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(Journal of Leukocyte Biology. 2000;68:260-266.)
© 2000 by Society for Leukocyte Biology

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

Alberto Chiarugi^*, Persio Dello Sbarba, Alessandro Paccagnini, Sandra Donnini^*, Sandra Filippi^* and Flavio Moroni^*

^* Department of Preclinical and Clinical Pharmacology and
Department of Experimental Pathology and Oncology, University of Florence, Italy

Correspondence: Dr. Flavio Moroni, Dipartimento di Farmacologia Preclinica e Clinica, Università di Firenze, Viale Pieraccini 6, 50139 Firenze, Italy. E-mail: moronif{at}ds.unifi.it

We evaluated the synthesis of nitric oxide (NO) and of the neurotoxic kynurenine metabolites 3OH-kynurenine and quinolinic acid (QUIN) in interferon- (IFN-)-activated macrophages of the murine BAC1.2F5 cell line with the aim of investigating the roles of mononuclear phagocytes in inflammatory neurological disorders. IFN- induced indoleamine 2,3-dioxygenase (IDO) and NO synthase (NOS) and increased the synthesis of 3OH-kynurenine, QUIN, and NO that accumulated in the incubation medium where they reached neurotoxic levels. Macrophage exposure to norharmane, an IDO inhibitor, resulted 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. Our findings suggest that activated macrophages release large amounts of neurotoxic molecules and that norharmane may represent a prototype compound to study macrophage involvement in inflammatory brain damage.

Key Words: neuroinflammation • kynurenine pathway • nitric oxide • quinolinic acid • 3OH-kynurenine

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