Resveratrol Pretreatment Attenuates Cerebral Ischemic Injury by Upregulating Expression of Transcription Factor Nrf2 and HO-1 in Rats

Abstract

Oxidative stress damage plays a vital role in cerebral ischemia/reperfusion (I/R) pathogenesis. The nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway can be activated by pharmacological and dietary means to attenuate cellular oxidative stress. Resveratrol, a plant-derived polyphenolic compound, has antioxidant property. Recent studies have demonstrated that resveratrol has protective effects against cerebral I/R injury. However, little is known about its mechanism. Hence, this study identified the neuroprotective effect of resveratrol pretreatment and elucidate the Nrf2/ARE signaling mechanism after focal cerebral I/R injury in rats. Adult male Sprague-Dawley rats were randomly assigned to sham-operated group, ischemia/reperfusion physiological saline-treated group, and ischemia/reperfusion resveratrol-pretreatmented (15 and 30 mg/kg) groups. Rats were pretreatmented with resveratrol or physiological saline of corresponding volume administered intraperitoneally for 7 days before surgery and 30 min before middle cerebral artery occlusion. At 24 h after reperfusion, neurological score, infarct volume, and brain water content were assessed. Oxidative stress was evaluated by malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity. Pathological changes of brain tissue were observed by HE staining. RT-PCR and Western blot analysed the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). TUNEL staining detected apoptotic cells. The protein expression of Caspase-3 were studied by immunohistochemistry. Resveratrol pretreatment significantly ameliorated neurological scores, reduced infarct volume and brain water content, decreased MDA levels, restored the SOD activity, upregulated the protein and mRNA expression of Nrf2 and HO-1, downregulated the protein expression of caspase-3. TUNEL-positive cells significantly decreased compared with the physiological saline-treated group. HE staining also showed that resveratrol significantly improved neuronal injury. These results showed that resveratrol pretreatment had neuroprotective effects on cerebral I/R injury. This neuroprotective effect is likely exerted by upregulated expression of transcription factor Nrf2 and HO-1 to ameliorate oxidative damage, decreased the protein expression of caspase-3. Our finding is important for understanding the neuroprotective mechanism of resveratrol and promoting its clinical therapeutic utility.