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  • The mechanisms of action of MMF


    The mechanisms of action of MMF and DMF are not well understood, but a growing body of evidence has demonstrated that DMF may act on both the neurodegenerative and inflammatory response of MS patients. The majority of the data related to the mechanism of action of DMF/MMF demonstrates the association of the compounds with the activation of the nuclear factor-(erythroid-derived 2) related factor 2 (Nrf2) pathway. Nrf2 activation leads to a type II antioxidant response, reducing both inflammatory responses and oxidative stress (Linker et al., 2011), which play a major role in demyelination and neurodegeneration in MS. In addition to the Nrf-2 signaling pathway, recent observations demonstrated that MMF/DMF could also downregulate the immune response through a non-Nrf2 related pathway. MMF has been shown to be an agonist of the hydroxycarboxylic PLX-4720 receptor 2 (HCA2) signaling pathway, also known as niacin receptor 1 or nicotinic acid receptor GPR109A (Chen et al., 2014; Parodi et al., 2015; Tang et al., 2008). Thus, it appears that DMF could also activate HCA2/GPR109A in addition to its effects on the Nrf2 pathway (unpublished data, Biogen). In this communication, we discuss DMF/MMF-induced HCA2/GPR109A pathway activation and its implications in the immune response and treatment of MS.
    Conclusions The complete mechanism of action of DMF in the treatment of MS remains to be elucidated. Recent observations highlight the importance of the activation of HCA2/GPR109A pathway by DMF/MMF in the downregulation of the immune response. Binding of DMF or MMF to HCA2/GPR109A on dendritic cells inhibits the production of pro-inflammatory cytokines in vitro and in EAE. There is a possibility that anti-inflammatory responses in intestinal mucosa are activated by DMF or MMF binding to HCA2/GPR109A, which is expressed on the surfaces of both immune cells and gut epithelial cells. Both forms can activate HCA2/GPR109A to differing extents, and therefore this possibility requires more study before an HCA2/GPR109A -mediated GI role for a specific form of fumarate can be determined. Given the extension of the gastrointestinal tract and the amount of cells expressing HCA2/GPR109A in intestinal mucosa, the immunomodulatory response in this compartment is relevant and may contribute to the reduction of tissue damage of CNS in patients with MS.
    Introduction Elevated plasma and tissue concentrations of non-esterified fatty acids (NEFA) and triglycerides are often observed in patients with type 2 diabetes mellitus (T2DM) (DeFronzo, 2004, Paolisso et al., 1995, Reaven and Greenfield, 1981) and are strongly associated with insulin resistance (Boden, 1997, Groop et al., 1989, Groop et al., 1991). Reduction of NEFA concentration in the circulation improves insulin sensitivity and β-cell function, thereby reducing the risk for diabetes (Bajaj et al., 2004, Bergman and Ader, 2000, Dobbins et al., 2013, Fulcher et al., 1992, Kumar et al., 1994, Randle et al., 1963, Worm et al., 1994). Suppression of lipolysis in the adipocytes by nicotinic acid or its analogues acutely improves glucose handling and insulin sensitivity in subjects with T2DM (Bajaj et al., 2004, Dobbins et al., 2013, Fulcher et al., 1992, Kumar et al., 1994, Liang et al., 2013, Santomauro et al., 1999, Worm et al., 1994). This effect is mediated by the G-protein-coupled receptor PLX-4720 109A (GPR109A, also called HCAR2 (hydroxycarboxylic acid receptor 2), Fig. 1) (Soga et al., 2003, Tunaru et al., 2003, Wise et al., 2003). However, GPR109A activation is associated with cutaneous vasodilatation manifested as flushing, due to release of vasodilatory prostanoids from epidermal Langerhans cells (Benyó et al., 2006, Benyó et al., 2005, Kamanna et al., 2009). Furthermore, the mechanism by which GPR109A reduces lipolysis also induces counter-regulatory processes manifested as tolerance development and rebound (Ahlström et al., 2011, Blackard and Heidingsfelder, 1969, Dobbins et al., 2015, Oh et al., 2011, Pereira, 1967, Worm et al., 1994). Thus, development of therapeutic agents that maintain the anti-lipolytic effect of GPR109A activation, but are not associated with the undesired effects of GPR109A, could significantly improve the treatment of T2DM.