title: Pneumococcal meningitis causes accumulation of neurotoxic kynurenine metabolites in brain regions prone to injury.
abstract: Pneumococcal meningitis (PM) is characterized by an intense inflammatory host reaction that contributes to the development of cortical necrosis and hippocampal apoptosis. Inflammatory conditions in the brain are known to induce tryptophan degradation along the kynurenine pathway, resulting in accumulation of neurotoxic metabolites. In the present study, we investigated the contribution of the kynurenine pathway to brain injury in experimental PM by measuring the concentration of its metabolites and the enzymatic activities and mRNA levels of its major enzymes in the vulnerable brain regions. In the late phase of acute PM, we found a significant transcriptional upregulation of kynurenine-3-hydroxylase and an accumulation of the neurotoxic metabolites 3-hydroxykynurenine (3-HKYN) and 3-hydroxyanthranilic acid in cortex and hippocampus. The positive correlation between the concentration of 3-HKYN and the extent of hippocampal apoptosis adds support to the concept that 3-HKYN contributes to brain injury in PM.
authors.affiliation: Institute for Infectious Diseases, University of Bern, Friedbuehlstrasse 51, PO Box 61, CH-3010 Bern, Switzerland.
authors.forename: Caroline L
authors.initials: CL
authors.lastname: Bellac
authors.forename: Roney S
authors.initials: RS
authors.lastname: Coimbra
authors.forename: Stephan
authors.initials: S
authors.lastname: Christen
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Leib
mesh_terms: D015095:3-Hydroxyanthranilic Acid / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001921:Brain / Q000378:metabolism* / Q000382:microbiology / Q000503:physiopathology; D004195:Disease Models, Animal; D004660:Encephalitis / Q000378:metabolism* / Q000382:microbiology / Q000503:physiopathology; D004789:Enzyme Activation / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism / Q000382:microbiology / Q000503:physiopathology; D007737:Kynurenine / Q000031:analogs & derivatives / Q000378:metabolism*; D050601:Kynurenine 3-Monooxygenase / Q000378:metabolism; D008586:Meningitis, Pneumococcal / Q000378:metabolism* / Q000503:physiopathology; D009410:Nerve Degeneration / Q000378:metabolism* / Q000382:microbiology / Q000503:physiopathology; D009498:Neurotoxins / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation / Q000502:physiology
chemical_list: D009498:Neurotoxins; D015095:3-Hydroxyanthranilic Acid; C005045:3-hydroxykynurenine; D007737:Kynurenine; D050601:Kynurenine 3-Monooxygenase