title: The pro-survival pathways of mTOR and protein kinase B target glycogen synthase kinase-3beta and nuclear factor-kappaB to foster endogenous microglial cell protection.
abstract: Microglia of the central nervous system serve a variety of functions that may ultimately lead to the development or detriment of neighboring neuronal and vascular cells. These scavengers of the nervous system have been associated with a variety of neurodegenerative disorders, but the toxic potential of microglia is equally balanced by the protective nature of these cells to exclude foreign microorganisms and promote new tissue proliferation and reorganization. To this extent, our work outlines a series of endogenous microglial cellular pathways that can constitute protection for microglia against during oxygen-glucose deprivation (OGD). We demonstrate in both primary microglia and the microglial cell line EOC 2 that endogenous microglial protection against OGD relies upon the activation and expression of the phosphatidylinositol 3-kinase pathways of mammalian target of rapamycin (mTOR) and protein kinase B (Akt1), since pharmacological inhibition of mTOR or Akt1 as well as the gene silencing of Akt1 protein expression leads to significantly increased microglial apoptotic cell injury, DNA fragmentation, and membrane phosphatidylserine exposure. The mTOR pathway may offer endogenous protection through mechanisms that do not entirely rely upon inhibition of glycogen synthase kinase-3beta (GSK-3beta) activity while Akt1 appears to converge upon the necessary blockade of GSK-3beta. Closely aligned to these endogenous protective mechanisms is the subcellular presence and nuclear translocation of nuclear factor-kappaB p65 (NF-kappaB p65), since microglial cell injury is significantly increased during the gene silencing of NF-kappaB p65. Elucidating the underlying pathways that can afford endogenous protection and maintain functional integrity of microglia should offer new prospects for the treatment of a broad range of nervous system disorders.
authors.affiliation: Division of Cellular and Molecular Cerebral Ischemia, Wayne State University School of Medicine, 4201 St. Antoine, Detroit, MI 48201, USA.
authors.forename: Zhao Zhong
authors.initials: ZZ
authors.lastname: Chong
authors.forename: Faqi
authors.initials: F
authors.lastname: Li
authors.forename: Kenneth
authors.initials: K
authors.lastname: Maiese
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000737:chemistry; D002470:Cell Survival; D002478:Cells, Cultured; D019610:Cytoprotection; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004789:Enzyme Activation; D005947:Glucose / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009457:Neuroglia / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D010100:Oxygen / Q000494:pharmacology; D010718:Phosphatidylserines / Q000737:chemistry / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
chemical_list: D016328:NF-kappa B; D010718:Phosphatidylserines; D047428:Protein Kinase Inhibitors; D021122:Protein Subunits; D034741:RNA, Small Interfering; D011494:Protein Kinases; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3; D005947:Glucose; D010100:Oxygen