title: Targeted activation of CREB in reactive astrocytes is neuroprotective in focal acute cortical injury.
abstract: The clinical challenge in acute injury as in traumatic brain injury (TBI) is to halt the delayed neuronal loss that occurs hours and days after the insult. Here we report that the activation of CREB-dependent transcription in reactive astrocytes prevents secondary injury in cerebral cortex after experimental TBI. The study was performed in a novel bitransgenic mouse in which a constitutively active CREB, VP16-CREB, was targeted to astrocytes with the Tet-Off system. Using histochemistry, qPCR, and gene profiling we found less neuronal death and damage, reduced macrophage infiltration, preserved mitochondria, and rescued expression of genes related to mitochondrial metabolism in bitransgenic mice as compared to wild type littermates. Finally, with meta-analyses using publicly available databases we identified a core set of VP16-CREB candidate target genes that may account for the neuroprotective effect. Enhancing CREB activity in astrocytes thus emerges as a novel avenue in acute brain post-injury therapeutics.
authors.affiliation: Institut De Neurociències and Unitat De Bioquímica, Facultat De Medicina, Universitat Autònoma De Barcelona, Bellaterra, Barcelona, 08193, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Pardo
authors.affiliation: Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, L'hospitalet De Llobregat, Barcelona, 08907, Spain.
authors.forename: Agatha
authors.initials: A
authors.lastname: Schlüter
authors.affiliation: Instituto De Neurociencias De Alicante, Universidad Miguel Hernández/Consejo Superior De Investigaciones Científicas, Sant Joan D'alacant, Alicante, 03550, Spain.
authors.forename: Luis M
authors.initials: LM
authors.lastname: Valor
authors.affiliation: Instituto De Neurociencias De Alicante, Universidad Miguel Hernández/Consejo Superior De Investigaciones Científicas, Sant Joan D'alacant, Alicante, 03550, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Barco
authors.affiliation: Institut De Neurociències and Department of Cellular Biology, Physiology and Immunology, Faculty of Biosciences, Universitat Autònoma, Barcelona, 08193, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Giralt
authors.affiliation: Institut De Neurociències and Unitat De Bioquímica, Facultat De Medicina, Universitat Autònoma De Barcelona, Bellaterra, Barcelona, 08193, Spain.
authors.forename: Arantxa
authors.initials: A
authors.lastname: Golbano
authors.affiliation: Institut De Neurociències and Department of Cellular Biology, Physiology and Immunology, Faculty of Biosciences, Universitat Autònoma, Barcelona, 08193, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Hidalgo
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee.|Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Peilin
authors.initials: P
authors.lastname: Jia
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee.|Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Experimental Medicine, University of Lleida-Biomedical Research Institute of Lleida, Lleida, 25198, Spain.
authors.forename: Mariona
authors.initials: M
authors.lastname: Jové
authors.affiliation: Department of Experimental Medicine, University of Lleida-Biomedical Research Institute of Lleida, Lleida, 25198, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Portero-Otin
authors.affiliation: Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, L'hospitalet De Llobregat, Barcelona, 08907, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Ruiz
authors.affiliation: Institut De Neurociènces and Department of Psychiatry and Forensic Medicine, School of Medicine, Universitat Autònoma De Barcelona, Bellaterra, 08193, Spain.
authors.forename: Lydia
authors.initials: L
authors.lastname: Giménez-Llort
authors.affiliation: Institut De Neurociències and Unitat De Bioquímica, Facultat De Medicina, Universitat Autònoma De Barcelona, Bellaterra, Barcelona, 08193, Spain.
authors.forename: Roser
authors.initials: R
authors.lastname: Masgrau
authors.affiliation: Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, L'hospitalet De Llobregat, Barcelona, 08907, Spain.|Institució Catalana De Recerca I Estudis Avançats (ICREA), Barcelona, Spain.
authors.forename: Aurora
authors.initials: A
authors.lastname: Pujol
authors.affiliation: Institut De Neurociències and Unitat De Bioquímica, Facultat De Medicina, Universitat Autònoma De Barcelona, Bellaterra, Barcelona, 08193, Spain.|Institució Catalana De Recerca I Estudis Avançats (ICREA), Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Galea
mesh_terms: D000818:Animals; D029681:Arabidopsis Proteins / Q000235:genetics / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001930:Brain Injuries / Q000473:pathology* / Q000628:therapy*; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005047:Etoposide / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000209:etiology / Q000517:prevention & control; D008297:Male; D015201:Meta-Analysis as Topic; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism
chemical_list: D029681:Arabidopsis Proteins; C469262:GFA2 protein, Arabidopsis; D005904:Glial Fibrillary Acidic Protein; D018832:Molecular Chaperones; D016900:Neurofilament Proteins; C061195:neurofilament protein M; D005047:Etoposide; D050882:CREB-Binding Protein
keywords: CREB; astrocytes; mitochondria; neuroinflammation; traumatic brain injury