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Glia. 2016 May;64(5):853-74. doi: 10.1002/glia.22969. Epub 2016 Feb 16.

Targeted activation of CREB in reactive astrocytes is neuroprotective in focal acute cortical injury.

Author information

1
Institut De Neurociències and Unitat De Bioquímica, Facultat De Medicina, Universitat Autònoma De Barcelona, Bellaterra, Barcelona, 08193, Spain.
2
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, L'hospitalet De Llobregat, Barcelona, 08907, Spain.
3
Instituto De Neurociencias De Alicante, Universidad Miguel Hernández/Consejo Superior De Investigaciones Científicas, Sant Joan D'alacant, Alicante, 03550, Spain.
4
Institut De Neurociències and Department of Cellular Biology, Physiology and Immunology, Faculty of Biosciences, Universitat Autònoma, Barcelona, 08193, Spain.
5
Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee.
6
Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee.
7
Department of Experimental Medicine, University of Lleida-Biomedical Research Institute of Lleida, Lleida, 25198, Spain.
8
Institut De Neurociènces and Department of Psychiatry and Forensic Medicine, School of Medicine, Universitat Autònoma De Barcelona, Bellaterra, 08193, Spain.
9
Institució Catalana De Recerca I Estudis Avançats (ICREA), Barcelona, Spain.

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.

KEYWORDS:

CREB; astrocytes; mitochondria; neuroinflammation; traumatic brain injury

PMID:
26880229
DOI:
10.1002/glia.22969
[Indexed for MEDLINE]

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