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

Abstract

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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“…DMF is a methyl ester of fumaric acid (chemical formula C 6 H 8 O 4 ) that is hydrolysed in the small intestine to the active metabolite monomethyl fumarate [ 5 , 6 , 7 , 8 ]. DMF is a potent activator of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway which modulates inflammation and oxidative stress by upregulating cellular defence mechanisms (i.e., cytoprotection through Phase II antioxidant expression, chiefly superoxide dismutase (SOD1), NAD(P)H quinone oxidoreductase-1 (NQO1) and heme oxygenase-1 (HO-1; Figure 2 ) [ 6 , 7 , 8 , 9 ].…”

“…DMF is a methyl ester of fumaric acid (chemical formula C 6 H 8 O 4 ) that is hydrolysed in the small intestine to the active metabolite monomethyl fumarate [ 5 , 6 , 7 , 8 ]. DMF is a potent activator of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway which modulates inflammation and oxidative stress by upregulating cellular defence mechanisms (i.e., cytoprotection through Phase II antioxidant expression, chiefly superoxide dismutase (SOD1), NAD(P)H quinone oxidoreductase-1 (NQO1) and heme oxygenase-1 (HO-1; Figure 2 ) [ 6 , 7 , 8 , 9 ]. In addition, DMF exerts some of its effects through Nrf2-independent mechanisms: (1) indirect inhibition of the inflammatory mediator, nuclear factor kappa B (NF-κB); and (2) hydroxycarboxylic acid receptor 2 (HCAR2) activation, which modulates immune cell (particularly neutrophil) infiltration, adhesion and chemotaxis, reduces pro-inflammatory cytokine production and inhibits NF-κB ( Figure 2 ) [ 6 , 8 , 9 , 10 , 11 , 12 ].…”

“…In addition, DMF exerts some of its effects through Nrf2-independent mechanisms: (1) indirect inhibition of the inflammatory mediator, nuclear factor kappa B (NF-κB); and (2) hydroxycarboxylic acid receptor 2 (HCAR2) activation, which modulates immune cell (particularly neutrophil) infiltration, adhesion and chemotaxis, reduces pro-inflammatory cytokine production and inhibits NF-κB ( Figure 2 ) [ 6 , 8 , 9 , 10 , 11 , 12 ]. DMF is clinically indicated for Multiple Sclerosis (MS) and psoriasis, diseases characterised by immune dysregulation, inflammation and oxidative stress [ 6 ]. Broadly, DMF treatment of these diseases: (1) Drives anti-inflammatory immune cell composition ( Table 1 ; for a detailed review see [ 13 ]); (2) increases the ratio of anti- to pro-inflammatory cytokines; (3) induces the anti-oxidative and cytoprotective response through Nrf2; and (4) inhibits NF-κB to convert T helper (Th) cells from the Th1/17 subset to the anti-inflammatory Th2 subset [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ].…”

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“…DMF undergoes rapid conversion to its active metabolite, monomethyl fumarate, whose terminal half-life is 1 h [ 6 ]. DMF has been approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) as a drug for the treatment of multiple sclerosis (trade name Tecfidera) and for the treatment of moderate-to-severe plaque psoriasis (trade name Skilarence) [ 7 ]. Methylene blue (MB), a thiazine dye derivative of phenothiazine, has been described as “the first fully synthetic drug used in medicine” [ 8 ] ( Figure 1 B).…”

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“…Topical drugs such as vitamin D derivatives and corticosteroids manage mild to moderate forms [ 6 ]. For more severe forms, systemic treatments such as cyclosporin, apremilast, dimethyl fumarate, or methotrexate were the drugs of choice [ 7 , 8 , 9 , 10 ]. In the last couple of years, biological treatments have been proposed to manage various inflammatory conditions, such as inflammatory bowel disease or psoriasis [ 11 ].…”