Resveratrol Restores Nrf2 Level and Prevents Ethanol-Induced Toxic Effects in the Cerebellum of a Rodent Model of Fetal Alcohol Spectrum Disorders

Abstract

In humans, ethanol exposure during pregnancy produces a wide range of abnormalities in infants collectively known as fetal alcohol spectrum disorders (FASD). Neuronal malformations in FASD manifest as postnatal behavioral and functional disturbances. The cerebellum is particularly sensitive to ethanol during development. In a rodent model of FASD, high doses of ethanol (blood ethanol concentration 80 mM) induces neuronal cell death in the cerebellum. However, information on potential agent(s) that may protect the cerebellum against the toxic effects of ethanol is lacking. Growing evidence suggests that a polyphenolic compound, resveratrol, has antioxidant and neuroprotective properties. Here we studied whether resveratrol (3,5,4Ј-trihydroxy-trans-stilbene), a phytoalexin found in red grapes and blueberries, protects the cerebellar granule neurons against ethanol-induced cell death. In the present study, we showed that administration of resveratrol (100 mg/kg) to postnatal day 7 rat pups prevents ethanol-induced apoptosis by scavenging reactive oxygen species in the external granule layer of the cerebellum and increases the survival of cerebellar granule cells. It restores ethanol-induced changes in the level of transcription factor nuclear factor-erythroid derived 2-like 2 (nfe2l2, also known as Nrf2) in the nucleus. This in turn retains the expression and activity of its downstream gene targets such as NADPH quinine oxidoreductase 1 and superoxide dismutase in cerebellum of ethanol-exposed pups. These studies indicate that resveratrol exhibits neuroprotective effects in cerebellum by acting at redox regulating proteins in a rodent model of FASD.

Topical treatment with pterostilbene, a natural phytoalexin, effectively protects hairless mice against UVB radiation-induced skin damage and carcinogenesis

“…The remaining pellet was washed with buffer A and, after centrifugation, at 4 ºC, for 10 min at 3,000 x g, we added 125 µL of buffer B (20 mM HEPES pH 7.9, 0.4 M NaCl, 1 mM EDTA, 1 mM EGTA, 5 µL/ml of Sigma's protease inhibitor, 1 mM DTT). Then, after active shacking, the samples were centrifuged, at 4 ºC, for 15 min at 12,000 x g. The resulting supernatants were separated as "nuclear extracts" [30] .…”

Role of Nrf2 in Oxidative Stress and Toxicity

“…chronic alcohol consumption and by overexpression of CYP2E1 (131,132). Chemoprotective agents activate Nrf2 and protect animals from ethanol-induced lesions, including fetal alcohol spectrum disorders (133,134). Nrf2 controlled the basal and ethanolinduced expression of Srx1, HO-1, and NQO1 in mouse liver (131,135).…”

Alcohol and Developing Neuronal Circuits

“…PPAR-γ agonists (e.g., rosiglitazone) are clinically used to treat patients with type II diabetes, and it will be interesting to determine if these can be safely administered during pregnancy and be used to ameliorate the impact of ethanol exposure on the cerebellum. Other potential interventions against cerebellar damage induced by developmental ethanol exposure that have been put forward in recent studies include acid-sensitive channel inhibitors (Ramadoss, Lunde, Ouyang, Chen, & Cudd, 2008), resveratrol (Kumar, Singh, Lavoie, Dipette, & Singh, 2011), neuroactive steroids (Ramezani et al, 2011), and taurine (Taranukhin et al, 2012). Additional studies are needed to further characterize the mechanisms of action of these agents and their potential utility in human populations.…”