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Research ArticleNeuropharmacology

Fumarates Promote Cytoprotection of Central Nervous System Cells against Oxidative Stress via the Nuclear Factor (Erythroid-Derived 2)-Like 2 Pathway

Robert H. Scannevin, Sowmya Chollate, Mi-young Jung, Melanie Shackett, Hiral Patel, Pradeep Bista, Weike Zeng, Sarah Ryan, Masayuki Yamamoto, Matvey Lukashev and Kenneth J. Rhodes
Journal of Pharmacology and Experimental Therapeutics April 2012, 341 (1) 274-284; DOI: https://doi.org/10.1124/jpet.111.190132
Robert H. Scannevin
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Sowmya Chollate
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Mi-young Jung
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Melanie Shackett
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Hiral Patel
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Pradeep Bista
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Weike Zeng
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Sarah Ryan
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Masayuki Yamamoto
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Matvey Lukashev
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Abstract

Oxidative stress is central to the pathology of several neurodegenerative diseases, including multiple sclerosis, and therapeutics designed to enhance antioxidant potential could have clinical value. The objective of this study was to characterize the potential direct neuroprotective effects of dimethyl fumarate (DMF) and its primary metabolite monomethyl fumarate (MMF) on cellular resistance to oxidative damage in primary cultures of central nervous system (CNS) cells and further explore the dependence and function of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in this process. Treatment of animals or primary cultures of CNS cells with DMF or MMF resulted in increased nuclear levels of active Nrf2, with subsequent up-regulation of canonical antioxidant target genes. DMF-dependent up-regulation of antioxidant genes in vivo was lost in mice lacking Nrf2 [Nrf2(−/−)]. DMF or MMF treatment increased cellular redox potential, glutathione, ATP levels, and mitochondrial membrane potential in a concentration-dependent manner. Treating astrocytes or neurons with DMF or MMF also significantly improved cell viability after toxic oxidative challenge in a concentration-dependent manner. This effect on viability was lost in cells that had eliminated or reduced Nrf2. These data suggest that DMF and MMF are cytoprotective for neurons and astrocytes against oxidative stress-induced cellular injury and loss, potentially via up-regulation of an Nrf2-dependent antioxidant response. These data also suggest DMF and MMF may function through improving mitochondrial function. The clinical utility of DMF in multiple sclerosis is being explored through phase III trials with BG-12, which is an oral therapeutic containing DMF as the active ingredient.

Footnotes

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

    http://dx.doi.org/10.1124/jpet.111.190132.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    MS
    multiple sclerosis
    CNS
    central nervous system
    Nrf2
    nuclear factor (erythroid-derived 2)-like 2
    DMF
    dimethyl fumarate
    MMF
    monomethyl fumarate
    qPCR
    quantitative polymerase chain reaction
    NQO1
    nicotinamide adenine dinucleotide phosphate dehydrogenase (quinone 1)
    Akr1b8
    aldo-keto reductase family 1, member B8
    HO1
    heme oxygenase 1
    GCLC
    glutamate-cysteine ligase catalytic subunit
    DMSO
    dimethyl sulfoxide
    GSH
    glutathione
    OPC
    oligodendrocyte precursor cell
    hOPC
    human OPC
    rOPC
    rat OPC
    hNeur
    human neuron
    DAPI
    4′,6-diamidino-2-phenylindole
    TMRE
    tetramethyl rhodamine ester
    RFU
    relative fluorescence units
    siRNA
    small interfering RNA
    HDAC
    histone deacetylase
    ROS
    reactive oxygen species
    ANOVA
    analysis of variance
    WT
    wild type
    KO
    knockout
    AM
    acetoxymethyl ester.

  • Received November 21, 2011.
  • Accepted January 19, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 341 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 341, Issue 1
1 Apr 2012
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Research ArticleNeuropharmacology

Nrf2-Dependent Cytoprotection against Oxidative Stress

Robert H. Scannevin, Sowmya Chollate, Mi-young Jung, Melanie Shackett, Hiral Patel, Pradeep Bista, Weike Zeng, Sarah Ryan, Masayuki Yamamoto, Matvey Lukashev and Kenneth J. Rhodes
Journal of Pharmacology and Experimental Therapeutics April 1, 2012, 341 (1) 274-284; DOI: https://doi.org/10.1124/jpet.111.190132

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Research ArticleNeuropharmacology

Nrf2-Dependent Cytoprotection against Oxidative Stress

Robert H. Scannevin, Sowmya Chollate, Mi-young Jung, Melanie Shackett, Hiral Patel, Pradeep Bista, Weike Zeng, Sarah Ryan, Masayuki Yamamoto, Matvey Lukashev and Kenneth J. Rhodes
Journal of Pharmacology and Experimental Therapeutics April 1, 2012, 341 (1) 274-284; DOI: https://doi.org/10.1124/jpet.111.190132
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