Dimethyl Fumarate
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Dimethyl Fumarate
Description
A fumarate derivative that is used as a DERMATOLOGIC AGENT in the treatment of PSORIASIS and SKIN DISEASES. It also may be used as an IMMUNOSUPPRESSIVE AGENT in the treatment of MULTIPLE SCLEROSIS.Read more
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Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis.
Journal: The New England journal of medicine
September/26/2012
Description

BACKGROUND

BG-12 (dimethyl fumarate) was shown to have antiinflammatory and cytoprotective properties in preclinical experiments and to result in significant reductions in disease activity on magnetic resonance imaging (MRI) in a phase 2, placebo-controlled study involving patients with relapsing-remitting multiple sclerosis.

METHODS

We conducted a randomized, double-blind, placebo-controlled phase 3 study involving patients with relapsing-remitting multiple sclerosis. Patients were randomly assigned to receive oral BG-12 at a dose of 240 mg twice daily, BG-12 at a dose of 240 mg three times daily, or placebo. The primary end point was the proportion of patients who had a relapse by 2 years. Other end points included the annualized relapse rate, the time to confirmed progression of disability, and findings on MRI.

RESULTS

The estimated proportion of patients who had a relapse was significantly lower in the two BG-12 groups than in the placebo group (27% with BG-12 twice daily and 26% with BG-12 thrice daily vs. 46% with placebo, P<0.001 for both comparisons). The annualized relapse rate at 2 years was 0.17 in the twice-daily BG-12 group and 0.19 in the thrice-daily BG-12 group, as compared with 0.36 in the placebo group, representing relative reductions of 53% and 48% with the two BG-12 regimens, respectively (P<0.001 for the comparison of each BG-12 regimen with placebo). The estimated proportion of patients with confirmed progression of disability was 16% in the twice-daily BG-12 group, 18% in the thrice-daily BG-12 group, and 27% in the placebo group, with significant relative risk reductions of 38% with BG-12 twice daily (P=0.005) and 34% with BG-12 thrice daily (P=0.01). BG-12 also significantly reduced the number of gadolinium-enhancing lesions and of new or enlarging T(2)-weighted hyperintense lesions (P<0.001 for the comparison of each BG-12 regimen with placebo). Adverse events associated with BG-12 included flushing and gastrointestinal events, such as diarrhea, nausea, and upper abdominal pain, as well as decreased lymphocyte counts and elevated liver aminotransferase levels.

CONCLUSIONS

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. (Funded by Biogen Idec; DEFINE ClinicalTrials.gov number, NCT00420212.).

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Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis.
Journal: The New England journal of medicine
September/26/2012
Description

BACKGROUND

BG-12 (dimethyl fumarate) is in development as an oral treatment for relapsing-remitting multiple sclerosis, which is commonly treated with parenteral agents (interferon or glatiramer acetate).

METHODS

In this phase 3, randomized study, we investigated the efficacy and safety of oral BG-12, at a dose of 240 mg two or three times daily, as compared with placebo in patients with relapsing-remitting multiple sclerosis. An active agent, glatiramer acetate, was also included as a reference comparator. The primary end point was the annualized relapse rate over a period of 2 years. The study was not designed to test the superiority or noninferiority of BG-12 versus glatiramer acetate.

RESULTS

At 2 years, the annualized relapse rate was significantly lower with twice-daily BG-12 (0.22), thrice-daily BG-12 (0.20), and glatiramer acetate (0.29) than with placebo (0.40) (relative reductions: twice-daily BG-12, 44%, P<0.001; thrice-daily BG-12, 51%, P<0.001; glatiramer acetate, 29%, P=0.01). Reductions in disability progression with twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate versus placebo (21%, 24%, and 7%, respectively) were not significant. As compared with placebo, twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate significantly reduced the numbers of new or enlarging T(2)-weighted hyperintense lesions (all P<0.001) and new T(1)-weighted hypointense lesions (P<0.001, P<0.001, and P=0.002, respectively). In post hoc comparisons of BG-12 versus glatiramer acetate, differences were not significant except for the annualized relapse rate (thrice-daily BG-12), new or enlarging T(2)-weighted hyperintense lesions (both BG-12 doses), and new T(1)-weighted hypointense lesions (thrice-daily BG-12) (nominal P<0.05 for each comparison). Adverse events occurring at a higher incidence with an active treatment than with placebo included flushing and gastrointestinal events (with BG-12) and injection-related events (with glatiramer acetate). There were no malignant neoplasms or opportunistic infections reported with BG-12. Lymphocyte counts decreased with BG-12.

