Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway
Ralf A. Linker,De-Hyung Lee,Sarah Ryan,Anne M van Dam,Rebecca Conrad,Pradeep Bista,Weike Zeng,Xiaoping Hronowsky,Alex Buko,Sowmya Chollate,Gisa Ellrichmann,Wolfgang Brück,Kate Dawson,Susan Goelz,Stefan Wiese,Robert H. Scannevin,Matvey E. Lukashev,Ralf Gold +17 more
TLDR
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.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.read more
Citations
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Placebo-Controlled Phase 3 Study of Oral BG-12 for Relapsing Multiple Sclerosis
Ralf Gold,Ludwig Kappos,Douglas L. Arnold,Amit Bar-Or,Gavin Giovannoni,Krzysztof Selmaj,Carlo Tornatore,Marianne T. Sweetser,Minhua Yang,Sarah Sheikh,Katherine Dawson,Define Study Investigators +11 more
TL;DR: In patients with relapsing-remitting multiple sclerosis, both BG-12 regimens, as compared with placebo, significantly reduced the proportion of patients who had a relapse, the annualized relapse rate, the rate of disability progression, and the number of lesions on MRI.
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Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism
TL;DR: This review summarizes knowledge about Nrf2 and HO-1 across different phyla suggesting their conservative role as stress-protective and anti-aging factors.
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Natural products in drug discovery: advances and opportunities.
TL;DR: In this article, the authors summarize recent technological developments that are enabling natural product-based drug discovery, highlight selected applications and discuss key opportunities, and discuss the potential of using natural products as drug leads.
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Placebo-Controlled Phase 3 Study of Oral BG-12 or Glatiramer in Multiple Sclerosis
Robert J. Fox,David Miller,J. Theodore Phillips,Michael Hutchinson,Eva Havrdova,Mariko Kita,Minhua Yang,Kartik Raghupathi,Mark Novas,Marianne T. Sweetser,Vissia Viglietta,Katherine Dawson,Christian Sindic +12 more
TL;DR: In patients with relapsing-remitting multiple sclerosis, BG-12 (at both doses) and glatiramer acetate significantly reduced relapse rates and improved neuroradiologic outcomes relative to placebo.
Journal ArticleDOI
Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1.
Evanna L. Mills,Dylan G. Ryan,Hiran A. Prag,Dina Dikovskaya,Deepthi Menon,Zbigniew Zaslona,Mark P. Jedrychowski,Ana S. H. Costa,Maureen Higgins,Emily Hams,John Szpyt,Marah C. Runtsch,Martin S. King,Joanna F. McGouran,Roman Fischer,Benedikt M. Kessler,Anne F. McGettrick,Mark M. Hughes,Richard G. Carroll,Richard G. Carroll,Lee M. Booty,Lee M. Booty,Elena V. Knatko,Paul J. Meakin,Michael L.J. Ashford,Louise K. Modis,Gino Brunori,Daniel C. Sévin,Padraic G. Fallon,Stuart T. Caldwell,Edmund R.S. Kunji,Edward T. Chouchani,Christian Frezza,Albena T. Dinkova-Kostova,Albena T. Dinkova-Kostova,Richard C. Hartley,Michael P. Murphy,Luke A. J. O'Neill,Luke A. J. O'Neill +38 more
TL;DR: It is shown that itaconate is required for the activation of the anti-inflammatory transcription factor Nrf2 by lipopolysaccharide in mouse and human macrophages and that type I interferons boost the expression of Irg1 (also known as Acod1) and itaconates production.
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