Dimethyl fumarate treatment in multiple sclerosis: Recent advances in clinical and immunological studies

Diaz, Gwendoline Montes; Hupperts, Raymond; Fraussen, Judith; Somers, Veerle

doi:10.1016/j.autrev.2018.07.001

Cited by 86 publications

(55 citation statements)

References 110 publications

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“…Accordingly, many studies suggest the potential cytoprotective role of small molecules as Nrf2 activators in retinal tissues and relative pathologies, such as AMD (Batliwala et al, 2017). With this purpose, we tested in ARPE-19 cells some compounds able to induce Nrf2 pathway (Simoni et al, 2017) (Supplementary Figure 3A), by comparing their effects with DMF, a Nrf2-activator currently used in clinic for multiple sclerosis (Montes Diaz et al, 2018). We show that, similarly to 10 mM DMF, each active hybrid (NIH1, NIH2, and NIH3), at 5 mM concentration, is able to induce an early activation of Nrf2, accompanied by an up-regulation of its own expression ( Figures 3B-D).…”

Section: Discussionmentioning

confidence: 99%

Eye-Light on Age-Related Macular Degeneration: Targeting Nrf2-Pathway as a Novel Therapeutic Strategy for Retinal Pigment Epithelium

et al. 2020

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Age-related macular degeneration (AMD) is a common disease with a multifactorial aetiology, still lacking effective and curative therapies. Among the early events triggering AMD is the deterioration of the retinal pigment epithelium (RPE), whose fundamental functions assure good health of the retina. RPE is physiologically exposed to high levels of oxidative stress during its lifespan; thus, the integrity and well-functioning of its antioxidant systems are crucial to maintain RPE homeostasis. Among these defensive systems, the Nrf2-pathway plays a primary role. Literature evidence suggests that, in aged and especially in AMD RPE, there is an imbalance between the increased pro-oxidant stress, and the impaired endogenous detoxifying systems, finally reverberating on RPE functions and survival. In this in vitro study on wild type (WT) and Nrf2-silenced (siNrf2) ARPE-19 cells exposed to various AMD-related noxae (H 2 O 2 , 4-HNE, MG132 + Bafilomycin), we show that the Nrf2-pathway activation is a physiological protective stress response, leading downstream to an up-regulation of the Nrf2targets HO1 and p62, and that a Nrf2 impairment predisposes the cells to a higher vulnerability to stress. In search of new pharmacologically active compounds potentially useful for AMD, four nature-inspired hybrids (NIH) were individually characterized as Nrf2 activators, and their pharmacological activity was investigated in ARPE-19 cells. The Nrf2 activator dimethyl-fumarate (DMF; 10 mM) was used as a positive control. Three out of the four tested NIH (5 mM) display both direct and indirect antioxidant properties, in addition to cytoprotective effects in ARPE-19 cells under pro-oxidant stimuli. The observed pro-survival effects require the presence of Nrf2, with the exception of the lead compound NIH1, able to exert a still significant, albeit lower, protection even in siNrf2 cells, supporting the concept of the existence of both Nrf2-dependent and independent pathways mediating pro-survival effects. In conclusion, by using some pharmacological tools as well as a reference compound, we dissected the role of the Nrf2-pathway in ARPE-19 stress response, suggesting that the Nrf2 induction represents an efficient defensive strategy to prevent the stressinduced damage.

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Section: Discussionmentioning

confidence: 99%

Eye-Light on Age-Related Macular Degeneration: Targeting Nrf2-Pathway as a Novel Therapeutic Strategy for Retinal Pigment Epithelium

et al. 2020

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“…The exact mechanism by which DMF exerts its beneficial effects has not been fully described, although multiple mechanisms including shifting toward anti-inflammatory immune balance, inhibition of T cell activation, induction of B and T cell apoptosis, inhibition of proinflammatory cytokines, and reduction of memory T cells have all been suggested as contributing factors (Treumer et al, 2003;Longbrake et al, 2016;Schulze-Topphoff et al, 2016;Smith et al, 2017;Montes Diaz et al, 2018a). There have been many clinical and basic science studies of DMF in MS. An excellent and thorough review of the history and mechanism of DMF as an MS therapy was recently published by Montes Diaz et al (2018b).…”

Section: Nrf2 and Msmentioning

confidence: 99%

NRF2 as a Therapeutic Target in Neurodegenerative Diseases

2020

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Increased reactive oxygen species production and oxidative stress have been implicated in the pathogenesis of numerous neurodegenerative conditions including among others Alzheimer's disease, Parkinson's disease, Huntington's disease, Friedrich's ataxia, multiple sclerosis, and stroke. The endogenous antioxidant response pathway protects cells from oxidative stress by increasing the expression of cytoprotective enzymes and is regulated by the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2). In addition to regulating the expression of antioxidant genes, NRF2 has also been shown to exert anti-inflammatory effects and modulate both mitochondrial function and biogenesis. This is because mitochondrial dysfunction and neuroinflammation are features of many neurodegenerative diseases as well NRF2 has emerged as a promising therapeutic target. Here, we review evidence for a beneficial role of NRF2 in neurodegenerative conditions and the potential of specific NRF2 activators as therapeutic agents.

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“…Various disease‐modifying therapies (DMTs) are currently available, and options include injectable drugs such as interferon β, glatiramer acetate and natalizumab, and oral drugs such as dimethyl fumarate, teriflunomide, fingolimod and cladribine. These drugs possess several immunological mechanisms, including restoration of immune balance, reduction of relapse rate and prevention of lesion accumulation on magnetic resonance imaging (MRI) . However, there is no medication that can reverse or prevent the neurological deterioration .…”

Section: Introductionmentioning

confidence: 99%

The efficacy and safety of fingolimod in patients with relapsing multiple sclerosis: A meta‐analysis

Yang

Tian

Chen

et al. 2020

Brit J Clinical Pharma

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Aims The aim of the present meta‐analysis was to evaluate the efficacy and safety of fingolimod in patients with relapsing multiple sclerosis (RMS). Methods PubMed, Embase, the Cochrane Library and http://ClinicalTrials.gov were searched for relevant studies. Two authors independently selected the studies, assessed the risk of bias, and extracted the data. The meta‐analysis was performed in RevMan 5.3 provided by the Cochrane Collaboration. Results Ten studies met the inclusion criteria. In patients with RMS, fingolimod demonstrated a significantly lower annualized relapse rate (0.5 mg/d: mean difference [95% confidence interval] = −0.22 [−0.29 to −0.14]; 1.25 mg/d: −0.26 [−0.36 to −0.16]; 5 mg/d: −0.41 [−0.72 to −0.10]) than placebo. Fingolimod also exhibited a favorable performance on other magnetic resonance imaging outcomes and improved the quality of life in patients. No significant difference was noted in the prevalence of adverse events between the fingolimod treatment group and the placebo/disease‐modifying therapy groups. Conclusions Fingolimod may offer benefits for RMS patients and presents an acceptable safety profile.

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Dimethyl fumarate treatment in multiple sclerosis: Recent advances in clinical and immunological studies

Cited by 86 publications

References 110 publications

Eye-Light on Age-Related Macular Degeneration: Targeting Nrf2-Pathway as a Novel Therapeutic Strategy for Retinal Pigment Epithelium

Eye-Light on Age-Related Macular Degeneration: Targeting Nrf2-Pathway as a Novel Therapeutic Strategy for Retinal Pigment Epithelium

NRF2 as a Therapeutic Target in Neurodegenerative Diseases

The efficacy and safety of fingolimod in patients with relapsing multiple sclerosis: A meta‐analysis

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