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Molecular Pharmacology

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Research ArticleArticle

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

Ambrish Kumar, Chandra K. Singh, Holly A. LaVoie, Donald J. DiPette and Ugra S. Singh
Molecular Pharmacology September 2011, 80 (3) 446-457; DOI: https://doi.org/10.1124/mol.111.071126
Ambrish Kumar
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Chandra K. Singh
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Holly A. LaVoie
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Donald J. DiPette
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Ugra S. Singh
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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 (3,5,4′-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.

Footnotes

  • This research was supported by the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism [Grant R21-AA016121] (to U.S.S.); and a Health Sciences Distinguished Professorship (to D.J.D.).

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.111.071126.

  • ABBREVIATIONS:

    FASD
    fetal alcohol spectrum disorders
    CGN
    cerebellar granule neuron
    BAC
    blood alcohol concentration
    PMSF
    phenylmethylsulfonyl fluoride
    TBST
    Tris-buffered saline/Tween 20
    DTT
    dithiothreitol
    EMSA
    electrophoretic mobility shift assay
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
    TUNEL
    terminal deoxynucleotidyl transferase dUTP nick-end labeling
    PBS
    phosphate-buffered saline
    ROS
    reactive oxygen species
    H2DCFDA
    2′,7′-dichlorodihydrofluorescein diacetate
    DAPI
    4′,6-diamidino-2-phenylindole
    HRP
    horseradish peroxidase
    4-HNE
    trans-4-hydroxy-2-nonenal
    MDA
    malondialdehyde
    SOD
    superoxide dismutase
    PGF
    prostaglandin F
    EGL
    external granule layer
    8-iso-PGF2α
    8-epimer of prostaglandin F2α
    ARE
    antioxidant response element
    HO-1
    heme oxygenase-1
    NQO1
    NAD(P)H dehydrogenase (quinone 1)
    Nrf2
    nuclear factor-erythroid derived 2-like 2
    Res
    resveratrol
    bw
    body weight
    OD
    optical density.

  • Received January 12, 2011.
  • Accepted June 21, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 80 (3)
Molecular Pharmacology
Vol. 80, Issue 3
1 Sep 2011
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Research ArticleArticle

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

Ambrish Kumar, Chandra K. Singh, Holly A. LaVoie, Donald J. DiPette and Ugra S. Singh
Molecular Pharmacology September 1, 2011, 80 (3) 446-457; DOI: https://doi.org/10.1124/mol.111.071126

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Research ArticleArticle

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

Ambrish Kumar, Chandra K. Singh, Holly A. LaVoie, Donald J. DiPette and Ugra S. Singh
Molecular Pharmacology September 1, 2011, 80 (3) 446-457; DOI: https://doi.org/10.1124/mol.111.071126
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