Figure 1.

Fumarates and proposed immune modulation mechanisms. Fumaric acid is a Krebs cycle intermediate, wherein, succinic and malic acids are precursor and product, respectively. DMF forms monomethyl fumarate, which crosses the BBB, and is speculated to subdue inflammation by two mechanisms: (1) NFκB pathway: When glutathione thio-succinate adduct complexes NFκB, it is expected to block the synthesis of TNF-α and other proinflammatory cytokines and prevents cell apoptosis, and (2) NrF2 pathway: When glutathione thio-succinate adduct complexes NrF2 it suppresses inflammatory cytokine syntheses and stimulates the production of antioxidants (catalase, glutathione, and superoxide dismutase, etc.) which then quench reactive oxygen and nitrogen free radicals and reduce oxidative stress. Prolonged use of DMF causes leukocytopenia. As opposed to wide spread immune suppression, as seen with steroids, immune modulation is considered targeted therapy because it acts on few physiological defenses. Coenzyme-A adds to fumarate by 1,2-addition (acylation, reaction B) and not by conjugate, 1,4-addition (reaction A). The resulting fumarate-, malate-, or succinyl-CoA adducts form normal Krebs cycle metabolites [13,14,24,25,26,27,28,29,30,31,32].