Effect of indoleamine dioxygenase-1 deficiency and kynurenine pathway inhibition on murine cerebral malaria

Jenny Miu; Helen J Ball; Andrew L Mellor; Nicholas H Hunt

doi:10.1016/j.ijpara.2008.10.005

Effect of indoleamine dioxygenase-1 deficiency and kynurenine pathway inhibition on murine cerebral malaria

Int J Parasitol. 2009 Feb;39(3):363-70. doi: 10.1016/j.ijpara.2008.10.005. Epub 2008 Oct 25.

Authors

Jenny Miu¹, Helen J Ball, Andrew L Mellor, Nicholas H Hunt

Affiliation

¹ Molecular Immunopathology Unit, Bosch Institute and School of Medical Sciences, University of Sydney, NSW, Australia.

PMID: 19000912
DOI: 10.1016/j.ijpara.2008.10.005

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain / drug effects
Brain / metabolism
Brain / physiopathology
Enzyme Inhibitors / pharmacology*
Female
Gas Chromatography-Mass Spectrometry
Humans
Indoleamine-Pyrrole 2,3,-Dioxygenase / biosynthesis
Indoleamine-Pyrrole 2,3,-Dioxygenase / deficiency*
Indoleamine-Pyrrole 2,3,-Dioxygenase / genetics
Kynurenic Acid / chemistry
Kynurenic Acid / metabolism
Kynurenine / metabolism*
Kynurenine 3-Monooxygenase / antagonists & inhibitors*
Malaria, Cerebral / metabolism*
Metabolic Networks and Pathways / drug effects*
Mice
Mice, Inbred C57BL
Picolinic Acids / chemistry
Picolinic Acids / metabolism
Quinolinic Acid / chemistry
Quinolinic Acid / metabolism
RNA, Messenger / biosynthesis
RNA, Messenger / genetics
Sulfonamides / pharmacology*
Thiazoles / pharmacology*
Tryptophan Oxygenase / biosynthesis
Tryptophan Oxygenase / genetics

Substances

Enzyme Inhibitors
Indoleamine-Pyrrole 2,3,-Dioxygenase
Picolinic Acids
RNA, Messenger
Ro 61-8048
Sulfonamides
Thiazoles
Kynurenine
Tryptophan Oxygenase
Kynurenine 3-Monooxygenase
Quinolinic Acid
Kynurenic Acid
picolinic acid