Effect of indoleamine dioxygenase-1 deficiency and kynurenine pathway inhibition on murine cerebral malaria.
Cerebral malaria (CM) can be a fatal manifestation of Plasmodium falciparum infection. In this study, two different approaches were used to examine the role of indoleamine 2,3-dioxygenase-1 (IDO-1) and its metabolites in the development of murine CM. Mice genetically deficient in IDO-1 were not protected against CM, but partial protection was observed in C57BL/6 mice treated with Ro 61-8048, an inhibitor of kynurenine-3-hydroxylase. This protection was associated with suppressed levels of picolinic acid (PA) within the brain, but not with changes in the levels of kynurenic acid (KA) or quinolinic acid (QA). These data suggest that although IDO-1 is not directly involved in the pathogenesis of CM in C57BL/6 mice, the production of the kynurenine pathway metabolite PA may contribute to the development of murine CM.
Miu
Jenny
J
Molecular Immunopathology Unit, Bosch Institute and School of Medical Sciences, University of Sydney, NSW, Australia.
Ball
Helen J
HJ
Mellor
Andrew L
AL
Hunt
Nicholas H
NH
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D007736:Kynurenic Acid / Q000737:chemistry / Q000378:metabolism; D007737:Kynurenine / Q000378:metabolism*; D050601:Kynurenine 3-Monooxygenase / Q000037:antagonists & inhibitors*; D016779:Malaria, Cerebral / Q000378:metabolism*; D053858:Metabolic Networks and Pathways / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D010848:Picolinic Acids / Q000737:chemistry / Q000378:metabolism; D017378:Quinolinic Acid / Q000737:chemistry / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D014366:Tryptophan Oxygenase / Q000096:biosynthesis / Q000235:genetics
D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D010848:Picolinic Acids; D012333:RNA, Messenger; C110196:Ro 61-8048; D013449:Sulfonamides; D013844:Thiazoles; D007737:Kynurenine; D014366:Tryptophan Oxygenase; D050601:Kynurenine 3-Monooxygenase; D017378:Quinolinic Acid; D007736:Kynurenic Acid; C030614:picolinic acid