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Cold Spring Harbor Perspectives in... Jan 2019Multiple sclerosis treatment faces tremendous changes owing to the approval of new medications, some of which are available as oral formulations. Until now, the four... (Review)
Review
Multiple sclerosis treatment faces tremendous changes owing to the approval of new medications, some of which are available as oral formulations. Until now, the four orally available medications, fingolimod, dimethylfumarate (BG-12), teriflunomide, and cladribine have received market authorization, whereas laquinimod is still under development. Fingolimod is a sphingosine-1-phosphate inhibitor, which is typically used as escalation therapy and leads to up to 60% reduction of the annualized relapse rate, but might also have neuroprotective properties. In addition, there are three more specific S1P agonists in late stages of development: siponimod, ponesimod, and ozanimod. Dimethylfumarate has immunomodulatory and cytoprotective functions and is used as baseline therapy. Teriflunomide, the active metabolite of the rheumatoid arthritis medication leflunomide, targets the dihydroorotate dehydrogenase, thus inhibiting the proliferation of lymphocytes by depletion of pyrimidines. Here we will review the mechanisms of action, clinical trial data, as well as data about safety and tolerability of the compounds.
Topics: Administration, Oral; Cladribine; Clinical Trials as Topic; Crotonates; Dimethyl Fumarate; Fingolimod Hydrochloride; Humans; Hydroxybutyrates; Immunosuppressive Agents; Multiple Sclerosis; Nitriles; Quinolones; Sphingosine 1 Phosphate Receptor Modulators; Toluidines
PubMed: 29500302
DOI: 10.1101/cshperspect.a032011 -
Irish Journal of Medical Science Dec 2022The disease-modifying therapies (DMT), dimethyl fumarate (DMF) and fingolimod (FTY) improve the outcomes in multiple sclerosis (MS) by reducing relapses and numbers and...
OBJECTIVE
The disease-modifying therapies (DMT), dimethyl fumarate (DMF) and fingolimod (FTY) improve the outcomes in multiple sclerosis (MS) by reducing relapses and numbers and volume of lesions. They mediate their effects through reduction of immune reactivation, which may potentially lead to lymphopaenia and increased risk of infections. Previous studies have examined the effects of these therapies on lymphocyte subsets; however, the in vivo effects on circulating lymphocyte proliferation require further elucidation. The aim of this study was to determine the effects of DMF and FTY on T-cell proliferation in patients with MS.
METHOD
We examined T-cell lymphocyte proliferation and lymphocyte subsets in ten patients (five on DMF, five on FTY) before starting DMT and again 4 to 11 months after being maintained on DMT.
RESULTS
In the FTY-treated group, the mean percentage proliferation was significantly lower using both assays (PHA assay mean percentage change - 51.2 ± 25.97, p < 0.05; anti-CD3/CD28 assay mean percentage change - 39.74 ± 27.85, p < 0.05). There was no statistical difference in T-cell lymphocyte proliferation in the DMF-treated group for either assay (PHA, p = 0.316; anti-CD3/CD28, p = 0.373).
CONCLUSIONS
This pilot study suggests that the T-lymphocytes of patients on FTY have an abnormal proliferation response as well as being reduced in the circulation.
Topics: Humans; Fingolimod Hydrochloride; Dimethyl Fumarate; Multiple Sclerosis; CD28 Antigens; Pilot Projects; Immunosuppressive Agents; Treatment Outcome; Lymphocytes; Cell Proliferation
PubMed: 35028898
DOI: 10.1007/s11845-021-02913-8 -
Anesthesia and Analgesia May 2021Complex regional pain syndrome (CRPS) is a highly disabling cause of pain often precipitated by surgery or trauma to a limb. Both innate and adaptive immunological...
BACKGROUND
Complex regional pain syndrome (CRPS) is a highly disabling cause of pain often precipitated by surgery or trauma to a limb. Both innate and adaptive immunological changes contribute to this syndrome. Dimethyl fumarate (DMF) works through the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor and other targets to activate antioxidant systems and to suppress immune system activation. We hypothesized that DMF would reduce nociceptive, functional, and immunological changes measured in a model of CRPS.
METHODS
Male C57BL/6 mice were used in the well-characterized tibial fracture model of CRPS. Some groups of mice received DMF 25 mg/kg/d orally, per os for 3 weeks after fracture versus vehicle alone. Homozygous Nrf2 null mutant mice were used as test subjects to address the need for this transcription factor for DMF activity. Allodynia was assessed using von Frey filaments and hindlimb weight-bearing data were collected. The markers of oxidative stress malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) were quantified in the skin of the fractured mice using immunoassays along with the innate immune system cytokines IL-1β and IL-6. The accumulation of IgM in the fractured limbs and lymph node hypertrophy were used as indexes of adaptive immune system activation, and the passive transfer of serum from wildtype fractured mice to B cell-deficient fractured muMT mice (mice lacking B cells and immunoglobulin) helped to assess the pronociceptive activity of humoral factors.
