Abstract T P247: Neuronal Sirt1 Activation Negatively Regulates Rho Kinase in Photothrombotic Stroke

Abstract

Background and Purpose: Sirt1 is a NAD+ dependent deacetylase that is known as one of important regulators for ischemic stroke. Because the role and mechanism of genetic sirt1 over-expression in ischemic brain injury has not yet been studied, we examined that brain-specific sirt1-overexpressing transgenic (BRASTO) mice might have significant beneficial effect in ischemic stroke through regulation of sirt1-Rho kinase (ROCK) signaling pathway. Methods: We induced a middle cerebral artery occlusion model in mice and tested the effect of resveratrol (100 mg/kg, i.p.) in ischemia/reperfusion (2h/22h) injury and tested the role and mechanism with BRASTO mice in photothrombotic stroke. Protein levels in mice brain tissue lysates were determined using western blotting. Results: Sirt1 activation by resveratrol treatment reduced infarction volume and improved neurological deficit score in transient focal cerebral ischemia. BRASTO mice did not show any obvious phenotypic abnormalities and BRASTO mice improved relative cerebral blood flow and reduced infarction volume by 68.4% compare to that of WT in photothrombotic stroke. Sirt1 over-expression in BRASTO mice was significantly increased by 4.2 fold higher than that of WT mice and Rho-kinase activity was significantly decreased by 54.6% in BRASTO mice. Conclusions: These findings indicate that neuronal specific sirt1 activation in BRASTO mice reduced infarction volume in photothrombotic stroke via down-regulation of ROCK signaling pathway. These results suggest that effect of neuronal sirt1 activation may have therapeutic benefits in ischemic stroke via ROCK signaling pathway.