The Unique Anti-inflammatory, Antioxidative Mechanism of Dimethyl Fumarate in Multiple Sclerosis
Fumaric acid esters (FAEs) are a known component of a centuries-old herbal medicine, have been used for over 50 years as a topical treatment for psoriasis, and most recently, have demonstrated efficacy in treating relapsing- remitting multiple sclerosis.
The unique mechanism of action of dimethyl fumarate (DMF) and its long history of use have made the DMF an attractive option for many patients. DMF belongs to a class of molecules known as fumaric acid esters (FAEs). FAEs are a known component of a centuries-old herbal medicine, have been used for over 50 years as a topical treatment for psoriasis, and most recently, have demonstrated efficacy in treating relapsing-remitting multiple sclerosis.1,2
Esters of fumarate are found in the leaves of the herb Fumaria officinalis, which is an herbal remedy recognized by the European Medicines Agency for its historical use as a diuretic, and as a remedy for eczema, asthma, and gastrointestinal disorders. It should be noted, however, that a variety of other compounds, including alkaloids, are found in this herb and it has no FDA-approved indications for use as a treatment for any medical condition.2
However, due to its historical use as an herbal remedy, in the 1950s, a chemist in Germany (Schweckendiek) isolated fumaric acid from the plant and tested its efficacy in the treatment of psoriasis, which (like MS) is an autoimmune disorder. In treating psoriasis, Schweckendiek found that FAEs were effective when used topically, and also when used orally.3
Not only are FAEs orally bioavailable, but the long history of use of FAEs, and emerging evidence of neuroprotective effects, make these agents desirable options for patients seeking a long-term maintenance treatment for MS.3
Mechanisms of Neuroprotection
FAEs exert several pharmacologic effects, including induction of T-cell apoptosis, reduction of CD4+ and CD8+ lymphocyte levels, and activation of antioxidative pathways.3-5 The neuroprotective effect of dimethyl fumarate (DMF) and its active metabolite, monomethyl fumarate (MMF) has been investigated through in vitro studies of living neurons.6
In Germany, investigators (Albrecht et al) recorded changes in expression of transcription factors with exposure of neurons to DMF and MMF. These changes in gene expression include upregulation of an antioxidative pathway known as the nuclear factor erythroid 2—related factor 2 (NRF2) pathway. NRF2 is a transcription factor that moves into the nucleus of cells and stimulates production of the antioxidant glutathione in cells (see Figure 2). Studies show that the presence of DMF and MMS stimulates the production of NRF2 and leads to measureable increases in glutathione levels in neurons at levels that protected neuronal cells from cytokine-induced degeneration.6
Neurons rely on oxidative pathways to maintain the electrical energy potentials necessary for neuronal functioning. To find out whether or not electrical signaling between neurons was affected by DMF, Albrecht and colleagues measured changes in the activity of neurons grown on an array of 64 electrodes. Electrical signals were measured before and after exposure of the cells to DMF. Even at high levels of exposure to DMF, both the frequency of electrical signaling and the intervals between electrical signals transmitted between neurons remained unchanged.6
Another study in Germany by Shilling et al shows not only an antioxidative effect of DMF, but a possible effect on improving the integrity of the blood-brain barrier. In an experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis, FAE reduced levels of the inflammatory cytokine IL-10 and slowed infiltration of lymphocytes into the central nervous system.7
Some researchers believe that the antioxidative effects induced by DMF may be neuroprotective.3 Biogen Idec’s Tecfidera (delayed-release DMF), has received FDA approval for patients with relapsing-remitting MS. Approval in the European Union is pending.3-5
Conclusion
Clinical trials with Tecfidera show reductions in MS-related brain lesions that scientists detected by injection of gadolinium contrast dye. Despite this benefit, it is important to note that serious potential adverse events are possible, including lymphopenia. In addition, with use of a topical formulation of DMF that has been available since 1994, at least 4 patients have experienced progressive multifocal leukoencephalopathy (PML). However, according to the package insert, PML has never been recorded in association with use of Tecfidera.3
The dual action of Tecfidera as a neuroprotective and anti-inflammatory agent, combined with the long history of use of DMF as a topical agent for psoriasis, have made Tecfidera an attractive option for people with relapsing-remitting MS. Demand for Tecfidera has grown quickly since March 2013, when Biogen Idec was granted approval.3,5
References:
1. Freedman MS, Hughes B, Mikol DD, et al. Efficacy of disease-modifying therapies in relapsing remitting multiple sclerosis: a systematic comparison. Eur Neurol. 2008;60(1):1-11.
2. European Medicines Agency. Assessment report on Fumaria officinalis. Accessed May 2014.
3. Salmen A, Gold R. Mode of action and clinical studies with fumarates in multiple sclerosis. Exp Neurol. 2014:1-21.
4. TECFIDERA (dimethyl fumarate) delayed-release capsules [package insert]. Cambridge, MA: Biogen Idec Inc; 2013.
5. Biogen Idec’s Q4 profit, sales surge, led by performance of Tecfidera. FirstWord Pharma website. Accessed May 2014.
6. Albrecht P, Bouchachia I, Goebels N, et al. Effects of dimethyl fumarate on neuroprotection and immunomodulation. J Neuroinflammation. 2012;9:163.
7. Schilling S, Goelz S, Linker R, Luehder F, Gold R. Fumaric acid esters are effective in chronic experimental autoimmune encephalomyelitis and suppress macrophage infiltration. Clin Exp Immunol. 2006;145(1):101-107.
