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Brain Research Oct 2021Alzheimer's disease (AD) is the leading cause of dementia and a major global health issue. Currently, only limited treatment options are available to patients. One...
INTRODUCTION
Alzheimer's disease (AD) is the leading cause of dementia and a major global health issue. Currently, only limited treatment options are available to patients. One possibility to expand the treatment repertoire is repurposing of existing drugs such as dimethyl fumarate (DMF). DMF is approved for treatment of multiple sclerosis and previous animal studies have suggested that DMF may also have a beneficial effect for the treatment of AD.
METHODS
We used an APPPS1 transgenic model of senile β-amyloidosis and treated female mice orally with DMF in two treatment paradigms (pre and post onset). We quantified learning and memory parameters, β-amyloidosis, and neuroinflammation to determine the potential of DMF as AD therapeutics.
RESULTS
Treatment with DMF had no influence on water maze performance, β-amyloid accumulation, plaque formation, microglia activation, and recruitment of immune cells to the brain. Compared to vehicle-treated animals, oral DMF treatment could not halt or retard disease progression in the mice.
DISCUSSION
Our results do not favour the use of DMF as treatment for AD. While our results stand in contrast to previous findings in other models, they emphasize the importance of animal model selection and suggest further studies to elucidate the mechanisms leading to conflicting results.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloidosis; Animals; Brain; Cognitive Dysfunction; Dimethyl Fumarate; Disease Models, Animal; Female; Hippocampus; Humans; Inflammation; Mice; Mice, Transgenic; Neuroinflammatory Diseases; Peptide Fragments
PubMed: 34233173
DOI: 10.1016/j.brainres.2021.147579 -
Multiple Sclerosis and Related Disorders May 2023Growing evidence has suggested the involvement of gut microbiota in the pathophysiology of multiple sclerosis (MS). Disease-modifying therapies (DMTs) exert a parallel... (Review)
Review
BACKGROUND
Growing evidence has suggested the involvement of gut microbiota in the pathophysiology of multiple sclerosis (MS). Disease-modifying therapies (DMTs) exert a parallel effect on the gut microenvironment with subsequent modulation of the intestinal and systemic immune system. Herein, we summarize the current literature on the effect of DMTs on the gut microbiome and possible implications for MS.
METHODS
All the literature available in PubMed on the effects of DMTs on the gut microbiota composition in patients with MS was reviewed. We used multiple combinations of the following keywords: "multiple sclerosis; demyelinating disease; gut microbiome; microbiome; brain-gut axis; diet; fecal microbiome; disease modifying therapy; immunomodulator; interferon; glatiramer acetate; teriflunomide; dimethyl fumarate; natalizumab; alemtuzumab; anti-CD20; fingolimod". All the original research articles available in English were included in this narrative review.
RESULTS
Ten original full-text articles were considered eligible, including seven case-control and three cohort studies. First-line DMTs, including oral and subcutaneous treatments (dimethyl fumarate, glatiramer acetate, and interferon β 1b) were considered, while a small number of patients with MS were under natalizumab, fingolimod and anti-CD20 treatments.
CONCLUSIONS
Emerging evidence reported changes in the gut microbiome during exposition to DMTs. However, the association between DMTs exposure and microbial changes was mostly indirect, and the results of the different studies needed to be more consistent. The mitigation of methodological bias is necessary for future studies to allow the identification of a "microbial signature" related to MS pathophysiology, the role of DMTs, and possible prognostic implications.
Topics: Humans; Multiple Sclerosis; Immunosuppressive Agents; Fingolimod Hydrochloride; Glatiramer Acetate; Natalizumab; Gastrointestinal Microbiome; Dimethyl Fumarate; Multiple Sclerosis, Relapsing-Remitting
PubMed: 37001407
DOI: 10.1016/j.msard.2023.104671 -
Molecular Biology Reports Sep 2021The poor survival rate and undesirable homing of transplanted stem cells are the major challenges in stem cell therapy. Addressing the challenge would improve the...
