C57BL/6J mice infected with Plasmodium berghei ANKA develop neurological dysfunction and die within 7 days of infection. We show that treatment of infected mice with a kynurenine-3-hydroxylase inhibitor prevents them from developing neurological symptoms and extends their life span threefold until severe anemia develops.One possible cause of death associated with cerebral malaria is an imbalance in the production of neurotoxic and neuroprotective factors brought about by parasite-triggered cerebral inflammation (7,13,14). A candidate mechanism in this process is the kynurenine pathway from tryptophan, which is activated in macrophages and microglia by inflammatory stimuli and which generates excitotoxic and neuroprotectant metabolites (1, 8). The compound 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulfonamide (Ro-61-8048; synthesized by F. Hoffmann-La Roche Ltd.) has been developed as a highaffinity inhibitor of kynurenine-3-hydroxylase (16) (Fig. 1). It has been shown to reduce the formation of quinolinic acid (5), a known excitant and neurotoxin acting through N-methyl-Daspartate (NMDA) receptors (19), and increase the formation of the neuroprotective glutamate antagonist kynurenic acid (5,19) in the brains of mice immune stimulated with pokeweed mitogen. In order to assess the importance of kynurenines in the morbidity and mortality associated with cerebral malaria, we tested the effect of Ro-61-8048 treatment in a well-characterized murine model of this condition. It has been commented that in mice, mononuclear leukocytes are the predominant cell type sequestered in the cerebral microvasculature, and in humans, parasitized red blood cells are prominent (10). However, recent work has shown that leukocytes are seen clearly in brain vessels in human cerebral malaria in adults and parasitized red blood cells are sequestered in the brain in the murine disease (10). Also, cerebral malaria is a syndrome in which the same altered cell (the endothelial cell) plays a pivotal role in both human and experimental lesions (10).C57BL/6J mice infected with asexual blood stages of Plasmodium berghei ANKA have been shown to develop neurological behavioral changes such as ataxia, convulsions, and coma at approximately day 5 after infection and usually die between days 6 and 8 postinfection (15). Similarly, in our study, all 10 mice infected with P. berghei ANKA (6) and receiving only the solvent in which Ro-61-8048 was dissolved (vehicle, 0.9% NaCl-60 mM NaOH, pH adjusted to 7.5) exhibited signs of cerebral involvement on day 6 postinfection, with reduced locomotion and marked ataxia. All the mice in this group died or were euthanized to avoid unnecessary suffering between days 7 and 9 postinfection. In contrast, none of nine infected mice treated intraperitoneally with 200 mg/kg Ro-61-8048 (days 1, 2, 3, 4, 6, 8, 10, and 12 postinfection) showed any signs of cerebral dysfunction throughout the duration of the experiment, and all were surviving on day 21 postinfection (P ϭ 0.0002, Fisher's exact test), when the expe...