CONCLUSIONS

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. (Funded by Biogen Idec; CONFIRM ClinicalTrials.gov number, NCT00451451.).

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Pubmed
Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study.
Journal: Lancet (London, England)
November/9/2008
Description

BACKGROUND

Oral fumarate (BG00012) might have dual anti-inflammatory and neuroprotective effects. Our aim was to assess the efficacy and safety of BG00012 in patients with relapsing-remitting multiple sclerosis.

METHODS

257 patients, aged 18-55 years, with relapsing-remitting multiple sclerosis were randomly assigned to receive 120 mg once daily (n=64), 120 mg three times daily (n=64), or 240 mg three times daily (n=64) BG00012, or placebo (n=65) for 24 weeks. During an extension period of 24 weeks for safety assessment, patients treated with placebo received BG00012 240 mg three times daily. The primary endpoint was total number of new gadolinium enhancing (GdE) lesions on brain MRI scans at weeks 12, 16, 20, and 24. Additional endpoints included cumulative number of new GdE lesions (weeks 4-24), new or enlarging T2-hyperintense lesions, new T1-hypointense lesions at week 24, and annualised relapse rate. Analysis was done on the efficacy-evaluable population. Safety and tolerability were also assessed. This study is registered with ClinicalTrials.gov, number NCT00168701.

RESULTS

Treatment with BG00012 240 mg three times daily reduced by 69% the mean total number of new GdE lesions from week 12 to 24 compared with placebo (1.4 vs 4.5, p<0.0001). It also reduced number of new or enlarging T2-hyperintense (p=0.0006) and new T1-hypointense (p=0.014) lesions compared with placebo. BG00012 reduced annualised relapse rate by 32% (0.44 vs 0.65 for placebo; p=0.272). Adverse events more common in patients given BG00012 than in those given placebo included abdominal pain, flushing, and hot flush. Dose-related adverse events in patients on BG00012 were headache, fatigue, and feeling hot.

CONCLUSIONS

The anti-inflammatory effects and favourable safety profile of BG00012 warrant further long-term phase III studies in large patient groups.

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Fumaric acid esters are effective in chronic experimental autoimmune encephalomyelitis and suppress macrophage infiltration.
Journal: Clinical and experimental immunology
August/6/2006
Description

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.

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PML in a patient treated with dimethyl fumarate from a compounding pharmacy.
Journal: The New England journal of medicine
May/1/2013
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Dimethylfumarate inhibits microglial and astrocytic inflammation by suppressing the synthesis of nitric oxide, IL-1beta, TNF-alpha and IL-6 in an in-vitro model of brain inflammation.
Journal: Journal of neuroinflammation
June/30/2010
Description

BACKGROUND

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.

METHODS

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-1beta, IL-6 and TNF-alpha 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.

RESULTS

Pretreatment with DMF decreased synthesis of the proinflammatory mediators iNOS, TNF-alpha, IL-1beta and IL-6 at the RNA level in activated microglia and astrocytes in vitro, associated with a decrease in ERK phosphorylation in microglia.

CONCLUSIONS

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.

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Dimethylfumarate is a potent inducer of apoptosis in human T cells.
Journal: The Journal of investigative dermatology
January/28/2004
Description

Fumaric acid esters (FAE) have been used for the systemic treatment of psoriasis in Germany for almost 50 years. Recently, it has been shown that dimethylfumarate (DMF) as the main ingredient of the marketed FAE mixture is a potent inhibitor of the nuclear transcription factor NF-kappaB. DMF was also shown to induce apoptosis in various cells. Because T cells play a crucial role in psoriasis pathogenesis, we asked whether DMF and its main metabolite methylhydrogenfumarate (MHF) were able to induce apoptosis in these cells. Purified human T cells were treated with DMF and MHF (1-20 microg/mL) and stimulated with interleukin 2, anti-CD3 antibodies or both for 48 h, and apoptosis was subsequently determined by the expression of Apo2.7 as well as by terminal deoxynucleotide transferase nick end labeling. The expression of antiapoptotic protein Bcl-2 was simultaneously determined. The results showed a dose-and-time dependent up-regulation of Apo2.7 expression and DNA fragmentation by DMF preferable in stimulated T cells. MHF and the solvent dimethyl sulfoxide were without effect. DMF, but not MHF, led to a concentration-dependent decrease of Bcl-2 expression in interleukin-2-stimulated T cells. The data provide evidence that the effect of FAE treatment of psoriasis may at least in part be due to induction of apoptosis in activated T cells.

