title: 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.
authors.affiliation: Department of Neurology, St Josef Hospital, Ruhr-University Bochum, D-44791 Bochum, Germany. ralf.linker@rub.de
authors.forename: Ralf A
authors.initials: RA
authors.lastname: Linker
authors.forename: De-Hyung
authors.initials: DH
authors.lastname: Lee
authors.forename: Sarah
authors.initials: S
authors.lastname: Ryan
authors.forename: Anne M
authors.initials: AM
authors.lastname: van Dam
authors.forename: Rebecca
authors.initials: R
authors.lastname: Conrad
authors.forename: Pradeep
authors.initials: P
authors.lastname: Bista
authors.forename: Weike
authors.initials: W
authors.lastname: Zeng
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Hronowsky
authors.forename: Alex
authors.initials: A
authors.lastname: Buko
authors.forename: Sowmya
authors.initials: S
authors.lastname: Chollate
authors.forename: Gisa
authors.initials: G
authors.lastname: Ellrichmann
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Brück
authors.forename: Kate
authors.initials: K
authors.lastname: Dawson
authors.forename: Susan
authors.initials: S
authors.lastname: Goelz
authors.forename: Stefan
authors.initials: S
authors.lastname: Wiese
authors.forename: Robert H
authors.initials: RH
authors.lastname: Scannevin
authors.forename: Matvey
authors.initials: M
authors.lastname: Lukashev
authors.forename: Ralf
authors.initials: R
authors.lastname: Gold
mesh_terms: D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000378:metabolism; D000449:Aldehyde Reductase / Q000378:metabolism; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D000975:Antioxidants / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects / Q000276:immunology; D001369:Axons / Q000378:metabolism / Q000473:pathology; D017252:CD3 Complex / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000517:prevention & control*; D005260:Female; D005650:Fumarates / Q000494:pharmacology / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects; D006023:Glycoproteins / Q000009:adverse effects; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009103:Multiple Sclerosis / Q000378:metabolism / Q000473:pathology; D009185:Myelin Proteins / Q000378:metabolism; D063308:Myelin-Oligodendrocyte Glycoprotein; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000070798:Nogo Proteins; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000009:adverse effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D012890:Sleep / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology; D018709:Statistics, Nonparametric; D053719:Tandem Mass Spectrometry / Q000379:methods; D013997:Time Factors; D014162:Transfection
chemical_list: D000943:Antigens, Differentiation; D000975:Antioxidants; D017252:CD3 Complex; D016207:Cytokines; D005650:Fumarates; D006023:Glycoproteins; D009185:Myelin Proteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; D000070798:Nogo Proteins; D010446:Peptide Fragments; D034741:RNA, Small Interfering; C000603199:RTN4 protein, human; C000603201:Rtn4 protein, mouse; C000603197:Rtn4 protein, rat; C036763:monocyte-macrophage differentiation antigen; C445081:myelin oligodendrocyte glycoprotein (35-55); D049452:Green Fluorescent Proteins; D006861:Hydrogen Peroxide; C553248:Akr1b10 protein, rat; D000449:Aldehyde Reductase; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases