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Molecular Pharmacology

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Research ArticleArticle

Resveratrol Protects Dopamine Neurons Against Lipopolysaccharide-Induced Neurotoxicity through Its Anti-Inflammatory Actions

Feng Zhang, Jing-Shan Shi, Hui Zhou, Belinda Wilson, Jau-Shyong Hong and Hui-Ming Gao
Molecular Pharmacology September 2010, 78 (3) 466-477; DOI: https://doi.org/10.1124/mol.110.064535
Feng Zhang
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Jing-Shan Shi
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Hui Zhou
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Belinda Wilson
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Jau-Shyong Hong
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Hui-Ming Gao
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This article has a correction. Please see:

  • Correction to “Resveratrol Protects Dopamine Neurons against Lipopolysaccharide-Induced Neurotoxicity through Its Anti-Inflammatory Actions” - November 01, 2010

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease characterized by a progressive loss of dopamine (DA) neurons in the substantia nigra. Accumulating evidence indicates that inhibition of microglia-mediated neuroinflammation may become a reliable protective strategy for PD. Resveratrol, a nonflavonoid polyphenol naturally found in red wine and grapes, has been known to possess antioxidant, anticancer, and anti-inflammatory properties. Although recent studies have shown that resveratrol provided neuroprotective effects against ischemia, seizure, and neurodegenerative disorders, the mechanisms underlying its beneficial effects on dopaminergic neurodegeneration are poorly defined. In this study, rat primary midbrain neuron-glia cultures were used to elucidate the molecular mechanisms underlying resveratrol-mediated neuroprotection. The results clearly demonstrated that resveratrol protected DA neurons against lipopolysaccharide (LPS)-induced neurotoxicity in concentration- and time-dependent manners through the inhibition of microglial activation and the subsequent reduction of proinflammatory factor release. Mechanistically, resveratrol-mediated neuroprotection was attributed to the inhibition of NADPH oxidase. This conclusion is supported by the following observations. First, resveratrol reduced NADPH oxidase-mediated generation of reactive oxygen species. Second, LPS-induced translocation of NADPH oxidase cytosolic subunit p47 to the cell membrane was significantly attenuated by resveratrol. Third and most importantly, resveratrol failed to exhibit neuroprotection in cultures from NADPH oxidase-deficient mice. Furthermore, this neuroprotection was also related to an attenuation of the activation of mitogen-activated protein kinases and nuclear factor-κB signaling pathways in microglia. These findings suggest that resveratrol exerts neuroprotection against LPS-induced dopaminergic neurodegeneration, and NADPH oxidase may be a major player in resveratrol-mediated neuroprotection.

Footnotes

  • This work was supported by the Intramural Research Program of the National Institutes of Health National Institute of Environmental Health Sciences; the National Natural Science Foundation of China [Grant 30960447]; and the Science and Technology Foundation of Guizhou Province of China [Grant 20107030].

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

    doi:10.1124/mol.110.064535.

  • ABBREVIATIONS:

    DA
    dopamine
    PD
    Parkinson's disease
    SN
    substantia nigra
    ROS
    reactive oxygen species
    ERK
    extracellular signal-regulated kinase
    LPS
    lipopolysaccharide
    NF-κB
    nuclear factor-κB
    iNOS
    inducible nitric-oxide synthase
    MAPK
    mitogen-activated protein kinase
    PCR
    polymerase chain reaction
    MPP+
    1-methyl-4-phenylpyridinium
    Nox
    NADPH oxidase
    DCFH-DA
    dichlorodihydrofluorescein diacetate
    SOD
    superoxide dismutase
    TH
    tyrosine hydroxylase
    RT-PCR
    reverse transcription-polymerase chain reaction
    TNFα
    tumor necrosis factor-α
    IL-1β
    interleukin-1β
    HBSS
    Hanks' balanced salt solution
    JNK
    c-Jun N-terminal kinase
    IκB
    inhibitor of κB
    IKK
    inhibitor of κB kinase
    Iba-1
    ionized calcium-binding adapter molecule-1
    ANOVA
    analysis of variance
    U0126
    1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene.

  • Received March 5, 2010.
  • Accepted June 15, 2010.
  • U.S. Government work not protected by U.S. copyright
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Molecular Pharmacology: 78 (3)
Molecular Pharmacology
Vol. 78, Issue 3
1 Sep 2010
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Research ArticleArticle

Resveratrol Protects Dopamine Neurons Against Lipopolysaccharide-Induced Neurotoxicity through Its Anti-Inflammatory Actions

Feng Zhang, Jing-Shan Shi, Hui Zhou, Belinda Wilson, Jau-Shyong Hong and Hui-Ming Gao
Molecular Pharmacology September 1, 2010, 78 (3) 466-477; DOI: https://doi.org/10.1124/mol.110.064535

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Research ArticleArticle

Resveratrol Protects Dopamine Neurons Against Lipopolysaccharide-Induced Neurotoxicity through Its Anti-Inflammatory Actions

Feng Zhang, Jing-Shan Shi, Hui Zhou, Belinda Wilson, Jau-Shyong Hong and Hui-Ming Gao
Molecular Pharmacology September 1, 2010, 78 (3) 466-477; DOI: https://doi.org/10.1124/mol.110.064535
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