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.
Highlights
The kynurenine pathway is the major route for tryptophan metabolism, oxidising around 95% of free tryptophan to several compounds with biological activity at glutamate receptors, such as quinolinic acid (Stone and Perkins, 1981; Stone and Darlington, 2002) and kynurenic acid (Perkins and Stone, 1982)
The importance of understanding the manner in which kynurenic acid and quinolinic acid production are regulated lies in the recognition that their modulation of NMDA receptor function may be relevant to several CNS disorders
Given the actions of quinolinic acid as an NMDA receptor agonist and kynurenic acid as an antagonist, and that their concentrations are altered by infection and stress, it is reasonable to consider the possibility that changes in kynurenine metabolism could be involved
Summary
The kynurenine pathway is the major route for tryptophan metabolism, oxidising around 95% of free tryptophan to several compounds with biological activity at glutamate receptors, such as quinolinic acid (Stone and Perkins, 1981; Stone and Darlington, 2002) and kynurenic acid (Perkins and Stone, 1982). Inhibition or deletion of KMO blocks the oxidation of kynurenine to 3-hydroxy-kynurenine, providing a higher concentration of kynurenine as a substrate for kynurenine aminotransferase, which metabolises it to kynurenic acid. These procedures have demonstrated that during early brain formation, in utero, an inhibitor of KMO produces changes in the morphological, biochemical and electrophysiological development of the brains of the offspring (Forrest et al, 2013a,b; Khalil et al, 2014; Pisar et al, 2014), indicating that activity along the kynurenine pathway is actively involved in early brain formation and its subsequent maturation
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call