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.

Highlights

  • Tryptophan was mainly metabolized through the kynurenine (KYN) pathway in the mammalian brain

  • Previous reports have shown that amino acids have the potential to suppress Kynurenic acid (KYNA) production via inhibition of KYN uptake and KYNA synthesis in the brain, we comprehensively investigated the effects of proteinogenic amino acids on regulating KYNA production in rat brain in vitro

  • We have investigated the effect of proteinogenic amino acids on KYNA production in rat brain in vitro

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Summary

Introduction

Tryptophan was mainly metabolized through the kynurenine (KYN) pathway in the mammalian brain. Patients with schizophrenia show higher KYNA levels in the prefrontal cortex and cerebrospinal fluid (Erhardt et al 2001; Schwarcz et al 2001; Linderholm et al 2010). Based on these findings, it has been suggested that KYNA is involved in the pathophysiology of psychiatric disorders including schizophrenia (Erhardt et al 2007; Erhardt et al 2009), and suppression of KYNA production may contribute to prevention or improvement in these disorders

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