The effect of vesnarinone on TNF alpha 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 (TNF alpha) produced by mitogen stimulated macrophages, and to inhibit phosphodiesterase (PDE) type III in cardiac muscle. TNF alpha and interferon-gamma (IFNgamma) have been implicated in the pathogenesis of autoimmune diseases, and both cytokines are targets for therapeutic intervention. IFNgamma can enhance autoimmune disease through direct effects, and indirectly by priming macrophages to produce TNF alpha. In this study, we demonstrate that while vesnarinone enhances basal TNF alpha levels, it inhibits TNF alpha production in peripheral blood mononuclear cells from multiple sclerosis (MS) patients and healthy donors stimulated with lipopolysaccharide (LPS) or primed with IFNgamma and stimulated with suboptimal doses of LPS. In addition, vesnarinone inhibited TNF alpha production in primary adult human microglial cultures. However, in contrast to rolipram, another TNF alpha inhibiting agent, vesnarinone failed to inhibit TNF alpha 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.
Department of Neurology, University of Maryland at Baltimore, 21201, USA.
H
H
Jiang
B
B
Bielekova
H
H
Okazaki
K
K
Clarence-Smith
K P
KP
Johnson
G
G
Bergey
R
R
Martin
S
S
Dhib-Jalbut
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000956:Antigens, Viral / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007251:Influenza, Human / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D011719:Pyrazines; D011760:Pyrrolidinones / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D020889:Rolipram; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism* / Q000821:virology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D000276:Adjuvants, Immunologic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000956:Antigens, Viral; D008070:Lipopolysaccharides; D011719:Pyrazines; D011760:Pyrrolidinones; D011804:Quinolines; D014409:Tumor Necrosis Factor-alpha; C041667:vesnarinone; D007371:Interferon-gamma; D020889:Rolipram