Prenatal Dynamics of Kynurenine Pathway Metabolism in Mice: Focus on Kynurenic Acid

Abstract

The kynurenine pathway (KP), the major catabolic route of tryptophan in mammals, contains several neuroactive metabolites, including kynurenic acid (KYNA) and 3-hydroxykynurenine (3-HK). KP metabolism, and especially the fate of KYNA, during pregnancy is poorly understood, yet it may play a significant role in the development of psychiatric disorders later in life. The present study was designed to investigate the prenatal features of KP metabolism in vivo, with special focus on KYNA. To this end, pregnant CD-1 mice were treated systemically with kynurenine (100 mg/kg), KYNA (10 mg/kg), or saline on embryonic day 18. As expected, administration of either kynurenine or KYNA increased KYNA levels in the maternal plasma and placenta. Maternal kynurenine treatment also raised kynurenine levels in the fetal plasma and brain, demonstrating the ability of this pivotal KP metabolite to cross the placenta and increase the levels of both KYNA and 3-HK in the fetal brain. In contrast, maternal administration of KYNA caused only a small, nonsignificant elevation in KYNA levels in fetal plasma and brain. Complementary experiments using an ex vivo placental perfusion procedure confirmed the significant transplacental transfer of kynurenine and demonstrated that only a very small fraction of maternal kynurenine is converted to KYNA in the placenta and released into the fetal compartment under physiological conditions. Jointly, these results help to clarify the contributions of the maternal circulation and the placenta to fetal KYNA in the late prenatal period.

Assessing Urinary Metabolomics in Giant Pandas Using Chromatography/Mass Spectrometry: Pregnancy-Related Changes in the Metabolome

“…Studies indicated that exogenous kynurenine supplementation promotes an increase in kynurenic acid levels in both the fetus and mother. However, exogenous kynurenic acid supplementation did not increase kynurenic acid levels in either the fetus or the mother (47). Therefore, we speculate that the elevated kynurenic acid levels in the urine of pregnant giant pandas may be attributable to the increased kynurenine content in the cord blood, and the presence of kynurenine promotes kynurenic acid production via the activity of kynurenine transaminase.…”

Elevated kynurenine pathway metabolism during neurodevelopment: Implications for brain and behavior

“…In line with these findings, it is possible that fetal brain kynurenine originates from tryptophan degradation in the placenta, which expresses both tryptophan-degrading enzymes IDO and TDO (Manuelpillai et al, 2005; Suzuki et al, 2001). Alternatively, kynurenine could be transferred to the fetus from the maternal circulation via transplacental transfer (Goeden et al, 2015). The placenta also expresses other KP enzymes, including kynureninase, KAT, KMO, 3-hydroxyanthranilic acid 3,4-dioxygenase and quinolinic acid phosphoribosyltransferase (see Fig.…”

Profiling of Tryptophan Metabolic Pathways in the Rat Fetoplacental Unit during Gestation

“…However, despite steady IDO activity, the placental content of KYN decreased significantly towards term. This can be explained by KYN transport to fetal circulation since fetal organs can utilize KYN for the synthesis of KYNA, which as an important neuroprotective metabolite [ 32 ]. Alternatively, this decrease might also be attributed to the rapid utilization of KYN for the synthesis of other metabolites inside the placenta; although statistically insignificant, we detected a steady increase in the KYNA placental content from GD 15 to 21.…”

“…Alternatively, this decrease might also be attributed to the rapid utilization of KYN for the synthesis of other metabolites inside the placenta; although statistically insignificant, we detected a steady increase in the KYNA placental content from GD 15 to 21. Nevertheless, placental handling of KYN and KYNA is not unified in the current literature [ 32 , 53 , 54 ] and requires further investigation.…”

“…Additionally, KYN metabolites such as 3-hydroxykynurenine, anthranilic acid, and 3-hydroxyanthranilic acid have been reported to exert cytotoxic activity [ 28 , 29 , 30 , 31 ]. Collectively, malfunctions of the KYN pathways in rats have been linked to poor pregnancy outcomes [ 1 , 32 ] and it has been suggested that placenta-derived KYN metabolites may be involved in the etiology of prenatal brain damage [ 32 ].…”