title: Activation of Type 4 Metabotropic Glutamate Receptor Attenuates Oxidative Stress-Induced Death of Neural Stem Cells with Inhibition of JNK and p38 MAPK Signaling.
abstract: Promoting both endogenous and exogenous neural stem cells' (NSCs) survival in the hostile host environments is essential to cell replacement therapy for central nervous system (CNS) disorders. Type 4 metabotropic glutamate receptor (mGluR4), one of the members of mGluRs, has been shown to protect neurons from acute and chronic excitotoxic insults in various brain damages. The present study investigated the preventive effects of mGluR4 on NSC injury induced by oxidative stress. Under challenge with H2O2, loss of cell viability was observed in cultured rat NSCs, and treatment with selective mGluR4 agonist VU0155041 conferred protective effects against the loss of cellular viability in a concentration-dependent manner, as shown by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Pretreatment of VU0155041 (30 μM) also inhibited the excessive NSC death induced by H2O2, and group III mGluRs antagonist (RS)-a-methylserine-O-phosphate (MSOP) or gene-targeted knockdown abolished the protective action of mGluR4, indicated by propidium iodide-Hoechst and terminal deoxynucleotidyl transferase-mediated UTP nick end labeling (TUNEL) staining. Western blot assay demonstrated that mGluR4 activation reversed the decreased procaspase-8/9/3and the destructed Bcl-2/Bax expressing balance, and likewise, MSOP and mGluR4 knockdown abrogated the action of mGluR4 activity. Furthermore, inhibition of JNK and p38 mitogen-activated protein kinases (MAPKs) were observed after mGluR4 activation, and as paralleling control, JNK-specific inhibitor SP600125 and p38-specific inhibitor SB203580 significantly rescued the H2O2-mediated NSC apoptosis and cleavage of procaspase-3. We suggest that activation of mGluR4 prevents oxidative stress-induced NSC death and apoptotic-associated protein activities with involvement of inhibiting the JNK and p38 pathways in cell culture. Our findings may help to develop strategies for enhancing the resided and transplanted NSC survival after oxidative stress insult of CNS.
authors.affiliation: 1 Institute of Neurobiology, Xi'an Jiaotong University Health Science Center , Xi'an, Shaanxi, China .
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: 1 Institute of Neurobiology, Xi'an Jiaotong University Health Science Center , Xi'an, Shaanxi, China .
authors.forename: Wen
authors.initials: W
authors.lastname: Ma
authors.affiliation: 2 Department of Obstetrics and Gynecology, The Affiliated Hospital of Xi'an Medical College , Xi'an, Shaanxi, China .
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: 1 Institute of Neurobiology, Xi'an Jiaotong University Health Science Center , Xi'an, Shaanxi, China .
authors.forename: Hanshi
authors.initials: H
authors.lastname: Gong
authors.affiliation: 3 Xi'an Mental Health Center , Xi'an, Shaanxi, China .
authors.forename: Yumei
authors.initials: Y
authors.lastname: Tian
authors.affiliation: 1 Institute of Neurobiology, Xi'an Jiaotong University Health Science Center , Xi'an, Shaanxi, China .
authors.forename: Jianshui
authors.initials: J
authors.lastname: Zhang
authors.affiliation: 1 Institute of Neurobiology, Xi'an Jiaotong University Health Science Center , Xi'an, Shaanxi, China .
authors.forename: Jianxin
authors.initials: J
authors.lastname: Liu
authors.affiliation: 1 Institute of Neurobiology, Xi'an Jiaotong University Health Science Center , Xi'an, Shaanxi, China .
authors.forename: Haixia
authors.initials: H
authors.lastname: Lu
authors.affiliation: 1 Institute of Neurobiology, Xi'an Jiaotong University Health Science Center , Xi'an, Shaanxi, China .
authors.forename: Xinlin
authors.initials: X
authors.lastname: Chen
authors.affiliation: 1 Institute of Neurobiology, Xi'an Jiaotong University Health Science Center , Xi'an, Shaanxi, China .
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D018094:Receptors, Metabotropic Glutamate; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C108823:metabotropic glutamate receptor 4