培养基诱导的原代培养中脑神经元凋亡。特异性II或III组mGluR拮抗剂APICA或MSOP完全消除了DCG-IV和L-AP 4的神经保护作用。形态学分析显示，DCG-IV或L-AP 4也可以减轻星形胶质细胞对多巴胺能神经元的神经毒性。细胞外谷氨酸浓度和[3 H]-谷氨酸摄取的测量表明，LPS处理的星形胶质细胞中谷氨酸摄取能力的恢复可能涉及激活星形胶质细胞II或III组mGluR的神经保护作用。此外，我们发现，星形胶质细胞摄取功能的抑制可以通过GSH恢复，并且II组和III组mGluR激动剂都可以恢复LPS处理的星形胶质细胞中的内源性还原型谷胱甘肽（GSH）水平。这些结果表明，通过II型或III型mGluR激活的神经保护的可能机制可能涉及内源性GSH的恢复，进而提供星形胶质细胞摄取谷氨酸的能力的恢复。© 2006 Wiley利斯公司
Altered glial function that leads to oxidative stress and excitotoxicity may contribute to the initiation or progression of neuronal death in neurodegenerative diseases. We report the pivotal role of astroglial Group II and III metabotropic glutamate receptors (mGluR) against neurotoxicity. Activation of Group II or III mGluR on astrocytes with selective agonists DCG‐IV or L‐AP4 respectively inhibited astroglial lipopolysaccharide (LPS)‐conditioned medium induced apoptosis of primary cultured mesencephalic neurons. Specific Group II or III mGluR antagonists APICA or MSOP completely abolished the neuroprotective effects of DCG‐IV and L‐AP4. Morphologic analysis showed that DCG‐IV or L‐AP4 could also attenuate the astroglial neurotoxicity to dopaminergic neurons. Measurement of extracellular glutamate concentration and [3H]‐glutamate uptake showed that the restoration of glutamate uptake capability in LPS‐treated astrocytes might be involved in the neuroprotective effects of activating astroglial Group II or III mGluR. Furthermore, we found that the repression of astroglial uptake function could be revived by GSH, and both Group II and III mGluR agonists could recover the endogenous reduced glutathione (GSH) level in LPS‐treated astrocytes. These results suggested that the possible mechanisms of neuroprotection by either Type II or Type III mGluR activation may involve restoration of endogenous GSH, in turn affording recovery of astroglial capability to take up glutamate. © 2006 Wiley‐Liss, Inc.