RESULTS
We observed that oral DMF administration strongly prevented nociceptive sensitization and reduced uneven hindlimb weight bearing after fracture. DMF was also very effective in reducing the accumulation of markers of oxidative stress, activation of innate immune mediator production, lymph node hypertrophy, and the accumulation of IgM in fractured limbs. The sera of fractured vehicle-treated but not DMF-treated mice conferred pronociceptive activity to recipient mice. Unexpectedly, the effects of DMF were largely unchanged in the Nrf2 null mutant mice.
CONCLUSIONS
Oxidative stress and immune system activation are robust after hindlimb fracture in mice. DMF strongly reduces activation of those systems, and the Nrf2 transcription factor is not required. DMF or drugs working through similar mechanisms might provide effective therapy for CRPS or other conditions where oxidative stress causes immune system activation.
Topics: Adaptive Immunity; Analgesics; Animals; Antioxidants; Biomarkers; Complex Regional Pain Syndromes; Dimethyl Fumarate; Disease Models, Animal; Immunity, Innate; Immunosuppressive Agents; Male; Mice, Inbred C57BL; Mice, Knockout; NF-E2-Related Factor 2; Nociception; Oxidative Stress; Tibial Fractures; Mice
PubMed: 33646995
DOI: 10.1213/ANE.0000000000005440 -
Frontiers in Immunology 2019Efficient personalized therapy paradigms are needed to modify the disease course and halt gray (GM) and white matter (WM) damage in patients with multiple sclerosis... (Clinical Trial)
Clinical Trial
Efficient personalized therapy paradigms are needed to modify the disease course and halt gray (GM) and white matter (WM) damage in patients with multiple sclerosis (MS). Presently, promising disease-modifying drugs show impressive efficiency, however, tailored markers of therapy responses are required. Here, we aimed to detect in a real-world setting patients with a more favorable brain network response and immune cell dynamics upon dimethyl fumarate (DMF) treatment. In a cohort of 78 MS patients we identified two thoroughly matched groups, based on age, disease duration, disability status and lesion volume, receiving DMF ( = 42) and NAT ( = 36) and followed them over 16 months. The rate of cortical atrophy and deep GM volumes were quantified. GM and WM network responses were characterized by brain modularization as a marker of regional and global structural alterations. In the DMF group, lymphocyte subsets were analyzed by flow cytometry and related to clinical and MRI parameters. Sixty percent (25 patients) of the DMF and 36% (13 patients) of the NAT group had disease activity during the study period. The rate of cortical atrophy was higher in the DMF group (-2.4%) compared to NAT (-2.1%, < 0.05) group. GM and WM network dynamics presented increased modularization in both groups. When dividing the DMF-treated cohort into patients free of disease activity ( = 17, DMF) and patients with disease activity ( = 25, DMF) these groups differed significantly in CD8+ cell depletion counts (DMF: 197.7 ± 97.1/μl; DMF: 298.4 ± 190.6/μl, = 0.03) and also in cortical atrophy (DMF: -1.7%; DMF: -3.2%, = 0.01). DMF presented reduced longitudinal GM and WM modularization and less atrophy as markers of preserved structural global network integrity in comparison to DMF and even NAT patients. NAT treatment contributes to a reduced rate of cortical atrophy compared to DMF therapy. However, patients under DMF treatment with a stronger CD8+ T cell depletion present a more favorable response in terms of cortical integrity and GM and WM network responses. Our findings may serve as basis for the development of personalized treatment paradigms.
Topics: Adult; Aged; Aged, 80 and over; CD8-Positive T-Lymphocytes; Cerebral Cortex; Dimethyl Fumarate; Female; Gray Matter; Humans; Immunologic Factors; Longitudinal Studies; Male; Middle Aged; Multiple Sclerosis; Nerve Net; White Matter
PubMed: 31417557
DOI: 10.3389/fimmu.2019.01779 -
International Journal of Pharmaceutics Jun 2024The nasal administration route has been studied for the delivery of active molecules directed to the Central Nervous System, thanks to the anatomical connection between...
The nasal administration route has been studied for the delivery of active molecules directed to the Central Nervous System, thanks to the anatomical connection between the nasal cavity and the brain. Dimethyl fumarate is used to treat relapsing-remitting multiple sclerosis, with a role as an immunomodulator towards T- T-cells and a cytoprotector towards neurons and glial cells. Its use in therapy is hindered by its low aqueous solubility, and low stability, due to hydrolysis and sublimation at room temperature. To overcome this limitation, in this study we evaluated the feasibility of using two amorphous β-cyclodextrin derivatives, namely hydroxypropyl β-cyclodextrin and methyl β-cyclodextrin, to obtain a nasally administrable powder with a view to nose-to-brain administration. Initially, the interaction product was studied using different analytical methods (differential scanning calorimetry, Fourier transform infrared spectroscopy and powder X-ray diffraction) to detect the occurrence of binary product formation, while phase solubility analysis was used to probe the complexation in solution. The dimethyl fumarate-cyclodextrin binary product showing best solubility and stability properties was subsequently used in the development of a chitosan-based mucoadhesive nasally administrable powder comparing different preparative methods. The best performance in terms of both hydrolytic stability and DMF recovery was achieved by the powder obtained via freeze-drying.
