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. 2014 Jan;39(1):83-96.
doi: 10.1111/ejn.12383. Epub 2013 Oct 16.

Stimulating ERK/PI3K/NFκB signaling pathways upon activation of mGluR2/3 restores OGD-induced impairment in glutamate clearance in astrocytes

Chia-Ho Lin  1 , Jie-Ru You, Kai-Che Wei, Po-Wu Gean
Affiliations

Stimulating ERK/PI3K/NFκB signaling pathways upon activation of mGluR2/3 restores OGD-induced impairment in glutamate clearance in astrocytes

Chia-Ho Lin et al. Eur J Neurosci. 2014 Jan.

Abstract

We used the oxygen and glucose deprivation (OGD) method in cultured astrocytes as an in vitro ischemic model. We investigated whether activation of group-II metabotropic glutamate receptors (mGluR2/3) can reverse OGD-induced impairment in astrocytic glutamate/aspartate transporter (GLAST) expression and elucidated the signaling pathways involving the GLAST expression. Cultured astrocytes exposed to OGD for 6 h resulted in significant reductions in the GLAST expression and extracellular glutamate clearance. These reductions were effectively restored by mGluR2/3 activation with mGluR2/3 agonists, LY379268 or DCG-IV, after the 6 h OGD insult. These mGluR2/3-mediated restorative effects were inhibited by selective mGluR2/3 antagonists LY341459 or EGLU. The mGluR2/3 activation also induced activations of signaling pathways including extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K) and nuclear transcription factor-κB (NFκB). These activations were prevented by blocking mGluR2/3 with LY341459, an mGluR2/3 antagonist. Furthermore, blocking ERK, PI3K and NFκB signaling pathways with U0126, LY294002 and pyrrolidine dithiocarbamate, respectively, significantly inhibited the mGluR2/3-mediated restorative effects. These results suggest that application of mGluR2/3 agonists after OGD insult can effectively reverse the OGD-reduced expression of GLAST proteins and restore clearance of extracellular glutamate by serially activating ERK/PI3K/NFκB signaling pathways in cultured astrocytes.

Keywords: astrocyte GLAST; extracellular signal-regulated kinase; mGluR2/3 agonists; nuclear transcription factor-κΒ; oxygen and glucose deprivation; phosphatidylinositol 3-kinase.

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