Abstract
Ischemic stroke is a devastating neurological disorder that currently has no clinically approved neuroprotective treatments. Resveratrol is a naturally occurring polyphenol that protects against cerebral ischemic injuries when administered in a prophylactic manner. Yet, the molecular underpinnings of resveratrol-induced neuroprotection are still unclear. This is partly because the metabolic adaptations induced by a major target of resveratrol, the NAD+-dependent deacetylase Sirt1, have not been characterized in the brain. The goal of this study was to better understand the efficacy of resveratrol as a therapeutic agent in ischemic stroke and the metabolic pathways regulated by brain Sirt1 that promote ischemic tolerance. Evaluation of different resveratrol treatment paradigms revealed that while repetitive administration does not enhance its neuroprotective effects, desensitization to multiple exposures does not occur. Remarkably, a single application of resveratrol protected mice from focal ischemia for up to two weeks, demonstrating a novel extended window of preconditioning-induced ischemic tolerance. Further experimentation suggested that Sirt1-mediated epigenetic modifications at DNA might underlie protection in the extended window. Using inducible, neuronal-specific Sirt1 knockout mice, we found that resveratrol is unable to induce neuroprotection without intact neuronal Sirt1. Metabolomics-based analyses identified glucose metabolism as a major metabolic pathway regulated by Sirt1 in the brain. More specifically, whereas resveratrol increased glycolytic rate in cultured neurons under basal and ischemic-penumbra-like conditions, Sirt1 inhibition blocked its metabolic effects. Together, these results provide preclinical evidence of the efficacy of resveratrol as a therapeutic agent in ischemic stroke and identify a novel mechanism of ischemic tolerance that hinges upon a Sirt1-mediated metabolic adaptation of glucose metabolism in neurons.