Journal ArticleDOI
Fumarates Promote Cytoprotection of Central Nervous System Cells against Oxidative Stress via the Nuclear Factor (Erythroid-Derived 2)-Like 2 Pathway
Robert H. Scannevin,Sowmya Chollate,Mi Young Jung,Melanie N. Shackett,Hiral Patel,Pradeep Bista,Weike Zeng,Sarah Ryan,Masayuki Yamamoto,Matvey E. Lukashev,Kenneth J. Rhodes +10 more
TLDR
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, and these data suggest DMF andMMF may function through improving mitochondrial function.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.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.
Journal ArticleDOI
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
NRF2 and cancer: the good, the bad and the importance of context
Michael B. Sporn,Karen T. Liby +1 more
TL;DR: This Opinion article aims to rationalize conflicting perspectives by critiquing the context dependence of NRF2 functions and the experimental methods behind these conflicting data.
Journal ArticleDOI
Progressive multiple sclerosis: pathology and pathogenesis
TL;DR: Oxidative stress seems to be mainly driven by inflammation and oxidative burst in microglia; however, its effects might be amplified in patients with progressive MS by age-dependent iron accumulation in the brain and by mitochondrial gene deletions, triggered by the chronic inflammatory process.
Journal ArticleDOI
New avenues for anti-epileptic drug discovery and development
TL;DR: It is proposed that future anti-epileptic drug development may be improved through a new joint endeavour between academia and the industry, through the identification and application of tools for new target-driven approaches, and through comparative preclinical proof-of-concept studies and innovative clinical trials designs.
References
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Journal ArticleDOI
An nrf2/small maf heterodimer mediates the induction of phase ii detoxifying enzyme genes through antioxidant response elements
Ken Itoh,Tomoki Chiba,Satoru Takahashi,Tetsuro Ishii,Kazuhiko Igarashi,Yasutake Katoh,Tatsuya Oyake,Norio Hayashi,Kimihiko Satoh,Ichiro Hatayama,Masayuki Yamamoto,Yo-ichi Nabeshima +11 more
TL;DR: It is demonstrated that Nrf2 is essential for the transcriptional induction of phase II enzymes and the presence of a coordinate transcriptional regulatory mechanism for phase II enzyme genes and the nrf2-deficient mice may prove to be a very useful model for the in vivo analysis of chemical carcinogenesis and resistance to anti-cancer drugs.
Journal ArticleDOI
Guide for the Care and Use of Laboratory Animals
TL;DR: The Guide for the Care and Use of Laboratory Animals by the Institute for Laboratory Animal Research (ILAR) of the National Research Council in the USA, is well known among most individuals involved in laboratory animal care and use and the overall intention is to support the readers to build a programme which creates a system of selfregulation and regulatory oversight.
Journal ArticleDOI
Regulatory Mechanisms Controlling Gene Expression Mediated by the Antioxidant Response Element
TL;DR: This review focuses on the molecular mechanisms whereby the transcriptional activation mediated by the interaction between the ARE and NF-E2-related factor 2 (Nrf2) is regulated.
Journal ArticleDOI
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
TL;DR: 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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