Insight into the mechanism of action of dimethyl fumarate in multiple sclerosis

Yadav, Sudhir Kumar; Soin, Devika; Ito, Kouichi; Dhib‐Jalbut, Suhayl

doi:10.1007/s00109-019-01761-5

Cited by 53 publications

(43 citation statements)

References 91 publications

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“…In patients, Dimethyl fumarate (Tecfidera) decreased B cell CD40 expression (disrupted B-cell activation), decreased memory T cells, and decreased T cell proliferation and activation; resulting in lymphopenia (Linker and Gold, 2013). The mechanism of action of dimethyl fumarate within the CNS involves both Nrf-2-dependent as well as independent pathways for neuroprotection involving diminished neuroinflammation (Mills et al, 2018;Yadav et al, 2019). The Nrf2-dependent pathway promotes neuroprotection, oligodendrocyte survival, and decreases astrocyte activation (Linker et al, 2011;Kalinin et al, 2013;Wang et al, 2015;Zarrouk et al, 2017).…”

Section: Ms Patient Therapeuticsmentioning

confidence: 99%

Pre-clinical and Clinical Implications of “Inside-Out” vs. “Outside-In” Paradigms in Multiple Sclerosis Etiopathogenesis

Titus

Chen

Podojil

et al. 2020

Front. Cell. Neurosci.

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Multiple Sclerosis (MS) is an immune-mediated neurological disorder, characterized by central nervous system (CNS) inflammation, oligodendrocyte loss, demyelination, and axonal degeneration. Although autoimmunity, inflammatory demyelination and neurodegeneration underlie MS, the initiating event has yet to be clarified. Effective disease modifying therapies need to both regulate the immune system and promote restoration of neuronal function, including remyelination. The challenge in developing an effective long-lived therapy for MS requires that three disease-associated targets be addressed: (1) self-tolerance must be re-established to specifically inhibit the underlying myelin-directed autoimmune pathogenic mechanisms; (2) neurons must be protected from inflammatory injury and degeneration; (3) myelin repair must be engendered by stimulating oligodendrocyte progenitors to remyelinate CNS neuronal axons. The combined use of chronic and relapsing remitting experimental autoimmune encephalomyelitis (C-EAE, R-EAE) ("outside-in") as well as progressive diphtheria toxin A chain (DTA) and cuprizone autoimmune encephalitis (CAE) ("inside-out") mouse models allow for the investigation and specific targeting of all three of these MSassociated disease parameters. The "outside-in" EAE models initiated by myelin-specific autoreactive CD4 + T cells allow for the evaluation of both myelin-specific tolerance in the absence or presence of neuroprotective and/or remyelinating agents. The "inside-out" mouse models of secondary inflammatory demyelination are triggered by toxin-induced oligodendrocyte loss or subtle myelin damage, which allows evaluation of novel therapeutics that could promote remyelination and neuroprotection in the CNS. Overall, utilizing these complementary pre-clinical MS models will open new avenues for developing therapeutic interventions, tackling MS from the "outside-in" and/or "inside-out".

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Section: Ms Patient Therapeuticsmentioning

confidence: 99%

Pre-clinical and Clinical Implications of “Inside-Out” vs. “Outside-In” Paradigms in Multiple Sclerosis Etiopathogenesis

Titus

Chen

Podojil

et al. 2020

Front. Cell. Neurosci.

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“…The therapeutic efficacy of FAEs appears to be mediated through the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) transcriptional pathway [ 14 , 15 , 16 ] as well as interaction with the anti-inflammatory hydroxycarboxylic acid receptor 2 (HCAR2) [ 17 , 18 ]. The Nrf2 pathway is considered a critical cellular defence system that responds to potentially toxic stimuli via the upregulation of antioxidant and Phase II cytoprotective response genes [ 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Dimethyl Fumarate and Its Esters: A Drug with Broad Clinical Utility?

et al. 2020

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Fumaric acid esters (FAEs) are small molecules with anti-oxidative, anti-inflammatory and immune-modulating effects. Dimethyl fumarate (DMF) is the best characterised FAE and is approved and registered for the treatment of psoriasis and Relapsing-Remitting Multiple Sclerosis (RRMS). Psoriasis and RRMS share an immune-mediated aetiology, driven by severe inflammation and oxidative stress. DMF, as well as monomethyl fumarate and diroximel fumarate, are commonly prescribed first-line agents with favourable safety and efficacy profiles. The potential benefits of FAEs against other diseases that appear pathogenically different but share the pathologies of oxidative stress and inflammation are currently investigated.

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“…Therefore, the pharmacological activation of Nrf2 is a promising therapeutic approach for several chronic diseases, including multiple sclerosis [15]. The utility of Nrf2 activators in the treatment of diabetic nephropathy and pulmonary hypertension was also suggested, and they are currently undergoing clinical trials [16].…”

Section: Introductionmentioning

confidence: 99%

Anti-Inflammatory Activity of Kurarinone Involves Induction of HO-1 via the KEAP1/Nrf2 Pathway

et al. 2020

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Kurarinone, a flavonoid isolated from the roots of Sophora flavescens, was suggested to exert potent antioxidant and immunosuppressive effects. However, the underlying mechanisms remain unclear. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor that regulates the antioxidant defense system with anti-inflammatory activity. In the present study, we demonstrated that kurarinone activated Nrf2 and increased the expression of antioxidant enzymes, including heme oxygenase-1 (HO-1). Mechanistically, kurarinone downregulated the expression of kelch-like ECH-associated protein 1 (KEAP1), subsequently leading to the activation of Nrf2. Kurarinone also inhibited the expression of the inflammatory cytokine, interleukin (IL)-1β, and inducible nitric oxide synthase (iNos) in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. The overexpression of HO-1 suppressed the LPS-induced production of inflammatory mediators in RAW264.7 cells, and the immunosuppressive effects of kurarinone were partially inhibited by a treatment with Tin Protomorphyrin IX (TinPPIX), an inhibitor of HO-1. These results indicate that kurarinone activates the KEAP1/Nrf2 pathway to induce HO-1 expression, thereby exerting immunosuppressive effects.

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Insight into the mechanism of action of dimethyl fumarate in multiple sclerosis

Cited by 53 publications

References 91 publications

Pre-clinical and Clinical Implications of “Inside-Out” vs. “Outside-In” Paradigms in Multiple Sclerosis Etiopathogenesis

Pre-clinical and Clinical Implications of “Inside-Out” vs. “Outside-In” Paradigms in Multiple Sclerosis Etiopathogenesis

Dimethyl Fumarate and Its Esters: A Drug with Broad Clinical Utility?

Anti-Inflammatory Activity of Kurarinone Involves Induction of HO-1 via the KEAP1/Nrf2 Pathway

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