nutrients Review Possibility of Amino Acid Treatment to Prevent the Psychiatric Disorders via Modulation of the Production of Tryptophan Metabolite Kynurenic Acid Tsutomu Fukuwatari Department of Nutrition, School of Human Cultures, the University of Shiga Prefecture, 2500 Hassaka, Hikone, Shiga 522-8533, Japan; [email protected]; Tel.: +81-749-28-8443 Received: 14 March 2020; Accepted: 12 May 2020; Published: 13 May 2020 Abstract: Kynurenic acid, a metabolite of the kynurenine pathway of tryptophan catabolism, acts as an antagonist for both the α7 nicotinic acetylcholine receptor and glycine coagonist sites of the N-methyl-d-aspartic acid receptor at endogenous brain concentrations. Elevation of brain kynurenic acid levels reduces the release of neurotransmitters such as dopamine and glutamate, and kynurenic acid is considered to be involved in psychiatric disorders such as schizophrenia and depression. Thus, the control of kynurenine pathway, especially kynurenic acid production, in the brain is an important target for the improvement of brain function or the effective treatment of brain disorders. Astrocytes uptake kynurenine, the immediate precursor of kynurenic acid, via large neutral amino acid transporters, and metabolize kynurenine to kynurenic acid by kynurenine aminotransferases. The former transport both branched-chain and aromatic amino acids, and the latter have substrate specificity for amino acids and their metabolites. Recent studies have suggested the possibility that amino acids may suppress kynurenic acid production via the blockade of kynurenine transport or via kynurenic acid synthesis reactions. This approach may be useful in the treatment and prevention of neurological and psychiatric diseases associated with elevated kynurenic acid levels. Keywords: dopamine; kynurenic acid; kynurenine; large neutral amino acid transporter; neuropsychiatric disorders; neurotransmitter; α7 nicotinic acetylcholine receptor; N-methyl-d-aspartic acid (NMDA) receptor; tryptophan 1. Introduction The essential amino acid tryptophan is well known as a precursor of several bioactive compounds such as serotonin and melatonin. More than 90% of tryptophan is metabolized by the kynurenine pathway [1], and this pathway plays a critical role in tryptophan catabolism and coenzyme nicotinamide adenine dinucleotide (NAD+) supply (Figure1). Recently, many researchers have studied the kynurenine pathway, because the pathway has interesting intermediates and metabolites. For example, kynurenine regulates immunoreaction as an aryl hydrocarbon receptor agonist [2], and kynurenic acid (KYNA) affects brain function as an antagonist for both the α7 nicotinic acetylcholine receptors (α7nAchRs) and the N-methyl-d-aspartic acid (NMDA) receptor [3,4] and an agonist for the G protein-coupled receptor (GPR) 35 (GPR35) [5]. 3-hydroxykynurenine is a potential endogenous neurotoxin and oxidative stress generator [6], and quinolinic acid produces excitotoxicity as an NMDA receptor agonist [7]. Especially, KYNA function research has dramatically developed since 2001, and one of the targets for KYNA research is to manipulate KYNA production in the brain to prevent and improve psychiatric disorders such as schizophrenia and depression. In the present article, we briefly review recent advances in KYNA research and further describe the ability of amino acids to modulate KYNA production. The structure of tryptophan, kynurenine, and KYNA are shown in Figure2. Nutrients 2020, 12, 1403; doi:10.3390/nu12051403 www.mdpi.com/journal/nutrients Nutrients 2020, 12, x FOR PEER REVIEW 2 of 11 Nutrients 2020, 12, x FOR PEER REVIEW 2 of 11 ability of amino acids to modulate KYNA production. The structure of tryptophan, kynurenine, and Nutrients 2020, 12, 1403 2 of 11 abilityKYNA of areamino shown acids in toFigure modulate 2. KYNA production. The structure of tryptophan, kynurenine, and KYNA are shown in Figure 2. FigureFigure 1.1. TryptophanTryptophan degradation degradation pathway. pathway. (1) (1)Tryptophan Tryptophan 2,3- 2,3-dioxygenasedioxygenase/Indoleamine/Indoleamine 2,3- Figure2,3-dioxygenasedioxygenase 1. Tryptophan (2) form (2) amidadegradation formamidase,se, (3) kynureninepathway. (3) kynurenine (1) 3- monoxygenTryptophan 3-monoxygenase,ase, 2,3 (4)-dioxygenase/Indoleamine kynureninase, (4) kynureninase,(5) kynurenine 2,3- dioxygenase(5)aminotransferase, kynurenine (2) form (6)amida aminotransferase,3-hydroxyanthranilicse, (3) kynurenine (6)3acid-monoxygen oxygenase, 3-hydroxyanthranilicase, (4)(7) kynureninase,2-amino-3- acidcarboxymuconate (5) kynurenine oxygenase,-6 - aminotransferase,(7)semialdehyde 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase, (6) 3-hydroxyanthranilic (8) nonenzymatic acid reaction, oxygenase, decarboxylase, (9) quinolinate (7) 2- (8)amino phosphoribosyltransferase, nonenzymatic-3-carboxymuconate reaction,-6- semialdehyde(9)(10) quinolinate nicotinic decarboxylase, acid phosphoribosyltransferase, (nicotinamide) (8) nonenzymatic mononucleotide (10) reaction, nicotinic adenylyltransfer (9) quinolinate acid (nicotinamide)ase, phosphoribosyltransferase, (11) NAD mononucleotide+ synthetase, (12) + + (10)adenylyltransferase,NAD nicotinic+ degrading acid (nicotinamide) (11)enzyme, NAD (13) mononucleotidesynthetase, nicotinamide (12) adenylyltransfer NADphosphoribosyltransferase,degradingase, enzyme,(11) NAD (13)+(14) synthetase, nicotinamidenicotinamide (12) NADphosphoribosyltransferase,methyltransferase,+ degrading enzyme,(15) 2-Py -(13)forming (14) nicotinamide nicotinamideN1-methylnicotinamide phosphoribosyltransferase, methyltransferase, oxidase, and (16) (15)(14) 4 -Pynicotinamide 2-Py-forming-forming N 1- 1 1 methyltransferase,Nmethylnicotinamide-methylnicotinamide (15) oxidase. oxidase,2-Py-forming Abbreviations: and (16) N1 4-Py-forming-methylnicotinamide NAD+:N nicotinamide-methylnicotinamide oxidase, adenine and (16) oxidase.dinucleotide 4-Py Abbreviations:-forming; 2 Py: N 1N- 1- + 1 methylnicotinamideNADmethyl: nicotinamide-2-pyridone -oxidase.5- adeninecarboxamide; Abbreviations: dinucleotide; and 4 Py: 2NA N Py:1-Dmethyl+N: nicotinamide-methyl-2-pyridone-5-carboxamide;-4-pyridone adenine-3-carboxamide dinucleotide. ; 2 and Py: 4N Py:1- 1 methylN -methyl-4-pyridone-3-carboxamide.-2-pyridone-5-carboxamide; and 4 Py: N1-methyl-4-pyridone-3-carboxamide. Figure 2. Structures of tryptophan, kynurenine, and kynurenic acid. Figure 2. Structures of tryptophan, kynurenine, and kynurenic acid. Figure 2. Structures of tryptophan, kynurenine, and kynurenic acid. Nutrients 2020, 12, 1403 3 of 11 Nutrients 2020, 12, x FOR PEER REVIEW 3 of 11 2. Function of Kynurenic Acid in the Brain 2. Function of Kynurenic Acid in the Brain In 1989, Kessler et al. found that KYNA competitively inhibited glycine coagonist site of the NMDAIn 1989, receptor Kessler at low et concentrational. found that with KYNA an ICcompetitively50 of 8 µmol/ L[inhibit3]. Aed decade glycine later, coagonist Hilmas etsite al. of found the NMDAthat KYNA receptor noncompetitively at low concentration inhibited withα an7nAchRs IC50 of 8 with μmol/L an IC [3]50. Aof decade 7 µmol /later,L using Hilmas the patch-clampet al. found thattechnique KYNA withnoncompetitively cultured hippocampal inhibited neuronsα7nAchRs [4 ].with Furthermore, an IC50 of 7 Wang μmol/L et al.using found the thatpatch KYNA-clamp is techniqueligand for with GPR35, cultured whose hippocampal EC50s are 10.7, neurons 7.4, and 39.2[4]. µFurthermore,mol/L in mouse, Wang rat, et and al. human, found respectivelythat KYNA [is5]. ligandSince physiologicalfor GPR35, wh concentrationsose EC50s are 10.7, of 7.4 brain, and KYNA 39.2 μmol/L are 5 pmol in mouse,/g wet rat wt,, and 15 human, pmol/g respectively wet wt, and [5].150 Since pmol physiological/g wet wt in mouse,concentrations rat and of human, brain KYNA respectively are 5 pmol/g [8], elevation wet wt, of 15 brain pmol/g KYNA wet haswt, beenand 150considered pmol/g wet to a ffwtect in these mouse, receptors. rat and E ffhuman,ects of KYNArespectively increase [8], on elevation the neurotransmitter of brain KYNA release has been were consideredinvestigated to usingaffect microdialysisthese receptors. technique, Effects of andKYNA KYNA increase concentration-dependently on the neurotransmitter and release reversibly were invesreducedtigated extracellular using microdialysis glutamate, technique, dopamine, and and KYNAγ-aminobutyric concentration acid-dependently (GABA) to less and than reversibly 50% of reducedbaseline extracellular concentrations glutamate, [9–11]. Conversely,dopamine, and inhibition γ-aminobutyric of endogenous acid (GABA) KYNA formationto less than by 50% reverse of baselinedialysis ofconcentrations KYNA synthesis [9–11]. inhibitor Conversely,(S)-4-(ethylsulfonyl) inhibition of benzoylalanine endogenous KYNA (S-ESBA) formation reversibly by increasesreverse dialysisdopamine, of glutamate,KYNA synthesis and GABA inhibitor levels in(S) the-4-( rodentethylsulfonyl) brain [11 benzoylalanine–13]. Although these(S-ESBA findings) reversibly suggest increasesthat changes dopamine, of brain glutamate KYNA levels, and aff ectGABA neurotransmitter levels in the release rodent via brain modulation [11–13]. of Although above receptors, these findingsunderstanding suggest thethat mechanism changes of brain of action KYNA of KYNAlevels affect is di ffineurotransmittercult. There is disagreementrelease via modulation about the ofinteraction above receptors between, KYNAunderstanding and α7nAchRs, the mechanism because several of action studies of