title: Stimulating ERK/PI3K/NFκB signaling pathways upon activation of mGluR2/3 restores OGD-induced impairment in glutamate clearance in astrocytes.
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.
authors.affiliation: Department of Pharmacology, College of Medicine, Tzu Chi University, Hualien, 970, Taiwan.
authors.forename: Chia-Ho
authors.initials: CH
authors.lastname: Lin
authors.forename: Jie-Ru
authors.initials: JR
authors.lastname: You
authors.forename: Kai-Che
authors.initials: KC
authors.lastname: Wei
authors.forename: Po-Wu
authors.initials: PW
authors.lastname: Gean
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D015687:Cell Hypoxia; D002478:Cells, Cultured; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism; D005947:Glucose / Q000172:deficiency*; D018698:Glutamic Acid / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D027341:Excitatory Amino Acid Transporter 1; D016328:NF-kappa B; D018094:Receptors, Metabotropic Glutamate; C493392:Slc1a3 protein, rat; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D018698:Glutamic Acid; D019869:Phosphatidylinositol 3-Kinases; D005947:Glucose
keywords: astrocyte GLAST; extracellular signal-regulated kinase; mGluR2/3 agonists; nuclear transcription factor-κΒ; oxygen and glucose deprivation; phosphatidylinositol 3-kinase