Details

Autor(en) / Beteiligte

• Forrest, Caroline M.
• Kennedy, Peter G.E.
• Rodgers, Jean
• Dalton, R. Neil
• Turner, Charles
• Darlington, L. Gail
• Cobb, Stuart R.
• Stone, Trevor W.

Titel

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

Ist Teil von

• Neurochemistry international, 2016-11, Vol.100, p.110-119

Ort / Verlag

England: Elsevier Ltd

Erscheinungsjahr

2016

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. •Pregnant rats were treated with an inhibitor of kynurenine-3-monoxygenase.•Levels of several kynurenine metabolites increased in the maternal and foetal brains.•The maternal changes at 5 h disappeared by 24 h, but were maintained in embryos.•No changes were noted in the brains of Mecp2+/− mice.•KMO inhibition but not Mecp2+/− suppression alters kynurenine metabolism.