Quercetin Enhances Exercise-Mediated Neuroprotective Effects in Brain Ischemic Rats

Purpose: Reactive oxygen species are markedly increased after ischemia and play important roles in the mechanism of ischemia-reperfusion injury. Regulating the oxidative stress response after brain ischemia provides a potential therapeutic strategy. Quercetin is a natural flavonoid that exhibits antioxidant properties. However, the mechanisms by which it protects cells are not fully understood. Exercise training also reduces oxidative stress and enhances brain recovery. The purpose of this study was to determine whether combined exercise training with quercetin treatment could result in better neuroprotection and functional recovery in rats subjected to brain ischemia. Methods: Rats were randomly assigned to the following groups: middle cerebral artery occlusion (MCAO) with rest control, MCAO with quercetin, MCAO with exercise, or MCAO with exercise and quercetin. To determine the effect of PI3K/Akt pathway in quercetin and exercise-mediated neuroprotection, two additional groups, a group of MCAO with quercetin and PI3K/Akt inhibitor (LY294002) and a group of MCAO with exercise, quercetin, and PI3K/Akt inhibitor, were added in this study. Motor function was examined at the 24th hour and 14th day post-MCAO. Brain samples were used to measure the expression of antioxidative and antiapoptotic proteins as well as to measure the infarct volume. Results: Treatment with either exercise or quercetin significantly decreased oxidative stress and infarct volume, increased antioxidative and antiapoptotic signaling, and improved motor function. Exercise training combined with quercetin treatment resulted in better outcomes than either treatment alone. PI3K/Akt inhibition eliminated the protective effects of exercise training and quercetin treatment. Conclusion: Quercetin enhances exercise-mediated functional recovery after brain ischemia via up-regulation of PI3K/Akt activity to promote antioxidative and antiapoptotic signaling.