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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autism Spectrum Disorder / genetics
  • Autism Spectrum Disorder / metabolism
  • Brain / drug effects*
  • Brain / metabolism
  • Chromatography, Liquid / methods
  • Female
  • Kynurenic Acid / pharmacology*
  • Kynurenine / metabolism*
  • Methyl-CpG-Binding Protein 2 / genetics*
  • Pregnancy
  • Rats, Wistar
  • Tandem Mass Spectrometry
  • Tryptophan / metabolism*
  • ortho-Aminobenzoates / pharmacology

Substances

  • Mecp2 protein, rat
  • Methyl-CpG-Binding Protein 2
  • ortho-Aminobenzoates
  • anthranilic acid
  • Kynurenine
  • Tryptophan
  • Kynurenic Acid