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Oral fumaric acid esters for the treatment of active multiple sclerosis: an open-label, baseline-controlled pilot study.
Journal: European journal of neurology
September/4/2006
Description

An exploratory, prospective, open-label study of fumaric acid esters (FAE, Fumaderm(R)) was conducted in patients with relapsing-remitting multiple sclerosis (RRMS). The study consisted of the following four phases: 6-week baseline, 18-week treatment (target dose of 720 mg/day), 4-week washout, and a second 48-week treatment phase (target dose of 360 mg/day). Ten patients with an Expanded Disability Status Scale (EDSS) score of 2.0-6.0 and at least one gadolinium-enhancing (Gd+) lesion on T1-weighted magnetic resonance imaging (MRI) brain scans participated in the study. Safety was assessed by adverse events (AEs), blood chemistry/hematology, electrocardiogram, and urinalysis. The primary efficacy outcomes were number and volume of Gd+ lesions. Other clinical outcomes included EDSS score, ambulation index (AI), and nine-hole peg test (9-HPT). Effects of FAE on intracellular cytokine profiles, T-cell apoptosis, and soluble adhesion molecules were also assessed. Three patients withdrew during the first 3 weeks of the study because of side effects, non-compliance, and follow-up loss. The most common AEs were gastrointestinal symptoms and flushing; all AEs were reported as mild and reversible. FAE produced significant reductions from baseline in number (P < 0.05) and volume (P < 0.01) of Gd+ lesions after 18 weeks of treatment; this effect persisted during the second treatment phase at half the target dose after the 4-week washout period. EDSS scores, AI, and 9-HPT remained stable or slightly improved from baseline in all patients. Measures of T-cell function demonstrated alterations in cytokines and circulating tumor necrosis factor. The results of this exploratory study suggest that further studies of FAE in patients with MS are warranted.

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PML in a patient with lymphocytopenia treated with dimethyl fumarate.
Journal: The New England journal of medicine
April/13/2015
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Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway.
Journal: Cell metabolism
July/2/2012
Description

The citric acid cycle (CAC) metabolite fumarate has been proposed to be cardioprotective; however, its mechanisms of action remain to be determined. To augment cardiac fumarate levels and to assess fumarate's cardioprotective properties, we generated fumarate hydratase (Fh1) cardiac knockout (KO) mice. These fumarate-replete hearts were robustly protected from ischemia-reperfusion injury (I/R). To compensate for the loss of Fh1 activity, KO hearts maintain ATP levels in part by channeling amino acids into the CAC. In addition, by stabilizing the transcriptional regulator Nrf2, Fh1 KO hearts upregulate protective antioxidant response element genes. Supporting the importance of the latter mechanism, clinically relevant doses of dimethylfumarate upregulated Nrf2 and its target genes, hence protecting control hearts, but failed to similarly protect Nrf2-KO hearts in an in vivo model of myocardial infarction. We propose that clinically established fumarate derivatives activate the Nrf2 pathway and are readily testable cytoprotective agents.

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Validation of the multiple sensor mechanism of the Keap1-Nrf2 system.
Journal: Free radical biology & medicine
December/20/2012
Description