BACKGROUND
The poor survival rate and undesirable homing of transplanted stem cells are the major challenges in stem cell therapy. Addressing the challenge would improve the therapeutic efficacy of these cells. Dimethyl fumarate (DMF) is an anti-inflammatory drug that exerts its effects through the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Therefore, its cytoprotective effects on human adipose-derived MSCs (hASCs) against various oxidative stresses have been investigated in this study.
METHODS AND RESULTS
hASCs were cultured with different concentrations of DMF to evaluate the cytotoxicity of DMF on hASCs using Cell Counting Kit-8 (CCK-8). Besides, the migration ability of the cells after DMF treatment was evaluated using the Transwell method. Furthermore, the expression of HO-1 and NQO-1 was determined using RT-PCR. The cytoprotective effects of DMF on hASCs against the oxidative stress caused by HO and Ultra Violet (UV) were evaluated by assessing cell proliferation and apoptosis. Our results demonstrated that under oxidative stress conditions induced by HO and UV, DMF increased the survival rate and proliferation of the cells and prevented apoptosis. Moreover, the expression of HO-1 and NQO-1 was upregulated in hASCs pretreated with DMF which confirms the activation of the Nrf2 pathway. However, DMF significantly decreased migration in hADSCs (P < 0.0001).
CONCLUSION
Our findings indicate that DMF enhances the proliferation capability and viability of hASCs and prevents their apoptosis in harsh stressful microenvironments. However, the applicability of DMF as a cytoprotective factor for the augmentation of hASCs requires in-depth preclinical and clinical studies.
Topics: Adipose Tissue; Apoptosis; Cell Movement; Cell Proliferation; Cells, Cultured; Cytoprotection; Dimethyl Fumarate; Heme Oxygenase-1; Humans; Hydrogen Peroxide; Mesenchymal Stem Cells; NAD(P)H Dehydrogenase (Quinone); NF-E2-Related Factor 2; Oxidative Stress; Protective Agents; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Ultraviolet Rays; Up-Regulation
PubMed: 34426902
DOI: 10.1007/s11033-021-06638-w -
International Immunopharmacology Jul 2021Corneal lymphangiogenesis induced by macrophages played a critical role in corneal allograft rejection (CGR). However, there are few Food and Drug Administration...
Corneal lymphangiogenesis induced by macrophages played a critical role in corneal allograft rejection (CGR). However, there are few Food and Drug Administration (FDA)-approved drugs that target lymphangiogenesis. The aim of our study is to evaluate the effects of dimethyl fumarate (DMF) on corneal allograft survival in rats. Penetrating corneal transplantation was performed in rats. Subconjunctival injections of dimethyl fumarate (20 µg) were administered at the end of the operation and postoperative day 3 to day 11. The clinical signs of corneal allografts were evaluated. Immunohistochemistry, quantitative real-time PCR (qPCR), flow cytometry and western blot were performed respectively. The effects and mechanism of DMF on RAW264.7 cells were determined by qPCR, enzyme-linked immunosorbent assay (ELISA), and western blot in vitro. The results showed that subconjunctival injections of DMF could significantly inhibit corneal lymphangiogenesis and CGR with decreased corneal macrophage infiltration compared with the vehicle group. Moreover, DMF could reduce the mRNA expression of monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), and vascular endothelial growth factor-C (VEGF-C) in the corneal grafts and RAW264.7 macrophages by inhibiting NF-κB activation. Furthermore, compared with the vehicle group, the number of dendritic cells in the ipsilateral cervical lymph nodes of the DMF-treated group was decreased significantly. Collectively, our findings showed that DMF could suppress CGR by inhibiting the macrophage-induced corneal lymphoangiogenesis.
