Prolonged Survival of a Murine Model of Cerebral Malaria by Kynurenine Pathway Inhibition

Abstract

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...

5-Hydroxyanthranilic Acid, a Tryptophan Metabolite, Generates Oxidative Stress and Neuronal Death via p38 Activation in Cultured Cerebellar Granule Neurones

“…There is also strong evidence linking quinolinic acid to the AIDS dementia complex (Heyes et al 1991;Medana et al 2003) and cerebral malaria (Sanni et al 1998;Clark et al 2005). In Huntington's disease brain, quinolinic acid is present in higher concentrations than controls Schwarcz 1999, Guidetti et al 2004), and in animals generates a model in which the behavioural, neurochemical and electrophysiological consequences closely mimic those seen in the human disease (Popoli et al 1994).…”

In Vitro Antimalarial Activity and Drug Interactions of Fenofibric Acid

“…This finding suggests that fenofibrate might also inhibit the P-glycoprotein homologue 1 (Pgh1) in P. falciparum and, thus, through reduced efflux of chloroquine (CQ) and mefloquine, reverse resistance (32). In addition, the beneficial anti-inflammatory properties of fibrates, such as those seen in a study of gemfibrozil in murine influenza (5), might attenuate host inflammatory responses that have been proposed to be part of the pathophysiology of complications of malaria, including coma (9)(10)(11). This mechanism is thought to underlie the disease-modifying effects of rosiglitazone (4).…”

Benzo[ b ]quinolizinium Derivatives Have a Strong Antimalarial Activity and Inhibit Indoleamine Dioxygenase

“…The kynurenine pathway and IDO-1 have been linked to the pathogenesis of CM in several studies of humans (23,24,71) and mice (9,10,(25)(26)(27)(28)(29). Moreover, IDO-1 has been suggested to be a target for therapeutic interventions in other diseases characterized by pathological immune suppression.…”

“…Moreover, the pathway has been implicated in parasitic infections, such as trypanosomiasis (6), toxoplasmosis (7,8), and cerebral malaria (CM), as shown in mouse model systems (9,10). CM is a potentially fatal consequence of infection with Plasmodium falciparum and can lead, in case of survival, to neurological or cognitive deficits (10). Severe malaria remains a global health problem.…”

“…Due to its potential role in diseases such as cancer (1), Alzheimer's disease (2), depression (3), stroke (4), and HIV infections (5), the kynurenine pathway is intensely studied with regard to chemotherapeutic applications in humans. Moreover, the pathway has been implicated in parasitic infections, such as trypanosomiasis (6), toxoplasmosis (7,8), and cerebral malaria (CM), as shown in mouse model systems (9,10). CM is a potentially fatal consequence of infection with Plasmodium falciparum and can lead, in case of survival, to neurological or cognitive deficits (10).…”