The Keap1-Nrf2 system plays a critical role in cellular defense against electrophiles and reactive oxygen species. Keap1 possesses a number of cysteine residues, some of which are highly reactive and serves as sensors for these insults. Indeed, point mutation of Cys151 abrogates the response to certain electrophiles. However, this mutation does not affect the other set of electrophiles, suggesting that multiple sensor systems reside within the cysteine residues of Keap1. The precise contribution of each reactive cysteine to the sensor function of Keap1 remains to be clarified. To elucidate the contribution of Cys151 in vivo, in this study we adopted transgenic complementation rescue assays. Embryonic fibroblasts and primary peritoneal macrophages were prepared from mice expressing the Keap1-C151S mutant. These cells were challenged with various Nrf2 inducers. We found that some of the inducers triggered only marginal responses in Keap1-C151S-expressing cells, while others evoked responses in a comparable magnitude to those observed in the wild-type cells. We found that tert-butyl hydroquinone, diethylmaleate, sulforaphane, and dimethylfumarate were Cys151 preferable, whereas 15-deoxy-Δ(12,14)-prostaglandin J(2) (15d-PG-J(2)), 2-cyano-3,12 dioxooleana-1,9 diene-28-imidazolide (CDDO-Im), ebselen, nitro-oleic acid, and cadmium chloride were Cys151 independent. Experiments with embryonic fibroblasts and primary macrophages yielded consistent results. Experiments testing protective effects against the cytotoxicity of 1-chloro-2,4-dinitrobenzene of sulforaphane and 15d-PG-J(2) in Keap1-C151S-expressing macrophages revealed that the former inducer was effective, while the latter was not. These results thus indicate that there exists distinct utilization of Keap1 cysteine residues by different chemicals that trigger the response of the Keap1-Nrf2 system, and further substantiate the notion that there are multiple sensing mechanisms within Keap1 cysteine residues.

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Effects of dimethyl fumarate on neuroprotection and immunomodulation.
Journal: Journal of neuroinflammation
January/16/2013
Description

BACKGROUND

Neuronal degeneration in multiple sclerosis has been linked to oxidative stress. Dimethyl fumarate is a promising novel oral therapeutic option shown to reduce disease activity and progression in patients with relapsing-remitting multiple sclerosis. These effects are presumed to originate from a combination of immunomodulatory and neuroprotective mechanisms. We aimed to clarify whether neuroprotective concentrations of dimethyl fumarate have immunomodulatory effects.

RESULTS

We determined time- and concentration-dependent effects of dimethyl fumarate and its metabolite monomethyl fumarate on viability in a model of endogenous neuronal oxidative stress and clarified the mechanism of action by quantitating cellular glutathione content and recycling, nuclear translocation of transcription factors, and the expression of antioxidant genes. We compared this with changes in the cytokine profiles released by stimulated splenocytes measured by ELISPOT technology and analyzed the interactions between neuronal and immune cells and neuronal function and viability in cell death assays and multi-electrode arrays. Our observations show that dimethyl fumarate causes short-lived oxidative stress, which leads to increased levels and nuclear localization of the transcription factor nuclear factor erythroid 2-related factor 2 and a subsequent increase in glutathione synthesis and recycling in neuronal cells. Concentrations that were cytoprotective in neuronal cells had no negative effects on viability of splenocytes but suppressed the production of proinflammatory cytokines in cultures from C57BL/6 and SJL mice and had no effects on neuronal activity in multi-electrode arrays.

CONCLUSIONS

These results suggest that immunomodulatory concentrations of dimethyl fumarate can reduce oxidative stress without altering neuronal network activity.

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PML in a patient without severe lymphocytopenia receiving dimethyl fumarate.
Journal: The New England journal of medicine
April/13/2015
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Dimethylfumarate inhibits TNF-induced nuclear entry of NF-kappa B/p65 in human endothelial cells.
Journal: Journal of immunology (Baltimore, Md. : 1950)
May/16/2002
Description

Fumaric acid esters, mainly dimethylfumarate (DMF), have been successfully used to treat psoriasis. Based on previous observations that DMF inhibited expression of several TNF-induced genes in endothelial cells, we wished to explore the molecular basis of DMF function in greater detail. In first experiments we analyzed DMF effects on tissue factor expression in human endothelial cells in culture, because tissue factor is expressed by two independent sets of transcription factors, by NF-kappa B via TNF and by early gene response-1 transcription factor via vascular endothelial growth factor (VEGF). We show that DMF inhibits TNF-induced tissue factor mRNA and protein expression as well as TNF-induced DNA binding of NF-kappa B proteins, but not VEGF-induced tissue factor protein, mRNA expression, or VEGF-induced early gene response-1 transcription factor/DNA binding. To determine where DMF interferes with the TNF/NF-kappa B signaling cascade, we next analyzed DMF effects on I kappa B and on the subcellular distribution of NF-kappa B. DMF does not inhibit TNF-induced I kappa B alpha phosphorylation and I kappa B degradation; thus, NF-kappa B is properly released from I kappa B complexes even in the presence of DMF. Importantly, DMF inhibits the TNF-induced nuclear entry of NF-kappa B proteins, and this effect appears selective for NF-kappa B after the release from I kappa B, because the constitutive shuttling of inactive NF-kappa B/I kappa B complexes into and out from the nucleus is not blocked by DMF. Moreover, DMF does not block NF-kappa B/DNA binding. In conclusion, DMF appears to selectively prevent the nuclear entry of activated NF-kappa B, and this may be the basis of its beneficial effect in psoriasis.

