1. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway.
- Author
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Linker RA, Lee DH, Ryan S, van Dam AM, Conrad R, Bista P, Zeng W, Hronowsky X, Buko A, Chollate S, Ellrichmann G, Brück W, Dawson K, Goelz S, Wiese S, Scannevin RH, Lukashev M, and Gold R
- Subjects
- 2',3'-Cyclic-Nucleotide Phosphodiesterases metabolism, Aldehyde Reductase metabolism, Animals, Antigens, Differentiation metabolism, Antioxidants metabolism, Astrocytes drug effects, Astrocytes immunology, Axons metabolism, Axons pathology, CD3 Complex metabolism, Cell Proliferation drug effects, Cells, Cultured, Chromatography, High Pressure Liquid methods, Cytokines metabolism, Disease Models, Animal, Embryo, Mammalian, Encephalomyelitis, Autoimmune, Experimental etiology, Female, Fumarates pharmacology, Gene Expression Regulation drug effects, Glycoproteins adverse effects, Green Fluorescent Proteins genetics, Humans, Hydrogen Peroxide pharmacology, Mass Spectrometry, Mice, Mice, Inbred C57BL, Motor Neurons cytology, Motor Neurons drug effects, Motor Neurons metabolism, Multiple Sclerosis metabolism, Multiple Sclerosis pathology, Myelin Proteins metabolism, Myelin-Oligodendrocyte Glycoprotein, NAD(P)H Dehydrogenase (Quinone) metabolism, Neuroprotective Agents pharmacology, Nogo Proteins, Oxidative Stress drug effects, Peptide Fragments adverse effects, RNA, Small Interfering pharmacology, Sleep physiology, Spinal Cord cytology, Statistics, Nonparametric, Tandem Mass Spectrometry methods, Time Factors, Transfection, Encephalomyelitis, Autoimmune, Experimental prevention & control, Fumarates therapeutic use, NF-E2-Related Factor 2 metabolism, Neuroprotective Agents therapeutic use, Signal Transduction drug effects
- 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.
- Published
- 2011
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