Dimethyl fumarate stimulates cyclic AMP production and suppresses production of pro-inflammatory mediators in immune cells (P5143)

Abstract

Abstract Multiple Sclerosis (MS) is a disease of the central nervous system that is characterized by chronic inflammation, demyelination, axonal damage and loss of oligodendrocytes. Current FDA approved therapies are only partially effective, have side-effects and are costly. Thus, there is a need for development of novel treatment alternatives for MS. Of interest is the investigational drug BG-12, also known as dimethyl fumarate (DMF). A phase III clinical trial showed that treatment with BG-12 reduced the annual relapse rate by 53% and decreased disability by 38%. Additionally, BG-12 reduced the number of gadolinium-enhancing lesions by 90%. However, the mechanisms of action of BG-12 are not fully understood. BG-12 is an activator of the nuclear factor (erythroid-derived 2)-like 2 (NRF2) transcriptional pathway. To determine if BG-12 is able to activate other signaling cascades, we treated human peripheral blood mononuclear cells with DMF. We discovered that DMF stimulates cAMP production by approximately 3.5 after 1 minute treatment in vitro. DMF also suppresses the production of interleukin (IL)-2, IL-17, regulated and normal T cell expressed and secreted (RANTES) and tumor necrosis factor (TNF)-α in these cells. Furthermore, inhibitor studies indicate that adenylyl cyclases mediate DMF induced cAMP production. These novel findings suggest that DMF may inhibit immune cell function via the cAMP signaling pathway and has implications for MS therapy.