title: miR-711 upregulation induces neuronal cell death after traumatic brain injury.
abstract: Traumatic brain injury (TBI) is a leading cause of mortality and disability. MicroRNAs (miRs) are small noncoding RNAs that negatively regulate gene expression at post-transcriptional level and may be key modulators of neuronal apoptosis, yet their role in secondary injury after TBI remains largely unexplored. Changes in miRs after controlled cortical impact (CCI) in mice were examined during the first 72 h using miR arrays and qPCR. One selected miR (711) was examined with regard to its regulation and relation to cell death; effects of miR-711 modulation were evaluated after CCI and using in vitro cell death models of primary cortical neurons. Levels of miR-711 were increased in the cortex early after TBI and in vitro models through rapid upregulation of miR-711 transcription (pri-miR-711) rather than catabolism. Increases coincided with downregulation of the pro-survival protein Akt, a predicted target of miR-711, with sequential activation of forkhead box O3 (FoxO3)a/glycogen synthase kinase 3 (GSK3)α/β, pro-apoptotic BH3-only molecules PUMA (Bcl2-binding component 3) and Bim (Bcl2-like 11 (apoptosis facilitator)), and mitochondrial release of cytochrome c and AIF. miR-711 and Akt (mRNA) co-immunoprecipitated with the RNA-induced silencing complex (RISC). A miR-711 hairpin inhibitor attenuated the apoptotic mechanisms and decreased neuronal death in an Akt-dependent manner. Conversely, a miR-711 mimic enhanced neuronal apoptosis. Central administration of the miR-711 hairpin inhibitor after TBI increased Akt expression and attenuated apoptotic pathways. Treatment reduced cortical lesion volume, neuronal cell loss in cortex and hippocampus, and long-term neurological dysfunction. miR-711 changes contribute to neuronal cell death after TBI, in part by inhibiting Akt, and may serve as a novel therapeutic target.
authors.affiliation: Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA.|Center for Shock, Trauma, and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: B
authors.initials: B
authors.lastname: Sabirzhanov
authors.affiliation: Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA.|Center for Shock, Trauma, and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Stoica
authors.affiliation: Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA.|Center for Shock, Trauma, and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA.|Center for Shock, Trauma, and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Loane
authors.affiliation: Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA.|Center for Shock, Trauma, and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: J
authors.initials: J
authors.lastname: Wu
authors.affiliation: University of Maryland School of Nursing, Baltimore, MD, USA.|Program in Neuroscience, University of Maryland, Baltimore, MD, USA.
authors.forename: S G
authors.initials: SG
authors.lastname: Dorsey
authors.affiliation: Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA.|Center for Shock, Trauma, and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: A I
authors.initials: AI
authors.lastname: Faden
mesh_terms: D000818:Animals; D017209:Apoptosis; D000070642:Brain Injuries, Traumatic / Q000378:metabolism* / Q000473:pathology; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D035683:MicroRNAs; D051057:Proto-Oncogene Proteins c-akt