title: Lithium-induced neuroprotection in stroke involves increased miR-124 expression, reduced RE1-silencing transcription factor abundance and decreased protein deubiquitination by GSK3β inhibition-independent pathways.
abstract: Lithium promotes acute poststroke neuronal survival, which includes mechanisms that are not limited to GSK3β inhibition. However, whether lithium induces long-term neuroprotection and enhanced brain remodeling is unclear. Therefore, mice were exposed to transient middle cerebral artery occlusion and lithium (1 mg/kg bolus followed by 2 mg/kg/day over up to 7 days) was intraperitoneally administered starting 0-9 h after reperfusion onset. Delivery of lithium no later than 6 h reduced infarct volume on day 2 and decreased brain edema, leukocyte infiltration, and microglial activation, as shown by histochemistry and flow cytometry. Lithium-induced neuroprotection persisted throughout the observation period of 56 days and was associated with enhanced neurological recovery. Poststroke angioneurogenesis and axonal plasticity were also enhanced by lithium. On the molecular level, lithium increased miR-124 expression, reduced RE1-silencing transcription factor abundance, and decreased protein deubiquitination in cultivated cortical neurons exposed to oxygen-glucose deprivation and in brains of mice exposed to cerebral ischemia. Notably, this effect was not mimicked by pharmacological GSK3β inhibition. This study for the first time provides efficacy data for lithium in the postacute ischemic phase, reporting a novel mechanism of action, i.e. increased miR-124 expression facilitating REST degradation by which lithium promotes postischemic neuroplasticity and angiogenesis.
authors.affiliation: 1 Department of Neurology, University of Duisburg-Essen, Essen, Germany.|2 Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Istanbul, Turkey.|3 Department of Neurology, University of Göttingen Medical School, Göttingen, Germany.
authors.forename: Thorsten R
authors.initials: TR
authors.lastname: Doeppner
authors.affiliation: 1 Department of Neurology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Kaltwasser
authors.affiliation: 1 Department of Neurology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Eduardo H
authors.initials: EH
authors.lastname: Sanchez-Mendoza
authors.affiliation: 2 Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Istanbul, Turkey.
authors.forename: Ahmet B
authors.initials: AB
authors.lastname: Caglayan
authors.affiliation: 3 Department of Neurology, University of Göttingen Medical School, Göttingen, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Bähr
authors.affiliation: 1 Department of Neurology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Hermann
mesh_terms: D000818:Animals; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors; D020244:Infarction, Middle Cerebral Artery; D008094:Lithium / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects; D000066829:Neuroprotection / Q000187:drug effects*; D012097:Repressor Proteins / Q000378:metabolism*; D020521:Stroke / Q000188:drug therapy*; D054875:Ubiquitination / Q000187:drug effects; D000099229:RE1-Silencing Transcription Factor
chemical_list: D000071679:Glycogen Synthase Kinase 3 beta; D008094:Lithium; D035683:MicroRNAs; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor; C540079:Mirn124 microRNA, mouse
keywords: Cerebral ischemia; RE1-silencing transcription factor; lithium; miRNA; neuroregeneration; stroke