Activation of group I metabotropic glutamate receptors reduces neuronal apoptosis but increases necrotic cell death in vitro
Activation of group I metabotropic glutamate receptors reduces neuronal apoptosis but increases necrotic cell death in vitro
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DOI：
10.1038/sj.cdd.4400678
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发表时间：
2000-05-01
影响因子：
12.4
通讯作者：
Faden, A
中科院分区：
文献类型：
--
作者：
Allen, JW;Knoblach, SM;Faden, A
急性中枢神经系统损伤期间释放的谷氨酸作用于代谢型谷氨酸受体 (mGluR)，包括 I 组 mGluR。在体外神经元创伤期间阻断 I 组 mGluR 可提供神经保护，而激活会加剧这种损伤。然而，I 组 mGluR 激动剂或拮抗剂的作用主要是在以坏死细胞死亡为特征的体外模型中研究的。我们研究了 I 组 mGluR 在调节氧糖剥夺（OGD）（一种经过充分研究的坏死模型）期间诱导的神经元损伤中的作用，并通过应用两种成熟的促凋亡剂：星形孢菌素和依托泊苷。抑制 I 组 mGluR 可减轻 OGD 诱导的坏死，而选择性激活 1 组 mGluR 会加剧这种损伤。相反，I组mGluR的激活，包括mGluR5的选择性激活，显着减弱由星形孢菌素和依托泊苷诱导的细胞凋亡。该效应通过共同应用I组mGluR拮抗剂而完全逆转。因此，I 组 mGluR 似乎对坏死和凋亡神经元细胞死亡表现出相反的作用。我们的研究结果表明，mGluR1 的激活会加剧神经元坏死，而 mGluR1 和 mGluR5 都在减弱神经元凋亡中发挥作用。
Glutamate released during acute CNS insults acts at metabotropic glutamate receptors (mGluR), including group I mGluR, Blockade of group I mGluR during in vitro neuronal trauma provides neuroprotection, whereas activation exacerbates such injury. However, the effects of group I mGluR agonists or antagonists have been primarily studied in in vitro models characterized by necrotic cell death. We examined the role of group I mGluR in the modulation of neuronal injury induced during oxygen-glucose deprivation (OGD), a well-studied model of necrosis, and by application of two well established pro-apoptotic agents: staurosporine and etoposide. Inhibition of group I mGluR attenuated necrosis induced by OGD, whereas selective activation of group 1 mGluR exacerbated such injury. In contrast, activation of group I mGluR, including selective activation of mGluR5, significantly attenuated apoptotic cell death induced by both staurosporine and etoposide, This effect was completely reversed by coapplication of a group I mGluR antagonist. Thus, group I mGluR appear to exhibit opposite effects on necrotic and apoptotic neuronal cell death. Our findings suggest that activation of mGluR1 exacerbates neuronal necrosis whereas both mGluR1 and mGluR5 play a role in attenuation of neuronal apoptosis.