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The anti-inflammatory effects of dimethyl fumarate in astrocytes involve glutathione and haem oxygenase-1.
Journal: ASN neuro
November/28/2011
Description

DMF (dimethyl fumarate) exerts anti-inflammatory and pro-metabolic effects in a variety of cell types, and a formulation (BG-12) is being evaluated for monotherapy in multiple sclerosis patients. DMF modifies glutathione (GSH) levels that can induce expression of the anti-inflammatory protein HO-1 (haem oxygenase-1). In primary astrocytes and C6 glioma cells, BG-12 dose-dependently suppressed nitrite production induced by either LI [LPS (lipopolysaccharide) at 1 μg/ml plus IFNγ (interferon γ) at 20 units/ml] or a mixture of pro-inflammatory cytokines, with greater efficacy in C6 cells. BG-12 reduced NOS2 (nitric oxide synthase 2) mRNA levels and activation of a NOS2 promoter, reduced nuclear levels of NF-κB (nuclear factor κB) p65 subunit and attenuated loss of IκBα (inhibitory κBα) in both cell types, although with greater effects in astrocytes. In astrocytes, LI decreased mRNA levels for GSHr (GSH reductase) and GCL (c-glutamylcysteine synthetase), and slightly suppressed GSHs (GSH synthetase) mRNAs. Co-treatment with BG-12 prevented those decreased and increased levels above control values. In contrast, LI reduced GSHp (GSH peroxidase) and GCL in C6 cells, and BG-12 had no effect on those levels. BG-12 increased nuclear levels of Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2), an inducer of GSH-related enzymes, in astrocytes but not C6 cells. In astrocytes, GSH was decreased by BG-12 at 2 h and increased at 24 h. Prior depletion of GSH using buthionine-sulfoximine increased the ability of BG-12 to reduce nitrites. In astrocytes, BG-12 increased HO-1 mRNA levels and effects on nitrite levels were blocked by an HO-1 inhibitor. These results demonstrate that BG-12 suppresses inflammatory activation in astrocytes and C6 glioma cells, but with distinct mechanisms, different dependence on GSH and different effects on transcription factor activation.

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Efficacy of fumaric acid esters in the R6/2 and YAC128 models of Huntington's disease.
Journal: PloS one
August/1/2011
Description

Huntington's disease (HD) is an autosomal dominantly inherited progressive neurodegenerative disease. The exact sequel of events finally resulting in neurodegeneration is only partially understood and there is no established protective treatment so far. Some lines of evidence speak for the contribution of oxidative stress to neuronal tissue damage. The fumaric acid ester dimethylfumarate (DMF) is a new disease modifying therapy currently in phase III studies for relapsing-remitting multiple sclerosis. DMF potentially exerts neuroprotective effects via induction of the transcription factor "nuclear factor E2-related factor 2" (Nrf2) and detoxification pathways. Thus, we investigated here the therapeutic efficacy of DMF in R6/2 and YAC128 HD transgenic mice which mimic many aspects of HD and are characterized by an enhanced generation of free radicals in neurons. Treatment with DMF significantly prevented weight loss in R6/2 mice between postnatal days 80-90. At the same time, DMF treatment led to an attenuated motor impairment as measured by the clasping score. Average survival in the DMF group was 100.5 days vs. 94.0 days in the placebo group. In the histological analysis on day 80, DMF treatment resulted in a significant preservation of morphologically intact neurons in the striatum as well as in the motor cortex. DMF treatment resulted in an increased Nrf2 immunoreactivity in neuronal subpopulations, but not in astrocytes. These beneficial effects were corroborated in YAC128 mice which, after one year of DMF treatment, also displayed reduced dyskinesia as well as a preservation of neurons. In conclusion, DMF may exert beneficial effects in mouse models of HD. Given its excellent side effect profile, further studies with DMF as new therapeutic approach in HD and other neurodegenerative diseases are warranted.