Topics: Dimethyl Fumarate; Chitosan; Powders; Administration, Intranasal; Drug Stability; beta-Cyclodextrins; Solubility; Brain; 2-Hydroxypropyl-beta-cyclodextrin; Spectroscopy, Fourier Transform Infrared; Calorimetry, Differential Scanning; X-Ray Diffraction
PubMed: 38734272
DOI: 10.1016/j.ijpharm.2024.124216 -
Oncotarget Jul 2017The effects of dimethyl fumarate (DMF) on mycotoxins and animal growth performance are well documented. However, its mechanism of anti-mildew effects is still unknown....
The effects of dimethyl fumarate (DMF) on mycotoxins and animal growth performance are well documented. However, its mechanism of anti-mildew effects is still unknown. The current study investigated how DMF detoxified the mycotoxin and improved the growth performance using BALB/c mice model, especially its effects on intestinal barrier function and gut micro-ecology. Our study also compared with the ultraviolet radiation (UR) treatment, a traditional anti-mildew control (TC). The results indicated that the DMF treatment had a lower contents of mycotoxin, better growth performance and improved mucosal morphology (P < 0.05), accompanied with the decreased intestinal permeability and the tighter gut barrier. Moreover, the efficiency of DMF was better than TC (P < 0.05). 16S rRNA gene sequence analysis revealed that the richness and diversity of bacteria was increased in DMF treatment. The most abundant OTUs belonged to Firmicutes and Bacteroidetes, and their changes in DMF were more moderate than the TC group, suggesting a more stable micro-ecology and the positive impact of DMF on the biodiversity of intestine. Specifically, the increased abundance of bacteria producing short-chain fatty acids (SCFAs), such as Gemella, Roseburia, Bacillus and Bacteroides in DMF group and prebiotics such as Lactobacillus in TC group, suggested a more healthier microbial composition and distribution. These findings supported that DMF had significant effects on animal's growth performance and intestinal barrier function by modulating the pathway of nutrient absorption and increasing the diversity and balance of gut microbes, which also illuminate that DMF is more efficient than traditional anti-mildew method.
Topics: Animal Feed; Animals; Biodiversity; Dimethyl Fumarate; Food Analysis; Immunosuppressive Agents; Intestinal Mucosa; Mice; Models, Animal; Mycotoxins; Ultraviolet Rays
PubMed: 28574825
DOI: 10.18632/oncotarget.17886 -
Experimental and Therapeutic Medicine Dec 2020Lower back pain is a common problem in middle-aged and elderly people, and intervertebral disc degeneration (IVDD) is often the main cause. The present study aimed to...
Lower back pain is a common problem in middle-aged and elderly people, and intervertebral disc degeneration (IVDD) is often the main cause. The present study aimed to explore the effects of dimethyl fumarate (DMF) on inflammation and oxidative stress in the intervertebral disc. C57/BL6 mice were used to construct an IVDD model by tail suspension and daily intraperitoneal injections of 10 mg/kg DMF were administered to analyze the effects of DMF on IVDD. In addition, human nucleus pulposus (NP) cells were cultured and stimulated cells with recombinant human IL-1β and DMF to examine the effects of DMF on inflammation and oxidative stress in NP cells. DMF significantly increased the intervertebral disc height index of mice and inhibited the degradation of the extracellular matrix of mouse NP tissue. In addition, DMF also decreased the expression of inflammatory factors [including IL-6, IL-8, matrix metalloproteinase (MMP)3 and MMP13] in NP cells. In terms of oxidative stress, DMF significantly increased the antioxidative stress response in NP cells and reduced endoplasmic reticulum stress. DMF also increased the activity of the nuclear factor erythroid 2-related factor (Nrf) 2/heme oxygenase (HO)-1 signaling pathway in NP cells and increased the phosphorylation of Akt. DMF also increased the anti-inflammatory and antioxidative ability of NP cells by promoting the activity of the Nrf2/HO-1 and PI3K/Akt signaling pathways, thus delaying IVDD.
PubMed: 33199994
DOI: 10.3892/etm.2020.9399 -
Journal of Neuroinflammation Mar 2018Systemic inflammation is associated with increased cognitive decline and risk for Alzheimer's disease. Microglia (MG) activated during systemic inflammation can cause...
