Kynurenine pathway metabolism following prenatal KMO inhibition and in Mecp2+/-mice, using liquid chromatography-tandem mass spectrometry.
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.
Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK.
Caroline M
CM
Forrest
Institute of Infection, Inflammation and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK.
Peter G E
PG
Kennedy
Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G61 1QH, UK.
Jean
J
Rodgers
WellChild Laboratory, Evelina London Children's Hospital, King's College London, Lambeth Palace Road, London, SE1 7EH, UK.
R Neil
RN
Dalton
WellChild Laboratory, Evelina London Children's Hospital, King's College London, Lambeth Palace Road, London, SE1 7EH, UK.
Charles
C
Turner
Department of Internal Medicine, Ashtead Hospital, Ashtead, Surrey, KT21 2SB, UK.
L Gail
LG
Darlington
Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK.
Stuart R
SR
Cobb
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.
Trevor W
TW
Stone
D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002853:Chromatography, Liquid / Q000379:methods; D005260:Female; D007736:Kynurenic Acid / Q000494:pharmacology*; D007737:Kynurenine / Q000378:metabolism*; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D011247:Pregnancy; D017208:Rats, Wistar; D053719:Tandem Mass Spectrometry; D014364:Tryptophan / Q000378:metabolism*; D062367:ortho-Aminobenzoates / Q000494:pharmacology
C497394:Mecp2 protein, rat; D051783:Methyl-CpG-Binding Protein 2; D062367:ortho-Aminobenzoates; C031385:anthranilic acid; D007737:Kynurenine; D014364:Tryptophan; D007736:Kynurenic Acid
Kynurenic acid; Kynurenine; Quinolinic acid; Rett syndrome; Tryptophan metabolism