Kynurenine pathway metabolism following prenatal KMO inhibition and in Mecp2+/- mice, using liquid chromatography-tandem mass spectrometry

Forrest, C., Kennedy, P. G., Rodgers, J., Dalton, R. N., Turner, C., Darlington, L. G., Cobb, S. and Stone, T. W. (2016) Kynurenine pathway metabolism following prenatal KMO inhibition and in Mecp2+/- mice, using liquid chromatography-tandem mass spectrometry. Neurochemistry International, 100, pp. 110-119. (doi:10.1016/j.neuint.2016.09.012) (PMID:27623092) (PMCID:PMC5115650)

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Abstract

To quantify the full range of tryptophan metabolites along the kynurenine pathway, a liquid chromatography – tandem mass spectrometry method was developed and used to analyse brain extracts of rodents treated with the kynurenine-3-mono-oxygenase (KMO) inhibitor Ro61-8048 during pregnancy. There were significant increases in the levels of kynurenine, kynurenic acid, anthranilic acid and 3-hydroxy-kynurenine (3-HK) in the maternal brain after 5 h but not 24 h, while the embryos exhibited high levels of kynurenine, kynurenic acid and anthranilic acid after 5 h which were maintained at 24 h post-treatment. At 24 h there was also a strong trend to an increase in quinolinic acid levels (P = 0.055). No significant changes were observed in any of the other kynurenine metabolites. The results confirm the marked increase in the accumulation of some neuroactive kynurenines when KMO is inhibited, and re-emphasise the potential importance of changes in anthranilic acid. The prolonged duration of metabolite accumulation in the embryo brains indicates a trapping of compounds within the embryonic CNS independently of maternal levels. When brains were examined from young mice heterozygous for the meCP2 gene – a potential model for Rett syndrome - no differences were noted from control mice, suggesting that the proposed roles for kynurenines in autism spectrum disorder are not relevant to Rett syndrome, supporting its recognition as a distinct, independent, condition.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Forrest, Dr Caroline and Stone, Professor Trevor and Cobb, Dr Stuart and Rodgers, Dr Jean and Kennedy, Professor Peter and Turner, Professor Charles
Authors: Forrest, C., Kennedy, P. G., Rodgers, J., Dalton, R. N., Turner, C., Darlington, L. G., Cobb, S., and Stone, T. W.
College/School:College of Medical Veterinary and Life Sciences > Institute of Biodiversity Animal Health and Comparative Medicine
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Journal Name:Neurochemistry International
Publisher:Elsevier
ISSN:0197-0186
ISSN (Online):1872-9754
Published Online:10 September 2016
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Neurochemistry International 100:110-119
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
554901Defining the role of kynurenine pathway metabolites in the inflammatory response to trypanosome invasion of the CNSPeter KennedyWellcome Trust (WELLCOME)094691/Z/10/ZIII - PARASITOLOGY