Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway
Abstract
Inflammation and oxidative stress are thought to promote tissue damage in multiple sclerosis. Thus, novel therapeutics enhancing cellular resistance to free radicals could prove useful for multiple sclerosis treatment. BG00012 is an oral formulation of dimethylfumarate. In a phase II multiple sclerosis trial, BG00012 demonstrated beneficial effects on relapse rate and magnetic resonance imaging markers indicative of inflammation as well as axonal destruction. First we have studied effects of dimethylfumarate on the disease course, central nervous system, tissue integrity and the molecular mechanism of action in an animal model of chronic multiple sclerosis: myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis in C57BL/6 mice. In the chronic phase of experimental autoimmune encephalomyelitis, preventive or therapeutic application of dimethylfumarate ameliorated the disease course and improved preservation of myelin, axons and neurons. In vitro, the application of fumarates increased murine neuronal survival and protected human or rodent astrocytes against oxidative stress. Application of dimethylfumarate led to stabilization of the transcription factor nuclear factor (erythroid-derived 2)-related factor 2, activation of nuclear factor (erythroid-derived 2)-related factor 2-dependent transcriptional activity and accumulation of NADP(H) quinoline oxidoreductase-1 as a prototypical target gene. Furthermore, the immediate metabolite of dimethylfumarate, monomethylfumarate, leads to direct modification of the inhibitor of nuclear factor (erythroid-derived 2)-related factor 2, Kelch-like ECH-associated protein 1, at cysteine residue 151. In turn, increased levels of nuclear factor (erythroid-derived 2)-related factor 2 and reduced protein nitrosylation were detected in the central nervous sytem of dimethylfumarate-treated mice. Nuclear factor (erythroid-derived 2)-related factor 2 was also upregulated in the spinal cord of autopsy specimens from untreated patients with multiple sclerosis. In dimethylfumarate-treated mice suffering from experimental autoimmune encephalomyelitis, increased immunoreactivity for nuclear factor (erythroid-derived 2)-related factor 2 was detected by confocal microscopy in neurons of the motor cortex and the brainstem as well as in oligodendrocytes and astrocytes. In mice deficient for nuclear factor (erythroid-derived 2)-related factor 2 on the same genetic background, the dimethylfumarate mediated beneficial effects on clinical course, axon preservation and astrocyte activation were almost completely abolished thus proving the functional relevance of this transcription factor for the neuroprotective mechanism of action. We conclude that the ability of dimethylfumarate to activate nuclear factor (erythroid-derived 2)-related factor 2 may offer a novel cytoprotective modality that further augments the natural antioxidant responses in multiple sclerosis tissue and is not yet targeted by other multiple sclerosis therapies.
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Dimethyl fumarate has been approved for the treatment of multiple sclerosis.
“Examples include dimethyl fumarate, which has been approved for the treatment of multiple sclerosis [224]”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [224]
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- Authors
- Linker, R. A., Lee, D.-H., Ryan, S., van Dam, A. M., Conrad, R., Bista, P., Zeng, W., Hronowsky, X., Buko, A., Chollate, S., Ellrichmann, G., Brück, W., Dawson, K., Goelz, S., Wiese, S., Scannevin, R. H., Lukashev, M., & Gold, R.
- Affiliations
- St. Josef-Hospital (DE)
- Biogen (United States) (US)
- Ruhr University Bochum (DE)
- Universitätsmedizin Göttingen (DE)
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-02-22
- Volume
- 134
- Issue
- 3
- Pages
- 678-692
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- OpenAlex
- W1978094617
- Cited by
- 1,155
- References
- 53
- Citations by year
- 2026: 53 · 2025: 64 · 2024: 73 · 2023: 60 · 2022: 120 · 2021: 90 · 2020: 103 · 2019: 82 · 2018: 80 · 2017: 77 · 2016: 62 · 2015: 92 · 2014: 83 · 2013: 64 · 2012: 33
- FWCI
- 44.34
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
- GRO (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Biogen
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- fumaric acid esters, multiple sclerosis, neuroinflammation, oxidative stress, Nrf2 antioxidant pathway, Keap1, NQO1, neuroprotection, experimental autoimmune encephalomyelitis, myelin oligodendrocyte glycoprotein, astrocytes, oligodendrocytes
- MeSH terms
- Nogo Proteins, Aldehyde Reductase, Animals, Antigens, Differentiation, Antioxidants, Astrocytes, Axons, Cells, Cultured, Chromatography, High Pressure Liquid, Disease Models, Animal, Embryo, Mammalian, Encephalomyelitis, Autoimmune, Experimental, Female, Fumarates, Gene Expression Regulation, Glycoproteins, Humans, Hydrogen Peroxide, Mice, Inbred C57BL, Motor Neurons, Multiple Sclerosis, Myelin Proteins, Peptide Fragments, Sleep, Mass Spectrometry, Spinal Cord, Time Factors, Transfection, 2',3'-Cyclic-Nucleotide Phosphodiesterases, Signal Transduction, Cytokines, NAD(P)H Dehydrogenase (Quinone), CD3 Complex, Oxidative Stress, Neuroprotective Agents, Statistics, Nonparametric, RNA, Small Interfering, Cell Proliferation, Green Fluorescent Proteins, NF-E2-Related Factor 2, Mice, Tandem Mass Spectrometry, Myelin-Oligodendrocyte Glycoprotein
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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