Inducible nitric oxide synthase and nitrotyrosine in the central nervous system of mice chronically infected with Trypanosoma brucei brucei

Human African trypanosomiasis, or sleeping sickness, evolves toward a menin goencephalitic stage, with a breakage in the blood-brain barrier, perivascu lar infiltrates, and astrocytosis. The involvement of nitric oxide (NO) has been evoked in the pathogenic development of the illness, since NO was fou nd to be increased in the brain of animals infected with Trypanosoma brucei (T b.) brucei. An excessive NO production can lead to alterations of neuro nal signaling and to cell damage through the cytotoxicity of NO and its der ivatives, especially peroxynitrites. In African trypanosomiasis, the sites of NO production and its role in the pathogenicity of lesions in the centra l nervous system (CNS) are unknown. In a chronic model of African trypanoso miasis (mice infected with T. b, brucei surviving with episodic suramin adm inistration), NADPH-diaphorase staining of brain slides revealed that NO sy nthase (NOS) activity is located not only in endothelial cells, choroid ple xus ependymal cells, and neurons as in control mice but also in mononuclear inflammatory cells located in perivascular and parenchyma infiltrates, An immunohistochemical study showed that the mononuclear inflammatory cells ex pressed an inducible NOS activity. Furthermore, the presence of nitrotyrosi ne in inflammatory lesions demonstrated an increased NO production acid the intermediate formation of peroxynitrites. The detection of extensive forma tion of nitrotyrosine in the CNS parenchyma was observed in mice having sho wn neurological disorders, suggesting the role of peroxynitrites in the app earance of neurological troubles. In conclusion, this study confirmed the i ncreased NO synthesis in the CNS of mice infected with T. b. brucei and sug gests a deleterious role for NO, through the formation of peroxynitrites, i n the pathogenesis of African CNS trypanosomiasis. (C) 2000 Academic Press.