Regulator of calcineurin 1 (Rcan1) has a protective role in brain ischemia/reperfusion injury
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Sobrado et al. Journal of Neuroinflammation 2012, 9:48 http://www.jneuroinflammation.com/content/9/1/48
RESEARCH
Open Access
Regulator of calcineurin 1 (Rcan1) has a protective role in brain ischemia/reperfusion injury Mónica Sobrado2, Belén G Ramirez5, Fernando Neria1, Ignacio Lizasoain2, Maria Lourdes Arbones3, Takashi Minami4, Juan Miguel Redondo5, María Ángeles Moro2 and Eva Cano1,6*
Abstract Background: An increase in intracellular calcium concentration [Ca2+]i is one of the first events to take place after brain ischemia. A key [Ca2+]i-regulated signaling molecule is the phosphatase calcineurin (CN), which plays important roles in the modulation of inflammatory cascades. Here, we have analyzed the role of endogenous regulator of CN 1 (Rcan1) in response to experimental ischemic stroke induced by middle cerebral artery occlusion. Methods: Animals were subjected to focal cerebral ischemia with reperfusion. To assess the role of Rcan1 after stroke, we measured infarct volume after 48 h of reperfusion in Rcan1 knockout (KO) and wild-type (WT) mice. In vitro studies were performed in astrocyte-enriched cortical primary cultures subjected to 3% oxygen (hypoxia) and glucose deprivation (HGD). Adenoviral vectors were used to analyze the effect of overexpression of Rcan1-4 protein. Protein expression was examined by immunohistochemistry and immunoblotting and expression of mRNA by quantitative real-time Reverse-Transcription Polymerase Chain Reaction (real time qRT-PCR). Results: Brain ischemia/reperfusion (I/R) injury in vivo increased mRNA and protein expression of the calcium-inducible Rcan1 isoform (Rcan1-4). I/R-inducible expression of Rcan1 protein occurred mainly in astroglial cells, and in an in vitro model of ischemia, HGD treatment of primary murine astrocyte cultures induced Rcan1-4 mRNA and protein expression. Exogenous Rcan1-4 overexpression inhibited production of the inflammatory marker cyclo-oxygenase 2. Mice lacking Rcan1 had higher expression of inflammation associated genes, resulting in larger infarct volumes. Conclusions: Our results support a protective role for Rcan1 during the inflammatory response to stroke, and underline the importance of the glial compartment in the inflammatory reaction that takes place after ischemia. Improved understanding of non-neuronal mechanisms in ischemic injury promises novel approaches to the treatment of acute ischemic stroke. Keywords: Calcineurin, Calcium, Glia, Hypoxia, Inflammation, Rcan1, Stroke
Background Stroke is a leading cause of human death and disability. However, despite the prevalence and consequences of brain ischemia the only effective treatment is to reinstate the blood supply, a course of action available in less than 3% of patients. Cerebral ischemia triggers a marked inflammatory reaction that involves local cellular activation in the brain and production of inflammatory mediators, including cytokines, chemokines, * Correspondence: [email protected] 1 Unidad de Neuroinflamación. Área de Biología Celular y del Desarrollo, Centro Nacional de
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