DRAMATIC CHANGES IN OXIDATIVE TRYPTOPHAN-METABOLISM ALONG THE KYNURENINE PATHWAY IN EXPERIMENTAL CEREBRAL AND NONCEREBRAL MALARIA

The pathogenesis of human cerebral malaria (CM) remains unresolved. In the most widely used murine model of CM, the presence of T lymphocyte s and/or interferon (IFN)-gamma is a prerequisite, IFN-gamma is the ke y inducer of indoleamine 2,3-dioxygenase (IDO), which is the catalyst of the first, and rate-limiting, step in the metabolism of tryptophan (Trp) along the kynurenine (Kyn) pathway, Quinolinic acid (QA), a prod uct of this pathway, is a neuro-excitotoxin, Like glutamic acid (Glu) and aspartic acid (Asp), Kynurenic acid(KA), also produced from the Ky n pathway, antagonizes the neuro-excitotoxic effects of QA, Glu, and A sp. We therefore examined the possible roles of IDO, metabolites of th e Kyn pathway, Glu, and Asp in the pathogenesis of fatal murine CM, Pl asmodium berghei ANKA infection was studied on days 6 and 7 post-inocu lation (p.i.), at which time the mice exhibited cerebral symptoms such as convulsions, ataxia, coma, and a positive Wooly/White sign and die d within 24 hours, A model for noncerebral malaria (NCM), P. berghei K 173 infection, was also studied on days 6 and 7 and 13 to 17 p.i. to e xamine whether any changes were a general response to malaria infectio n, Biochemical analyses were done by high-pressure liquid chromatograp hy and gas chromatography/mass spectrometry/mass spectrometry (GC/MS/M S), IDO activity was low Or absent in the brains of uninfected mice an d NCM mice (days 6 and 7 p.i.) and was induced strongly in the brains of fatal murine CM mice (days 6 and 7 p.i.) and NCM animals (days 13 t o 17 p.i.), This induction was inhibited greatly by administration of dexamethasone, a treatment that also prevented CM symptoms and death. Furthermore, IDO induction was absent in IFN-gamma gene knockout mice, which were also resistant to CM, Brain concentrations of Kyn, 3-hydro xykynurenine, and the neuro-excitotoxin QA were significantly increase d in both CM mice on days 6 and 7 p.i. and NCM mice on days 13 to 17 p .i., whereas an increase in the ratio of brain QA to KA occurred only in the CM mice at the time they were exhibiting cerebral symptoms, Bra in concentrations of Glu and Asp were significantly decreased in CM an d NCM mice (days 13 to 17 p.i.). The results imply that neuro-excitati on induced by QA may contribute to the convulsions and neuro-excitator y signs observed in CM.