BACKGROUND
Systemic inflammation is associated with increased cognitive decline and risk for Alzheimer's disease. Microglia (MG) activated during systemic inflammation can cause exaggerated neuroinflammatory responses and trigger progressive neurodegeneration. Dimethyl fumarate (DMF) is a FDA-approved therapy for multiple sclerosis. The immunomodulatory and anti-oxidant properties of DMF prompted us to investigate whether DMF has translational potential for the treatment of cognitive impairment associated with systemic inflammation.
METHODS
Primary murine MG cultures were stimulated with lipopolysaccharide (LPS) in the absence or presence of DMF. MG cultured from nuclear factor (erythroid-derived 2)-like 2-deficient (Nrf2 ) mice were used to examine mechanisms of DMF actions. Conditioned media generated from LPS-primed MG were used to treat hippocampal neuron cultures. Adult C57BL/6 and Nrf2 mice were subjected to peripheral LPS challenge. Acute neuroinflammation, long-term memory function, and reactive astrogliosis were examined to assess therapeutic effects of DMF.
RESULTS
DMF suppressed inflammatory activation of MG induced by LPS. DMF suppressed NF-κB activity through Nrf2-depedent and Nrf2-independent mechanisms in MG. DMF treatment reduced MG-mediated toxicity towards neurons. DMF suppressed brain-derived inflammatory cytokines in mice following peripheral LPS challenge. The suppressive effect of DMF on neuroinflammation was blunted in Nrf2 mice. Importantly, DMF treatment alleviated long-term memory deficits and sustained reactive astrogliosis induced by peripheral LPS challenge. DMF might mitigate neurotoxic astrocytes associated with neuroinflammation.
CONCLUSIONS
DMF treatment might protect neurons against toxic microenvironments produced by reactive MG and astrocytes associated with systemic inflammation.
Topics: Animals; CX3C Chemokine Receptor 1; Cells, Cultured; Cytokines; Dimethyl Fumarate; Disease Models, Animal; Green Fluorescent Proteins; Hippocampus; Immunosuppressive Agents; Inflammation; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; NF-E2-Related Factor 2; NF-kappa B; Neurons
PubMed: 29598822
DOI: 10.1186/s12974-018-1125-5 -
Journal of Neuroinflammation Jul 2012Neuronal degeneration in multiple sclerosis has been linked to oxidative stress. Dimethyl fumarate is a promising novel oral therapeutic option shown to reduce disease...
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.
FINDINGS
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.
Topics: Animals; Cell Death; Cells, Cultured; Dimethyl Fumarate; Female; Fumarates; Immunomodulation; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Oxidative Stress; Spleen; Treatment Outcome
PubMed: 22769044
DOI: 10.1186/1742-2094-9-163 -
JCI Insight Oct 2017Sickle cell disease (SCD) results from a point mutation in the β-globin gene forming hemoglobin S (HbS), which polymerizes in deoxygenated erythrocytes, triggering...
Sickle cell disease (SCD) results from a point mutation in the β-globin gene forming hemoglobin S (HbS), which polymerizes in deoxygenated erythrocytes, triggering recurrent painful vaso-occlusive crises and chronic hemolytic anemia. Reactivation of fetal Hb (HbF) expression ameliorates these symptoms of SCD. Nuclear factor (erythroid derived-2)-like 2 (Nrf2) is a transcription factor that triggers cytoprotective and antioxidant pathways to limit oxidative damage and inflammation and increases HbF synthesis in CD34+ stem cell-derived erythroid progenitors. We investigated the ability of dimethyl fumarate (DMF), a small-molecule Nrf2 agonist, to activate γ-globin transcription and enhance HbF in tissue culture and in murine and primate models. DMF recruited Nrf2 to the γ-globin promoters and the locus control region of the β-globin locus in erythroleukemia cells, elevated HbF in SCD donor-derived erythroid progenitors, and reduced hypoxia-induced sickling. Chronic DMF administration in SCD mice induced HbF and increased Nrf2-dependent genes to detoxify heme and limit inflammation. This improved hematological parameters, reduced plasma-free Hb, and attenuated inflammatory markers. Chronic DMF administration to nonanemic primates increased γ-globin mRNA in BM and HbF protein in rbc. DMF represents a potential therapy for SCD to induce HbF and augment vasoprotection and heme detoxification.
Topics: Anemia; Anemia, Sickle Cell; Animals; Antioxidants; Dimethyl Fumarate; Disease Models, Animal; Fetal Hemoglobin; Gene Expression Regulation; Hematopoietic Stem Cells; Heme; Humans; Inflammation; Leukemia, Erythroblastic, Acute; Mice; NF-E2-Related Factor 2; RNA, Messenger; Spleen; gamma-Globins
PubMed: 29046485
DOI: 10.1172/jci.insight.96409