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Neurochem Int. 2016 Nov;100:110-119. doi: 10.1016/j.neuint.2016.09.012. Epub 2016 Sep 10.

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

Author information

1
Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK.
2
Institute of Infection, Inflammation and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK.
3
Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G61 1QH, UK.
4
WellChild Laboratory, Evelina London Children's Hospital, King's College London, Lambeth Palace Road, London, SE1 7EH, UK.
5
Department of Internal Medicine, Ashtead Hospital, Ashtead, Surrey, KT21 2SB, UK.
6
Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK. Electronic address: Trevor.Stone@glasgow.ac.uk.

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.

KEYWORDS:

Kynurenic acid; Kynurenine; Quinolinic acid; Rett syndrome; Tryptophan metabolism

PMID:
27623092
PMCID:
PMC5115650
DOI:
10.1016/j.neuint.2016.09.012
[Indexed for MEDLINE]
Free PMC Article

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