Anti-Inflammatory Dimethylfumarate: A Potential New Therapy for Asthma?

Seidel, Petra; Roth, Michael

doi:10.1155/2013/875403

Cited by 33 publications

(29 citation statements)

References 109 publications

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“…In conclusion, our data show that DMF, but none of the other FAEs, induces apoptosis in human mast cells, which appears to be primarily mediated via the mitochondrial apoptotic pathway. Our findings may in part explain the therapeutic as well as side effects of FAEs in psoriasis and multiple sclerosis and may serve to develop new treatment strategies for other diseases associated with mast cells .…”

Section: Discussionmentioning

confidence: 82%

Dimethylfumarate induces apoptosis in human mast cells

Förster

Preussner

Seeger

et al. 2013

Experimental Dermatology

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Mast cells modulate autoimmune diseases such as psoriasis and multiple sclerosis. Fumaric acid esters (FAEs) are widely used for the treatment of psoriasis, and dimethylfumarate (DMF) has recently been approved for multiple sclerosis. In this study, we analysed the cytotoxic effect of FAEs on human mast cells. Specifically, cell death was analysed in the human mast cell line HMC-1 and in primary cord blood-derived mast cells (CBMCs) after incubation with fumaric acid (FA), monomethylfumarate (MMF), DMF and calcium bis(monomethylfumarate) (Ca-MF). Our data show that only DMF potently induces apoptotic cell death in HMC-1 cells and CBMCs. DMF-mediated apoptosis was associated with increased expression of Bax and Bak and activation of caspase-9 and caspase-6. Interestingly, DMF also enhanced the sensitivity of CBMCs towards TRAIL- and dexamethasone-induced apoptosis. These findings demonstrate for the first time that DMF induces apoptosis of human mast cells, primarily via the mitochondrial apoptotic pathway. Our study contributes to the understanding of the beneficial effects of FAEs in autoimmune diseases and provides a rationale for exploiting FAEs for other diseases associated with mast cells.

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Section: Discussionmentioning

confidence: 82%

Dimethylfumarate induces apoptosis in human mast cells

Förster

Preussner

Seeger

et al. 2013

Experimental Dermatology

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“…Both DMF and MMF (and fumarate if it were present) covalently modify KEAP1, which results in an accumulation of NRF2, leading to up-regulation of the transcriptional NRF2 signature (11). The immune modulatory effect of DMF has been exploited for other autoimmune diseases such as psoriasis (2), lupus erythematosus (69), asthma, and arthritis (63). Very importantly, DMF is an approved drug for relapsing-remitting multiple sclerosis as an oral formulation termed BG-12.…”

Section: Innovationmentioning

confidence: 99%

Repurposing the NRF2 Activator Dimethyl Fumarate as Therapy Against Synucleinopathy in Parkinson's Disease

Lastres‐Becker

García-Yagüe

Scannevin

et al. 2016

Antioxidants & Redox Signaling

219

223

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Aims: This preclinical study was aimed at determining whether pharmacological targeting of transcription factor NRF2, a master controller of many homeostatic genes, might provide a disease-modifying therapy in the animal model of Parkinson's disease (PD) that best reproduces the main hallmark of this pathology, that is, a-synucleinopathy, and associated events, including nigral dopaminergic cell death, oxidative stress, and neuroinflammation. Results: Pharmacological activation of NRF2 was achieved at the basal ganglia by repurposing dimethyl fumarate (DMF), a drug already in use for the treatment of multiple sclerosis. Daily oral gavage of DMF protected nigral dopaminergic neurons against a-SYN toxicity and decreased astrocytosis and microgliosis after 1, 3, and 8 weeks from stereotaxic delivery to the ventral midbrain of recombinant adeno-associated viral vector expressing human a-synuclein. This protective effect was not observed in Nrf2-knockout mice. In vitro studies indicated that this neuroprotective effect was correlated with altered regulation of autophagy markers SQTSM1/p62 and LC3 in MN9D, BV2, and IMA 2.1 and with a shift in microglial dynamics toward a less pro-inflammatory and a more wound-healing phenotype. In postmortem samples of PD patients, the cytoprotective proteins associated with NRF2 expression, NQO1 and p62, were partly sequestered in Lewy bodies, suggesting impaired neuroprotective capacity of the NRF2 signature. Innovation: These experiments provide a compelling rationale for targeting NRF2 with DMF as a therapeutic strategy to reinforce endogenous brain defense mechanisms against PD-associated synucleinopathy. Conclusion: DMF is ready for clinical validation in PD. Antioxid. Redox Signal. 25, 61-77.

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“…Dimethyl fumarate (DMF), is shown to possess anti-inflammatory 16 property that can be explored to target the cellular inflammatory response pathway 6 and protect against oxidative stress in patients with COPD 17 . DMF is a fumaric acid ester known for its therapeutic activity in treating multiple sclerosis (MS) and psoriasis.…”

Section: Introductionmentioning

confidence: 99%

Microparticulate/nanoparticulate powders of a novel Nrf2 activator and an aerosol performance enhancer for pulmonary delivery targeting the lung Nrf2/Keap-1 pathway

Muralidharan

Hayes

Black

et al. 2016

Mol. Syst. Des. Eng.

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This systematic and comprehensive study reports for the first time on the successful rational design of advanced inhalable therapeutic dry powders containing dimethyl fumarate, a first-in-class Nrf2 activator drug to treat pulmonary inflammation, using particle engineering design technology for targeted delivery to the lungs as advanced spray dried (SD) one-component DPIs. In addition, two-component co-spray dried (co-SD) DMF:D-Man DPIs with high drug loading were successfully designed for targeted lung delivery as advanced DPIs using organic solution advanced spray drying in closed mode. Regional targeted deposition using design of experiments (DoE) for in vitro predictive lung modeling based on aerodynamic properties was tailored based on composition and spray drying parameters. These findings indicate the significant potential of using D-Man in spray drying to improve particle formation and aerosol performance of small molecule with a relatively low melting point. These respirable microparticles/nanoparticles in the solid-state exhibited excellent aerosol dispersion performance with an FDA-approved human DPI device. Using in vitro predictive lung deposition modeling, the aerosol deposition patterns of these particles show the capability to reach lower airways to treat inflammation in this region in pulmonary diseases such as acute lung injury (ALI), chronic obstructive pulmonary disease (COPD), pulmonary hypertension (PH), and pulmonary endothelial disease.

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Anti-Inflammatory Dimethylfumarate: A Potential New Therapy for Asthma?

Cited by 33 publications

References 109 publications

Dimethylfumarate induces apoptosis in human mast cells

Dimethylfumarate induces apoptosis in human mast cells

Repurposing the NRF2 Activator Dimethyl Fumarate as Therapy Against Synucleinopathy in Parkinson's Disease

Microparticulate/nanoparticulate powders of a novel Nrf2 activator and an aerosol performance enhancer for pulmonary delivery targeting the lung Nrf2/Keap-1 pathway

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