Glycogen synthase kinase-3 inhibition reduces ischemic cerebral damage, restores impaired mitochondrial biogenesis and prevents ROS production

• Published in: Journal of neurochemistry Vol. 116; no. 6; pp. 1148 - 1159
• Main Authors: Valerio, Alessandra, Bertolotti, Paola, Delbarba, Andrea, Perego, Carlo, Dossena, Marta, Ragni, Maurizio, Spano, PierFranco, Carruba, Michele O, De Simoni, Maria Grazia, Nisoli, Enzo
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.03.2011; Wiley-Blackwell
• Subjects: Animals; Antioxidants; Biological and medical sciences; Blood and lymphatic vessels; Brain; Cardiology. Vascular system; Cells, Cultured; Cerebral blood flow; Cerebral Cortex - cytology; cerebral ischemia; Cortex; Disease Models, Animal; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; DNA, Mitochondrial - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Dose-Response Relationship, Drug; Embryo, Mammalian; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Glucose; Glucose - deficiency; Glycogen synthase kinase 3; Glycogen Synthase Kinase 3 - metabolism; High Mobility Group Proteins - genetics; High Mobility Group Proteins - metabolism; Hypoxia; Indoles - pharmacology; Indoles - therapeutic use; Infarction, Middle Cerebral Artery - drug therapy; Infarction, Middle Cerebral Artery - enzymology; Infarction, Middle Cerebral Artery - pathology; Injuries; Ischemia; L-Lactate Dehydrogenase - metabolism; Maleimides - pharmacology; Maleimides - therapeutic use; Medical sciences; Mice; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; mitochondrial biogenesis; Mitochondrial DNA; Mutation - genetics; Neurochemistry; Neurology; Neurons; Neurons - drug effects; Neurons - metabolism; Neurons - ultrastructure; Nuclear Respiratory Factor 1 - genetics; Nuclear Respiratory Factor 1 - metabolism; Organelle Biogenesis; Oxidative stress; Oxygen; PGC‐1α; Reactive oxygen species; Reactive Oxygen Species - metabolism; Receptor mechanisms; Respiration; RNA, Messenger - metabolism; Stroke; Transfection - methods; Vascular diseases and vascular malformations of the nervous system; Infarct; Glycogen synthase kinase-3; Cardiovascular disease; Activation; Glucose; Cerebral artery; mitochondrial biogenesis; Arterial disease; Vascular disease; Mitochondria; cerebral ischemia; reactive oxygen species; Cerebrovascular disease; Biological receptor; Nervous system diseases; Oxygen; Deprivation; Program; Rodentia; PGC-1α; Antioxidant; In vitro; Cerebral disorder; Vertebrata; Mammalia; Neuron; Mouse; Central nervous system disease; Brain ischemia; Artery occlusion
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2011.07171.x

J. Neurochem. (2011) 116, 1148-1159. ABSTRACT: This study was designed to test the hypothesis that improved mitochondrial biogenesis could help reducing ischemic cerebral injury. We found that levels of proliferator-activated receptor γ coactivator 1α and nuclear respiratory factor-1, mitochondrial DNA content and other markers of mitochondrial biogenesis and function were reduced in primary mouse cortical neurons under oxygen-glucose deprivation (OGD). The glycogen synthase kinase-3 (GSK-3) inhibitor SB216763 activated an efficient mitochondrial biogenesis program in control cortical neurons and counteracted the OGD-mediated mitochondrial biogenesis impairment. This was accompanied by the activation of an antioxidant response that reduced mitochondrial reactive oxygen species generation and ischemic neuronal damage. The in vitro effects of SB216763 were mimicked by two other structurally unrelated GSK-3 inhibitors. The protective effects of SB216763 on OGD-mediated neuronal damage were abolished in the presence of diverse mitochondrial inhibitors. Finally, when systemically administered in vivo, SB216763 reduced the infarct size and recovered the loss of mitochondrial DNA in mice subjected to permanent middle cerebral artery occlusion. We conclude that GSK-3 inhibition by SB216763 might pave the way of novel promising therapies aimed at stimulating the renewal of functional mitochondria and reducing reactive oxygen species-mediated damage in ischemic stroke.