Topics: Allografts; Animals; Conjunctiva; Corneal Transplantation; Dimethyl Fumarate; Graft Rejection; Humans; Immunosuppressive Agents; Injections; Lymphangiogenesis; Mice; RAW 264.7 Cells; Rats; Rats, Sprague-Dawley; Rats, Wistar; Transplantation, Homologous
PubMed: 33823430
DOI: 10.1016/j.intimp.2021.107580 -
CNS Drugs Jan 2020Disease-modifying therapies have now become standard treatment for multiple sclerosis. These include five oral therapies for relapsing-remitting multiple sclerosis,... (Review)
Review
Disease-modifying therapies have now become standard treatment for multiple sclerosis. These include five oral therapies for relapsing-remitting multiple sclerosis, namely fingolimod, dimethyl fumarate, teriflunomide, cladribine, and siponimod, although there is some discrepancy on the relative efficacy and safety of these agents. To gain further insight on these oral agents in relapsing-remitting multiple sclerosis, we performed a narrative review of fingolimod, dimethyl fumarate, teriflunomide, cladribine, and siponimod. We limited the analysis to randomized clinical studies in which a comparator was used (i.e., placebo or other disease-modifying therapy). As relapsing-remitting multiple sclerosis is a chronic disease and treatment is lifelong, long-term outcomes were an additional focus. A total of 37 studies met inclusion criteria: 15 for fingolimod, 8 for dimethyl fumarate, 7 for teriflunomide, 4 for cladribine, and 3 for siponimod. All drugs showed some functional and magnetic resonance imaging benefit in nearly all clinical studies. The reduction in annual relapse rate was similar for fingolimod, dimethyl fumarate, and cladribine, and somewhat greater than for teriflunomide; there is limited information on the annual relapse rate for siponimod. For all drugs, the benefits reported at short follow-up times are broadly consistent with those seen at longer follow-up times. For fingolimod and dimethyl fumarate, there was a definite trend towards a progressively lower annual relapse rate with continuing treatment. The safety profile of all five drugs was considered to be acceptable, even after extended treatment. While these results should be treated with caution, they highlight that future head-to-head studies are needed to better understand the long-term benefits of disease-modifying therapies. Such information will be of value when considering the risk-benefit profile of these oral therapies.
Topics: Administration, Oral; Disease Progression; Humans; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Recurrence
PubMed: 31898276
DOI: 10.1007/s40263-019-00691-7 -
Pharmaceutics Dec 2022(1) Background: In their 60-year history, dimethyl fumarate and other salts of fumaric acid have been used for the treatment of psoriasis and other immune-mediated... (Review)
Review
(1) Background: In their 60-year history, dimethyl fumarate and other salts of fumaric acid have been used for the treatment of psoriasis and other immune-mediated diseases for their immune-modulating properties. Over the years, new mechanisms of action have been discovered for this evergreen drug that remains a first-line treatment for several different inflammatory diseases. Due to its pleiotropic effects, this molecule is still of great interest in varied conditions, not exclusively inflammatory diseases. (2) Methods: The PubMed database was searched using combinations of the following keywords: dimethyl fumarate, pharmacokinetics, pharmacodynamics, adverse effects, psoriasis, multiple sclerosis, and clinical indications. This article reviews and updates the pharmacokinetics, mechanisms of action, and clinical indications of dimethyl fumarate. (3) Conclusions: The pharmacology of dimethyl fumarate is complex, fascinating, and not fully known. Progressive insights into the molecule's mechanisms of action will make it possible to maximize its clinical efficacy, reduce concerns about adverse effects, and find other possible areas of application.
PubMed: 36559226
DOI: 10.3390/pharmaceutics14122732 -
Molecular Vision 2019Dimethyl fumarate (DMF) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of relapsing-remitting multiple sclerosis (RRMS), a...
PURPOSE
Dimethyl fumarate (DMF) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of relapsing-remitting multiple sclerosis (RRMS), a demyelinating autoimmune disease characterized by acute episodes of motor, sensory, and cognitive symptoms. Optic neuritis is an episodic sequela experienced by some patients with RRMS that typically presents as acute, monocular vision loss. Episodes of optic neuritis damage and kill retinal ganglion cells (RGCs), and can culminate in permanent vision loss. The purpose of these studies was to evaluate the capacity of DMF to mitigate optic neuritis. The work presented combines studies of a mouse model of MS and a retrospective chart analysis of files of patients with RRMS treated at the MS Center of Excellence within the Oklahoma Medical Research Foundation.
