The effect of vesnarinone on TNFα production in human peripheral blood mononuclear cells and microglia: A preclinical study for the treatment of multiple sclerosis

Vesnarinone (OPC-8212) is a synthetic quinolinone derivative with inotropic and immunomodulatory effects. Vesnarinone has been shown to inhibit tumor necrosis factor-alpha (TNFα) produced by mitogen stimulated macrophages, and to inhibit phosphodiesterase (PDE) type III in cardiac muscle. TNFα and interferon-gamma (IFNγ) have been implicated in the pathogenesis of autoimmune diseases, and both cytokines are targets for therapeutic intervention. IFNγ can enhance autoimmune disease through direct effects, and indirectly by priming macrophages to produce TNFα. In this study, we demonstrate that while vesnarinone enhances basal TNFα levels, it inhibits TNFα production in peripheral blood mononuclear cells from multiple sclerosis (MS) patients and healthy donors stimulated with lipopolysaccharide (LPS) or primed with IFNγ and stimulated with suboptimal doses of LPS. In addition, vesnarinone inhibited TNFα production in primary adult human microglial cultures. However, in contrast to rolipram, another TNFα inhibiting agent, vesnarinone failed to inhibit TNFα production by myelin basic protein specific T-cell lines. As oral TNF inhibitors are currently being considered in the USA for clinical application in MS, the implications of our findings on the development of vesnarinone for treatment of MS are discussed.