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