METHODS
Experimental autoimmune encephalomyelitis (EAE) is a well-established mouse model that recapitulates cardinal features of somatic and visual MS pathologies. EAE was induced in female C57BL/6J mice by inoculation with myelin oligodendrocyte glycoprotein peptide (residues 35-55; MOG). DMF or vehicle was administered twice a day by oral gavage. Visual acuity was measured longitudinally with optokinetic tracking. Post-mortem analyses included quantification of RGCs in retinal flatmounts and quantitative PCR (qPCR) of target genes and regulators of myelin. Retrospective chart analyses were performed using data obtained from deidentified files of patients with RRMS.
RESULTS
In the EAE mouse studies, DMF decreased optic neuritis severity, preserved vision and RGCs, and concomitantly reduced motor deficits when administered by two different treatment regimens (prevention or interventional). DMF was more efficacious when administered as an interventional therapy, and the beneficial effects occurred independently of the induction of target genes. A complementary retrospective chart analysis demonstrated that DMF increased the time to a recurrence of optic neuritis, and protected against subsequent bouts of optic neuritis.
CONCLUSIONS
This work underscores the potential of DMF to mitigate the severity and recurrence of optic neuritis episodes in patients with RRMS.
Topics: Animals; Dimethyl Fumarate; Eye Proteins; Female; Male; Mice, Inbred C57BL; Motor Activity; Optic Neuritis; Retinal Ganglion Cells; Vision, Ocular; Visual Acuity
PubMed: 31523122
DOI: No ID Found -
Journal of Alzheimer's Disease : JAD 2022Dimethyl fumarate (DMF) has been approved for clinical treatment of multiple sclerosis based on its antioxidant and anti-inflammatory effects by activating the Nrf2...
BACKGROUND
Dimethyl fumarate (DMF) has been approved for clinical treatment of multiple sclerosis based on its antioxidant and anti-inflammatory effects by activating the Nrf2 pathway. Since both oxidative stress and inflammation are involved in Alzheimer's disease (AD), DMF is a potential therapeutic option for AD.
OBJECTIVE
This study aims to test the therapeutic effects of DMF on AD model mice and to reveal its underlying molecular mechanisms.
METHODS
Cell viability assay and in vitro immunofluorescence imaging were used to evaluate the antioxidant effect of DMF on embryonic mouse hippocampal neurons. Behavioral test and brain magnetic resonance imaging were used to assess the therapeutic effects of DMF on spatial learning and memory as well as hippocampal volume in AD model mice with and without Nrf2 knockdown. Western blotting was used to analyze the expression of antioxidant enzymes and molecules associated with AD-related pathological pathways.
RESULTS
DMF inhibits reactive oxygen species overproduction and protects neurons without Nrf2 knockdown from death. DMF reduces amyloid-β induced memory impairment and hippocampal atrophy in AD model mice rather than in Nrf2 knockdown AD mice. DMF delays the progression of AD by activating the Nrf2 pathway to enhance the expression of downstream antioxidant enzymes and inhibits lipid peroxidation, apoptosis, inflammation, mitochondrial dysfunction and amyloid-β deposition.
