Combined inhibition of indoleamine 2,3-dioxygenase and nitric oxide synthase modulates neurotoxin release by interferon-gamma-activated macrophages

We evaluated the synthesis of nitric oxide (NO) and of the neurotoxic kynur enine metabolites 3OH-kynurenine and quinolinic acid (QUIN) in interferon-g amma (IFN-gamma-activated macrophages of the murine BAC1.2F5 cell line with the aim of investigating the roles of mononuclear phagocytes in inflammato ry neurological disorders. IFN-gamma induced indoleamine 2,3-dioxygenase (I DO) and NO synthase (NOS) and increased the synthesis of 3OH-kynurenine, QU IN, and NO that accumulated in the incubation medium where they reached neu rotoxic levels. Macrophage exposure to norharmane, an IDO inhibitor, result ed in a decreased formation of not only the kynurenine metabolites but also NO. The inhibition of NO synthesis could not be ascribed to reduced NADPH availability or decreased NOS induction. Norharmane inhibited NOS activity also in coronary vascular endothelial cells and in isolated aortic rings. O ur findings suggest that activated macrophages release large amounts of neu rotoxic molecules and that norharmane may represent a prototype compound to study macrophage involvement in inflammatory brain damage.