title: Downregulation of miR-23a and miR-27a following experimental traumatic brain injury induces neuronal cell death through activation of proapoptotic Bcl-2 proteins.
abstract: MicroRNAs (miRs) are small noncoding RNAs that negatively regulate gene expression at the post-transcriptional level. To identify miRs that may regulate neuronal cell death after experimental traumatic brain injury (TBI), we profiled miR expression changes during the first several days after controlled cortical impact (CCI) in mice. miR-23a and miR-27a were rapidly downregulated in the injured cortex in the first hour after TBI. These changes coincided with increased expression of the proapoptotic Bcl-2 family members Noxa, Puma, and Bax. In an etoposide-induced in vitro model of apoptosis in primary cortical neurons, miR-23a and miR-27a were markedly downregulated as early as 1 h after exposure, before the upregulation of proapoptotic Bcl-2 family molecules. Administration of miR-23a and miR-27a mimics attenuated etoposide-induced changes in Noxa, Puma, and Bax, reduced downstream markers of caspase-dependent (cytochrome c release and caspase activation) and caspase-independent (apoptosis-inducing factor release) pathways, and limited neuronal cell death. In contrast, miRs hairpin inhibitors enhanced etoposide-induced neuronal apoptosis and caspase activation. Importantly, administration of miR-23a and miR-27a mimics significantly reduced activation of Puma, Noxa, and Bax as well as attenuated markers of caspase-dependent and -independent apoptosis after TBI. Furthermore, miR-23a and miR-27a mimics significantly attenuated cortical lesion volume and neuronal cell loss in the hippocampus after TBI. These findings indicate that post-traumatic decreases in miR-23a and miR-27a contribute to neuronal cell death after TBI by upregulating proapoptotic Bcl-2 family members, thus providing a novel therapeutic target.
authors: Department of Anesthesiology and Center for Shock, Trauma, and Anesthesiology Research, University of Maryland School of Medicine, bsabirzhanov@anes.umm.edu bstoica@anes.umm.edu.
authors: Boris
authors: B
authors: Sabirzhanov
authors: Department of Anesthesiology and Center for Shock, Trauma, and Anesthesiology Research, University of Maryland School of Medicine.
authors: Zaorui
authors: Z
authors: Zhao
authors: Department of Anesthesiology and Center for Shock, Trauma, and Anesthesiology Research, University of Maryland School of Medicine, bsabirzhanov@anes.umm.edu bstoica@anes.umm.edu.
authors: Bogdan A
authors: BA
authors: Stoica
authors: Department of Anesthesiology and Center for Shock, Trauma, and Anesthesiology Research, University of Maryland School of Medicine.
authors: David J
authors: DJ
authors: Loane
authors: Department of Anesthesiology and Center for Shock, Trauma, and Anesthesiology Research, University of Maryland School of Medicine.
authors: Junfang
authors: J
authors: Wu
authors: University of Maryland, School of Nursing, and.
authors: Carlos
authors: C
authors: Borroto
authors: University of Maryland, School of Nursing, and Program in Neuroscience, University of Maryland, Baltimore, Maryland 21201.
authors: Susan G
authors: SG
authors: Dorsey
authors: Department of Anesthesiology and Center for Shock, Trauma, and Anesthesiology Research, University of Maryland School of Medicine, Program in Neuroscience, University of Maryland, Baltimore, Maryland 21201.
authors: Alan I
authors: AI
authors: Faden
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001930:Brain Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism* / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; D035683:MicroRNAs; C534062:Mirn23b microRNA, mouse; C540674:Mirn27 microRNA, mouse; D019253:Proto-Oncogene Proteins c-bcl-2
keywords: Bcl-2 proteins; apoptosis; microRNA; neuroprotection; traumatic brain injury