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Dimethyl fumarate

About: Dimethyl fumarate is a research topic. Over the lifetime, 835 publications have been published within this topic receiving 18148 citations. The topic is also known as: BG-12 & fumaric acid.


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Journal ArticleDOI
27 Apr 2018-Science
TL;DR: It is found that DMF succinates and inactivates the catalytic cysteine of the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in mice and humans, both in vitro and in vivo, and represents a proof of concept that aerobic Glycolysis is a therapeutic target in autoimmunity.
Abstract: Activated immune cells undergo a metabolic switch to aerobic glycolysis akin to the Warburg effect, thereby presenting a potential therapeutic target in autoimmune disease. Dimethyl fumarate (DMF), a derivative of the Krebs cycle intermediate fumarate, is an immunomodulatory drug used to treat multiple sclerosis and psoriasis. Although its therapeutic mechanism remains uncertain, DMF covalently modifies cysteine residues in a process termed succination. We found that DMF succinates and inactivates the catalytic cysteine of the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in mice and humans, both in vitro and in vivo. It thereby down-regulates aerobic glycolysis in activated myeloid and lymphoid cells, which mediates its anti-inflammatory effects. Our results provide mechanistic insight into immune modulation by DMF and represent a proof of concept that aerobic glycolysis is a therapeutic target in autoimmunity.

420 citations

Journal ArticleDOI
TL;DR: 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.

414 citations

Journal ArticleDOI
TL;DR: Pretreatment with DMF decreased synthesis of the proinflammatory mediators iNOS, TNF-α, IL-1β and IL-6 at the RNA level in activated microglial and astrocytes in vitro, associated with a decrease in ERK phosphorylation in microglia.
Abstract: Brain inflammation plays a central role in multiple sclerosis (MS). Dimethylfumarate (DMF), the main ingredient of an oral formulation of fumaric acid esters with proven therapeutic efficacy in psoriasis, has recently been found to ameliorate the course of relapsing-remitting MS. Glial cells are the effector cells of neuroinflammation; however, little is known of the effect of DMF on microglia and astrocytes. The purpose of this study was to use an established in vitro model of brain inflammation to determine if DMF modulates the release of neurotoxic molecules from microglia and astrocytes, thus inhibiting glial inflammation. Primary microglial and astrocytic cell cultures were prepared from cerebral cortices of neonatal rats. The control cells were treated with LPS, an accepted inducer of pro-inflammatory properties in glial cells, and the experimental groups with LPS and DMF in different concentrations. After stimulation/incubation, the generation of nitric oxide (NO) in the cell culture supernatants was determined by measuring nitrite accumulation in the medium using Griess reagent. After 6 hours of treatment RT-PCR was used to determine transcription levels of iNOS, IL-1β, IL-6 and TNF-α mRNA in microglial and astrocytic cell cultures initially treated with DMF, followed after 30 min by LPS treatment. Moreover, we investigated possible involvement of the ERK and Nrf-2 transduction pathway in microglia using western blot analysis. Pretreatment with DMF decreased synthesis of the proinflammatory mediators iNOS, TNF-α, IL-1β and IL-6 at the RNA level in activated microglia and astrocytes in vitro, associated with a decrease in ERK phosphorylation in microglia. Collectively, these results suggest that the neuroprotective effects of DMF may be in part functionally attributable to the compound's ability to inhibit expression of multiple neuroinflammatory mediators in brain of MS patients.

316 citations

Journal ArticleDOI
S. Schilling1, Susan Goelz, Ralf A. Linker1, F. Luehder1, Ralf Gold1 
TL;DR: The underlying biological activity of FAE in EAE is complex and, to elucidate the molecular mechanisms, further investigation is needed.
Abstract: Fumaric acid esters (FAE) have proven their therapeutic efficacy in psoriasis, a Th1 mediated skin disease. More recently, preliminary data have suggested an activity in multiple sclerosis (MS) as well. To investigate further possible mechanisms of action of these compounds in inflammatory diseases, we studied the FAE methyl hydrogen fumarate (MHF) and dimethyl fumarate (DMF) in chronic experimental autoimmune encephalomyelitis (EAE) induced by immunization of C57BL/6 mice with MOG peptide aa 35–55. Preventive treatment with these FAE was delivered twice a day by oral gavage. Both esters had a significant therapeutic effect on the disease course and histology showed a strongly reduced macrophage inflammation in the spinal cord. Multiparameter cytokine analysis from blood detected an increase of IL-10 in the treated animals. We conclude that the underlying biological activity of FAE in EAE is complex and, to elucidate the molecular mechanisms, further investigation is needed.

302 citations

Journal ArticleDOI
TL;DR: Fumaric acid derivatives were found to be effective and safe in the treatment of psoriasis and indicated statistically significant superiority of the fumaric Acid derivatives over placebo.
Abstract: Background : Psoriasis vulgaris may benefit from treatment with fumaric acid and/or its derivatives; however, because different preparations have been used, results have been contradictory and difficult to interpret. Objective : The purpose of this clinical trial was to evaluate the therapeutic value of fumaric acid derivatives. Methods : A randomized double-blind study was carried out in patients with psoriasis, comparing a well-characterized formulation of fumaric acid derivatives with placebo. Results : The results indicated statistically significant superiority of the fumaric acid derivatives over placebo. Adverse events (flush, gastrointestinal disturbances) were initially relatively frequent, but decreased thereafter. Conclusion : Fumaric acid derivatives were found to be effective and safe in the treatment of psoriasis.

296 citations


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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
202378
2022135
2021103
202089
201990
201887