Metabotropic glutamate receptor 3 activation prevents nitric oxide-induced death in cultured rat astrocytes
Metabotropic glutamate receptor 3 activation prevents nitric oxide-induced death in cultured rat astrocytes
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DOI：
10.1111/j.1471-4159.2009.06469.x
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发表时间：
2010-01-01
影响因子：
4.7
通讯作者：
Lasaga, Mercedes
中科院分区：
文献类型：
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作者：
Durand, Daniela;Caruso, Carla;Lasaga, Mercedes
神经胶质功能改变可能导致神经退行性疾病中神经元死亡的开始或进展。因此，星形胶质细胞死亡的调制可能是必不可少的，以防止在中枢神经系统的病理过程。近年来，代谢型谷氨酸受体（mGluR）激活已成为神经保护的关键靶点。我们研究了亚型3 mGluR（mGluR 3）激活对一氧化氮（NO）诱导的星形胶质细胞死亡的影响。一种mGluR 3选择性激动剂LY 379268，减少诱导型NO合成酶的表达和NO释放诱导细菌脂多糖和干扰素-γ在培养的大鼠星形胶质细胞。反过来，一个NO供体（二乙烯三胺/NO）诱导的星形胶质细胞，这表明凋亡形态和DNA片段化，但没有半胱天冬酶3激活的凋亡样死亡。LY 379268阻止了由NO暴露诱导的星形胶质细胞死亡，这与磷脂酰丝氨酸外化、p53和Bax活化以及线粒体通透性的降低相关。mGluR 3拮抗剂-α-乙基谷氨酸可预防报告的LY 379268效应。总之，这些发现显示了mGluR 3活化对星形胶质细胞死亡的保护作用，并提供了这些受体在预防由与NO产生失调相关的几种炎症过程引发的CNS损伤中的作用的进一步证据。
Altered glial function may contribute to the initiation or progression of neuronal death in neurodegenerative diseases. Thus, modulation of astrocyte death may be essential for preventing pathological processes in the CNS. In recent years, metabotropic glutamate receptor (mGluR) activation has emerged as a key target for neuroprotection. We investigated the effect of subtype 3 mGluR (mGluR3) activation on nitric oxide (NO)-induced astroglial death. A mGluR3 selective agonist, LY379268, reduced inducible NO synthase expression and NO release induced by bacterial lipopolysaccharide and interferon-gamma in cultured rat astrocytes. In turn, a NO donor (diethylenetriamine/NO) induced apoptotic-like death in cultured astrocytes, which showed apoptotic morphology and DNA fragmentation, but no caspase 3 activation. LY379268 prevented astrocyte death induced by NO exposure, which correlates with a reduction in: phosphatidylserine externalization, p53 and Bax activation and mitochondrial permeability. The reported effects of LY379268 were prevented by the mGluR3 antagonist (s)-alpha-ethylglutamic acid. All together, these findings show the protective effect of mGluR3 activation on astroglial death and provide further evidence of a role of these receptors in preventing CNS injury triggered by several inflammatory processes associated with dysregulated NO production.