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Dimethyl fumarate inhibits dendritic cell maturation via nuclear factor κB (NF-κB) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) and mitogen stress-activated kinase 1 (MSK1) signaling.
Journal: The Journal of biological chemistry
November/4/2012
Description

Dimethyl fumarate (DMF) is an effective novel treatment for multiple sclerosis in clinical trials. A reduction of IFN-γ-producing CD4(+) T cells is observed in DMF-treated patients and may contribute to its clinical efficacy. However, the cellular and molecular mechanisms behind this clinical observation are unclear. In this study, we investigated the effects of DMF on dendritic cell (DC) maturation and subsequent DC-mediated T cell responses. We show that DMF inhibits DC maturation by reducing inflammatory cytokine production (IL-12 and IL-6) and the expression of MHC class II, CD80, and CD86. Importantly, this immature DC phenotype generated fewer activated T cells that were characterized by decreased IFN-γ and IL-17 production. Further molecular studies demonstrated that DMF impaired nuclear factor κB (NF-κB) signaling via reduced p65 nuclear translocalization and phosphorylation. NF-κB signaling was further decreased by DMF-mediated suppression of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and its downstream kinase mitogen stress-activated kinase 1 (MSK1). MSK1 suppression resulted in decreased p65 phosphorylation at serine 276 and reduced histone phosphorylation at serine 10. As a consequence, DMF appears to reduce p65 transcriptional activity both directly and indirectly by promoting a silent chromatin environment. Finally, treatment of DCs with the MSK1 inhibitor H89 partially mimicked the effects of DMF on the DC signaling pathway and impaired DC maturation. Taken together, these studies indicate that by suppression of both NF-κB and ERK1/2-MSK1 signaling, DMF inhibits maturation of DCs and subsequently Th1 and Th17 cell differentiation.

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Dimethylfumarate induces immunosuppression via glutathione depletion and subsequent induction of heme oxygenase 1.
Journal: The Journal of investigative dermatology
April/4/2007
Description

A mixture of different fumaric acid esters (FAE) is established for systemic therapy of psoriasis, a frequent inflammatory skin disease. The main active compound of FAE, however, has not been identified so far, and the mechanisms of activity are only partially understood. We analyzed the impact of FAE on in vitro immune function and aimed to gain knowledge about the mode of action. Dimethylfumarate (DMF) and diethylfumarate (DEF), but not fumaric acid, methylhydrogenfumarate and ethylhydrogenfumarate, exhibited potent depression of inflammatory cytokine secretion (e.g., tumor necrosis factoralpha, IL-12, and IFNgamma) in activated human peripheral blood mononuclear cells. Moreover, solely DMF and DEF inhibited alloreactive T-cell proliferation in mixed leukocyte reaction. Interestingly, these immunosuppressive effects were accompanied by the strong induction of the anti-inflammatory stress protein heme oxygenase 1 (HO-1). Supplementation with exogenous glutathione (GSH), which is known to bind DMF, prevented both HO-1 induction as well as the anti-inflammatory effects of DMF. Moreover, inhibition of HO-1 activity restored the diminished IL-12 and IFNgamma production after FAE treatment. These results suggest that DMF acts as active compound within the FAE mixture and at least partially mediates its immunomodulatory activity by the induction of the anti-inflammatory stress protein HO-1 ascribed to the functional depletion of reduced GSH.

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Manufacturer's response to case reports of PML.
Journal: The New England journal of medicine
May/1/2013
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Hydroxycarboxylic acid receptor 2 mediates dimethyl fumarate's protective effect in EAE.
Journal: The Journal of clinical investigation
June/15/2014
Description

Taken orally, the drug dimethyl fumarate (DMF) has been shown to improve functional outcomes for patients with MS; however, it is unclear how DMF mediates a protective effect. DMF and, more so, its active metabolite, monomethyl fumarate, are known agonists of the hydroxycarboxylic acid receptor 2 (HCA₂), a G protein-coupled membrane receptor. Here, we evaluated the contribution of HCA₂ in mediating the protective effect afforded by DMF in EAE, a mouse model of MS. DMF treatment reduced neurological deficit, immune cell infiltration, and demyelination of the spinal cords in wild-type mice, but not in Hca2⁻/⁻ mice, indicating that HCA₂ is required for the therapeutic effect of DMF. In particular, DMF decreased the number of infiltrating neutrophils in a HCA₂-dependent manner, likely by interfering with neutrophil adhesion to endothelial cells and chemotaxis. Together, our data indicate that HCA₂ mediates the therapeutic effects of DMF in EAE. Furthermore, identification of HCA₂ as a molecular target may help to optimize MS therapy.

