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.

Dose-dependent protection of reseveratrol against spinal cord ischemic-reperfusion injury in rats

“…Due to the vasoprotective effects of RESV [16], the electrolytic balance was significantly maintained, thus attenuating E. Our results are in agreement with those of Yang et al, who showed that RESV treatment can revert E successfully in the SCIR-injured rat model [17]. Similarly, Ren et al also inferred that RESV can effectively reduce E under ischemic conditions [18].…”

Resveratrol Mitigates Rat Retinal Ischemic Injury: The Roles of Matrix Metalloproteinase-9, Inducible Nitric Oxide, and Heme Oxygenase-1

“…23 In addition to the above, the polyphenol antioxidant resveratrol 24 has been reported to exert its neuroprotective effect by decreasing the expression of caspase-3, increasing the amounts of an antioxidant enzyme superoxide dismutase, and upregulating expression of transcription factor Nrf2 during brain ischemia. 25 Therefore, it is possible that resveratrol might inhibit inflammasome assembly through an inhibition of upstream ROS formation. Sakata et al 26 and Ren et al 25 have also reported that resveratrol selectively induces HO-1 in a dose-dependent and time-dependent manner in in vitro mouse or in vivo rat cortical neurons and provided neuroprotection against freeradical or excitotoxicity damage.…”

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

“…Reduced expression of Nrf2 has been observed in mice with SNPs. An antineoplastic compound, brusatol, is an Nrf2 inhibitor that increases the chemotherapeutic efficacy of cisplatin, a common chemotherapeutic (Ren et al 2011). PI3K inhibitors (Mitsuishi et al 2012) and Nrf2 siRNA inhibit Nrf2 in cancer cells.…”

“…Various pharmacological agents like curcumin (Yang et al 2009), resveratrol (Ren et al 2011), MMF (Cho et al 2015), DMF (Albrecht et al 2012) and other FAEs (Linker et al 2011) have been found to exert Nrf2-dependent reduction of oxidative stress. The other agents that can be used for the treatment of neurodegenerative disorders through Nrf2-dependent strategies are sulphoraphane, VEDA-1209 and synthetic triterpenoids.…”