Amino acids inhibit kynurenic acid formation via suppression of kynurenine uptake or kynurenic acid synthesis in rat brain in vitro

Abstract

The tryptophan metabolite, kynurenic acid (KYNA), is a preferential antagonist of the α7 nicotinic acetylcholine receptor at endogenous brain concentrations. Recent studies have suggested that increase of brain KYNA levels is involved in psychiatric disorders such as schizophrenia and depression. KYNA-producing enzymes have broad substrate specificity for amino acids, and brain uptake of kynurenine (KYN), the immediate precursor of KYNA, is via large neutral amino acid transporters (LAT). In the present study, to find out amino acids with the potential to suppress KYNA production, we comprehensively investigated the effects of proteinogenic amino acids on KYNA formation and KYN uptake in rat brain in vitro. Cortical slices of rat brain were incubated for 2 h in Krebs-Ringer buffer containing a physiological concentration of KYN with individual amino acids. Ten out of 19 amino acids (specifically, leucine, isoleucine, phenylalanine, methionine, tyrosine, alanine, cysteine, glutamine, glutamate, and aspartate) significantly reduced KYNA formation at 1 mmol/L. These amino acids showed inhibitory effects in a dose-dependent manner, and partially inhibited KYNA production at physiological concentrations. Leucine, isoleucine, methionine, phenylalanine, and tyrosine, all LAT substrates, also reduced tissue KYN concentrations in a dose-dependent manner, with their inhibitory rates for KYN uptake significantly correlated with KYNA formation. These results suggest that five LAT substrates inhibit KYNA formation via blockade of KYN transport, while the other amino acids act via blockade of the KYNA synthesis reaction in brain. Amino acids can be a good tool to modulate brain function by manipulation of KYNA formation in the brain. This approach may be useful in the treatment and prevention of neurological and psychiatric diseases associated with increased KYNA levels.

Role of the Kynurenine Metabolism Pathway in Inflammation-Induced Depression: Preclinical Approaches

“…Proof of principle for this possibility was recently obtained in vitro using cortical slices of rat brain incubated with kynurenine and competing amino acids for LAT1. Leucine and other branched-chain amino acids inhibited the uptake of kynurenine by brain slices (Sekine et al 2015). …”

Single cell analysis of kynurenine and System L amino acid transport in T cells

“…One other possible explanation for the relatively high kynurenine concentrations required for AHR triggering, compared with other ligands, could be differential membrane transport requirements for kynurenine versus other ligands, that is, active transport versus passive diffusion across the plasma membrane. Indeed, kynurenine has been shown to be transported by large neutral amino acid transporters (LAT) in rat astrocytes 17 .…”

Severity of experimental traumatic brain injury modulates changes in concentrations of cerebral free amino acids

“…Under physiological conditions, free amino acids (FAA) and amino group containing compounds (AGCC), exert fundamental biochemical roles in numerous brain functions. They can roughly be divided into different categories: (1) those directly involved in neurotransmission, such as glutamate (Glu) and c-aminobutyrric acid (GABA) [1]; (2) those participating to neurotransmission, such as D-serine (D-Ser) and glycine (Gly) [2]; (3) those indirectly controlling neurotransmission, such as glutamine (Gln), aspartate (Asp), triptophane (Trp), phenylalanine (Phe) and tyrosine (Tyr) [3][4][5]; (4) those indirectly involved in cellular energy metabolism, such as leucine (Leu), isoleucine (Ile) and valine (Val) [6]; (5) those involved in specific metabolic pathways, such as methione (Met), cystathionine (L-Cystat) and S-adenosylhomocysteine (SAH) [7].…”