title: Resveratrol protects astrocytes against traumatic brain injury through inhibiting apoptotic and autophagic cell death.
abstract: Traumatic brain injury (TBI) is often caused by accidents that damage the brain. TBI can induce glutamate excitotoxicity and lead to neuronal and glial cell death. In this study, we investigated the mechanism of cell death during the secondary damage caused by TBI in vivo and in vitro, as well as the protective effect of resveratrol (RV). Here we report that glycogen synthase kinase-3β (GSK-3β) activation and microtubule-associated protein light chain 3 processing were induced in rat brains exposed to TBI. In the in vitro TBI model, apoptotic and autophagic cell death were induced through glutamate-mediated GSK-3β activation in normal CTX TNA2 astrocytes. The GSK-3β inhibitor SB216763 or transfection of GSK-3β small-interfering RNA increases cell survival. By contrast, overexpression of GSK-3β enhanced glutamate excitotoxicity. Administration of RV reduced cell death in CTX TNA2 astrocytes by suppressing reactive oxygen species (ROS)-mediated GSK-3β activation, the mechanism by which RV also exerted protective effects in vivo. Mitochondrial damages, including the opening of mitochondrial permeability transition pore (MPTP) and mitochondrial depolarization, were induced by glutamate through the ROS/GSK-3β pathway. Moreover, cyclosporine A, an MPTP inhibitor, suppressed mitochondrial damage and the percentages of cells undergoing autophagy and apoptosis and thereby increased cell survival. Taken together, our results demonstrated that cell death occurring after TBI is induced through the ROS/GSK-3β/mitochondria signaling pathway and that administration of RV can increase cell survival by suppressing GSK-3β-mediated autophagy and apoptosis. Therefore, the results indicated that resveratrol may serve as a potential therapeutic agent in the treatment of TBI.
authors.affiliation: 1] Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan [2] Department of Biochemistry, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: C-J
authors.initials: CJ
authors.lastname: Lin
authors.affiliation: Division of Cardiovascular Surgery, Department of Surgery, Cathay General Hospital, Taipei 106, Taiwan.
authors.forename: T-H
authors.initials: TH
authors.lastname: Chen
authors.affiliation: 1] Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan [2] Department of Physiology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: L-Y
authors.initials: LY
authors.lastname: Yang
authors.affiliation: 1] Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan [2] Department of Biochemistry, College of Medicine, Taipei Medical University, Taipei 110, Taiwan [3] Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei 110, Taiwan [4] Center for Reproductive Medicine and Sciences, Taipei Medical University Hospital, Taipei 110, Taiwan.
authors.forename: C-M
authors.initials: CM
authors.lastname: Shih
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology*; D001343:Autophagy / Q000187:drug effects*; D001930:Brain Injuries / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D018698:Glutamic Acid / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology* / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D013267:Stilbenes; D018698:Glutamic Acid; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D000077185:Resveratrol