CONCLUSION
These results indicate that DMF is a potential therapeutic option for AD through its antioxidant, anti-inflammatory, anti-apoptotic, and other anti-AD effects by activating the Nrf2 pathway.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Cell Survival; Dimethyl Fumarate; Disease Models, Animal; Hippocampus; Inflammation; Male; Memory Disorders; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; NF-kappa B; Neurons; Oxidative Stress; Protective Agents; Reactive Oxygen Species
PubMed: 34842188
DOI: 10.3233/JAD-215074 -
Neurotherapeutics : the Journal of the... Sep 2023In the absence of head-to-head comparison trials, we aimed to compare the effectiveness of two largely prescribed oral platform disease-modifying treatments for... (Meta-Analysis)
Meta-Analysis
In the absence of head-to-head comparison trials, we aimed to compare the effectiveness of two largely prescribed oral platform disease-modifying treatments for relapsing-remitting multiple sclerosis, namely, dimethyl fumarate (DMF) and teriflunomide (TRF). We searched scientific databases to identify real-world studies reporting a direct comparison of DMF versus TRF. We fitted inverse-variance weighted meta-analyses with random effects models to estimate the risk ratio (RR) of relapse, confirmed disability worsening (CDW), and treatment discontinuation. Quantitative synthesis was accomplished on 14 articles yielding 11,889 and 8133 patients treated with DMF and TRF, respectively, with a follow-up ranging from 1 to 2.8 years. DMF was slightly more effective than TRF in reducing the short-term relapse risk (RR = 0.92, p = 0.01). Meta-regression analyses showed that such between-arm difference tends to fade in studies including younger patients and a higher proportion of treatment-naïve subjects. There was no difference between DMF and TRF on the short-term risk of CDW (RR = 0.99, p = 0.69). The risk of treatment discontinuation was similar across the two oral drugs (RR = 1.02, p = 0.63), but it became slightly higher with DMF than with TRF (RR = 1.07, p = 0.007) after removing one study with a potential publication bias that altered the final pooled result, as also confirmed by a leave-one-out sensitivity analysis. Discontinuation due to side effects and adverse events was reported more frequently with DMF than with TRF. Our findings suggest that DMF is associated with a lower risk of relapses than TRF, with more nuanced differences in younger naïve patients. On the other hand, TRF is associated with a lower risk of treatment discontinuation for side effects and adverse events.
Topics: Humans; Dimethyl Fumarate; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Recurrence
PubMed: 37528262
DOI: 10.1007/s13311-023-01416-x -
Multiple Sclerosis and Related Disorders Nov 2020The safety profile of dimethyl fumarate (DMF) for multiple sclerosis (MS) is not fully understood. (Meta-Analysis)
Meta-Analysis
BACKGROUND
The safety profile of dimethyl fumarate (DMF) for multiple sclerosis (MS) is not fully understood.
OBJECTIVE
To systematically review the literature for adverse events (AE) associated with DMF for MS.
METHODS
We searched MEDLINE, EMBASE, CINAHL, Web of Science, CENTRAL, and clinicaltrials.gov for articles published from database inception to May/2019. Studies (observational and randomized controlled trials (RCTs)) reporting AEs, serious AEs (SAE), or discontinuation due to AEs were included. We summarized the proportion of DMF-exposed patients affected and calculated the risk ratios (RR) and number needed to treat for an additional harmful outcome (NNTH) and 95% confidence intervals (CI) for the DMF relative to placebo-exposed participants. RCT findings were pooled via meta-analyses.
RESULTS
Twenty-one observational studies, 4 RCTs, 1 RCT extension study, and 2 open-label studies were included, totalling 12,380 MS patients on DMF followed for an average of 19.8 months. Compared to placebo, DMF-exposed patients had a higher risk of grade III/IV lymphopenia (NNTH = 28.8;95%CI:20.2-50.5), pruritus (NNTH = 22.1;95%CI:14.0-52.3), flushing (NNTH = 3.7;95%CI:3.3-4.1), gastrointestinal related events (NNTH = 5.7;95%CI:3.5-15.7), nausea (NNTH = 23.4;95%CI:14.9-54.7), diarrhea (NNTH = 21.2;95%CI:13.6-47.6), and abdominal pain (NNTH = 19.2;95%CI:12.9-37.9). Patients discontinued DMF because of GI symptoms (498/5619;8.9%), lymphopenia (163/4003;4.1%), and flushing (173/4779;3.6%). From pooled analyses of 4 RCTs, AE risks were higher in the DMF versus placebo groups (RR = 1.37;95%CI:1.27-1.48), but SAEs were similar (RR = 1.01;95%CI:0.77-1.33).
CONCLUSION
Over the short-term, DMF was associated with a higher risk of AEs. The NNTH included 4 for flushing, 6 for gastrointestinal complaints, and 29 for severe or life-threatening (grade III/IV) lymphopenia. The longer-term safety of DMF, including consequences of lymphopenia remain unknown.
Topics: Dimethyl Fumarate; Humans; Multiple Sclerosis
PubMed: 33296968
DOI: 10.1016/j.msard.2020.102566