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Dimethylfumarate for psoriasis: more than a dietary curiosity.
Journal: Trends in molecular medicine
August/28/2005
Description

Fumaric acid esters (FAEs) have been used for the oral treatment of psoriasis since 1959 and have been registered for this indication in Germany since 1994. Dimethylfumarate (DMF) and its metabolite methylhydrogenfumarate (MHF) are the pharmacologically active compounds, with DMF being the main component of the marketed FAE-mixture. However, the mechanism of action of FAE is yet to be fully understood. It has been shown that DMF inhibits NFkappaB translocation, which leads to (i) the inhibition of pro-inflammatory cytokine production and adhesion molecule expression, (ii) the inhibition of dendritic cell differentiation and, at higher concentrations, (iii) the induction of apoptosis. Recent evidence also shows that these effects are mediated through the interference of the intracellular redox system by DMF. Here, the mode of action of FAE and its clinical use for psoriasis will be discussed.

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Antipsoriatic effect of fumaric acid derivatives. Results of a multicenter double-blind study in 100 patients.
Journal: Journal of the American Academy of Dermatology
June/20/1994
Description

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.

CONCLUSIONS

Fumaric acid derivatives were found to be effective and safe in the treatment of psoriasis.

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Oral treatment for multiple sclerosis.
Journal: The Lancet. Neurology
December/7/2011
Description

BACKGROUND

The armamentarium for the treatment of relapsing-remitting multiple sclerosis (RRMS) is increasing rapidly. Several oral treatments have shown benefit and will generate much interest because of the convenience of such administration. However, availability of convenient oral drugs will not necessarily translate into clinical effectiveness and safety. Here, we provide an interim report about the mechanisms of action, and efficacy and safety results that have been reported since January, 2010, for five new oral drugs. Additionally, we draw attention to issues that neurologists and patients will encounter when considering the use of new oral drugs.

BACKGROUND

Positive results have been reported for five new oral drugs for RRMS--fingolimod, cladribine, teriflunomide, laquinimod, and dimethyl fumarate--in phase 3 studies; a few new oral drugs are likely to be approved for RRMS soon. WHERE NEXT?: Emerging oral treatments are ushering in a new era in the treatment of MS, providing not only new treatment options but also new challenges. Since data for some of the new drugs have not been reported in peer-reviewed journals yet and safety profiles are not yet fully developed, opinions about the use of these new oral drugs in practice are preliminary and tentative. Practice will evolve with time as information and experience accumulates. Of importance will be results from comparator trials, information about management of patients with breakthrough disease, results from long-term safety studies, and results of studies to assess the potential for neuroprotective effects of the new drugs.

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Detoxication enzyme inducers modify cytokine production in rat mixed glial cells.
Journal: Journal of neuroimmunology
September/19/2005
Description

Pro-inflammatory cytokines, e.g. interleukin-1beta (IL-1beta), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFalpha) as well as neurotoxic molecules such as nitric oxide (NO), that are produced and released by activated glial cells, play an important role in inflammation and oxidative stress occurring during Multiple Sclerosis (MS). Reduction of these processes could therefore be of therapeutic interest. Dimethylfumarate (DMF) and sulforaphane (SP) are well known for their detoxicating properties. Furthermore, they have anti-inflammatory effects as shown clinically by the treatment of inflammatory skin diseases. However, their detoxication and anti-inflammatory action on brain-derived cells is unknown. In the present study we have studied, within the same concentration range, the anti-inflammatory and detoxicating effects of DMF and SP on the production and release of mediators of inflammation and detoxication from lipopolysaccharide (LPS) activated primary co-cultures of rat microglial and astroglial cells. DMF and SP attenuated the LPS-induced production and release of TNFalpha, IL-1beta, IL-6 and NO. In addition, DMF and SP increase both mRNA level and activity of NAD(P)H:quinone reductase (NQO-1), a detoxication enzyme, as well as the cellular glutathione content. We conclude that DMF or SP simultaneously can (1) reduce mediators of inflammation and (2) enhance detoxication enzymes in LPS stimulated co-cultures of astroglial and microglial cells. This double-sided effect could potentially be of therapeutic interest.

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