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 Turner, Professor Charles and Kennedy, Professor Peter and Rodgers, Dr Jean |
| 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 > School of Infection & Immunity College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine |
| 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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