Kynurenic Acid Synthesis Research Articles

Jerusalem Balsam Lowers Kynurenic Acid Formation: An In Vitro Study

The present study evaluates the action of Jerusalem Balsam with respect to the biosynthetic machinery of Kynurenic Acid (KYNA) synthesis e.g. the activity of the enzyme synthesizing KYNA, Kynurenine Aminotransferase II (KAT II) in the rat liver homogenate. Subsequently we compared the action of Jerusalem Balsam on KAT II activity in the rat liver homogenate with the action of Cerebrolysin and D-cycloserine, known to inhibit rat liver KAT II activities. We found that Jerusalem Balsam blocked dose-dependently and significantly KAT II activity in the rat liver homogenate. The effect of Jerusalem Balsam on KAT II activity comparing to action of Cerebrolysin or D-cycloserine was strong and significant and the inhibition was seen up to 5 hrs of assay incubation time. Obtained data suggest that lowering of KYNA synthesis by Jerusalem Balsam is notable biochemical effect since it might influence KYNA levels. Increased KYNA levels, respectively KYNA synthesis has been reported in stroke patient, in patient with respiration and cardiovascular problem and in neuropsychiatric disorders. The possible therapeutic mechanism and advantage of the remedy Jerusalem Balsam, i.e., mixture of plants might be due to modulation of KYNA synthesis and improvement of biochemical processes in the periphery and likely in the CNS.

Adaptive and Behavioral Changes in Kynurenine 3-Monooxygenase Knockout Mice: Relevance to Psychotic Disorders

BackgroundKynurenine 3-monooxygenase converts kynurenine to 3-hydroxykynurenine, and its inhibition shunts the kynurenine pathway—which is implicated as dysfunctional in various psychiatric disorders—toward enhanced synthesis of kynurenic acid, an antagonist of both α7 nicotinic acetylcholine and N-methyl-D-aspartate receptors. Possibly as a result of reduced kynurenine 3-monooxygenase activity, elevated central nervous system levels of kynurenic acid have been found in patients with psychotic disorders, including schizophrenia. MethodsIn the present study, we investigated adaptive—and possibly regulatory—changes in mice with a targeted deletion of Kmo (Kmo–/–) and characterized the kynurenine 3-monooxygenase–deficient mice using six behavioral assays relevant for the study of schizophrenia. ResultsGenome-wide differential gene expression analyses in the cerebral cortex and cerebellum of these mice identified a network of schizophrenia- and psychosis-related genes, with more pronounced alterations in cerebellar tissue. Kynurenic acid levels were also increased in these brain regions in Kmo–/– mice, with significantly higher levels in the cerebellum than in the cerebrum. Kmo–/– mice exhibited impairments in contextual memory and spent less time than did controls interacting with an unfamiliar mouse in a social interaction paradigm. The mutant animals displayed increased anxiety-like behavior in the elevated plus maze and in a light/dark box. After a D-amphetamine challenge (5 mg/kg, intraperitoneal), Kmo–/– mice showed potentiated horizontal activity in the open field paradigm. ConclusionsTaken together, these results demonstrate that the elimination of Kmo in mice is associated with multiple gene and functional alterations that appear to duplicate aspects of the psychopathology of several neuropsychiatric disorders.

Angiotensin-converting enzyme inhibitors modulate kynurenic acid production in rat brain cortex in vitro

It is well established that the renin-angiotensin system (RAS) is present in the brain and that glutamate activates the brain centers responsible for blood pressure control. An antagonist of glutamate, kynurenic acid (KYNA) was shown to decrease blood pressure after intracerebral administration. KYNA is an endogenous metabolite of tryptophan produced from the breakdown of kynurenine by kynurenine aminotransferases (KAT), mainly within astrocytes.The purpose of this study was to evaluate the influence of three angiotensin-converting enzyme inhibitors (lisinopril, perindopril and ramipril) on KYNA production and KAT activity in the rat brain cortex in vitro.The effect of the angiotensin-converting enzyme inhibitors on KYNA production was examined on rat brain cortical slices incubated for 2h in the presence of l-kynurenine and the angiotensin-converting enzyme inhibitors. To analyze KAT I and KAT II activity, brain cortical homogenates were incubated for 2h with L-kynurenine and the tested drugs. KYNA was separated by HPLC and quantified fluorometrically.Among the examined angiotensin-converting enzyme inhibitors, lisinopril increased KYNA production, perindopril was ineffective, and ramipril decreased KYNA synthesis in rat brain cortical slices. Lisinopril increased KAT I activity and perindopril did not affect it. However, ramipril lowered KAT I activity in rat brain cortex in vitro. Neither lisinopril nor perindopril affected KAT II activity, but ramipril decreased KAT II activity in the rat brain cortex in vitro.Our study reveals that angiotensin-converting enzyme inhibitors show various influences on KYNA production in rat brain cortical slices and activity of KATs.

Direct effects of exercise on kynurenine metabolism in people with normal glucose tolerance or type 2 diabetes

Systemic kynurenine levels are associated with resistance to stress-induced depression and are modulated by exercise. Tryptophan is a precursor for serotonin and kynurenine synthesis. Kynurenine is transformed into the neuroprotective catabolite kynurenic acid by kynurenine aminotransferases (KATs). PGC-1α1 increases KAT mRNA and induces kynurenic acid synthesis. We tested the hypothesis that skeletal muscle PGC-1α1/KAT-kynurenine pathway is altered by exercise and type 2 diabetes. Skeletal muscle and plasma from men with normal glucose tolerance (n = 12) or type 2 diabetes (n = 12) was studied at rest, after acute exercise and during recovery. Tryptophan, Kynurenine and kynurenic acid plasma concentration were measured as well as mRNA of genes related to exercise and kynurenine metabolism. mRNA expression of KAT1, KAT2 and PPARα was modestly reduced in type 2 diabetic patients. In response to exercise, mRNA expression of KAT4 decreased and PGC-1α1 increased in both groups. Exercise increased plasma kynurenic acid and reduced kynurenine in normal glucose tolerance and type 2 diabetic participants. Plasma tryptophan was reduced and the ratio of [kynurenic acid] * 1000/[kynurenine] increased in both groups at recovery, suggesting an improved balance between neurotoxic and neuroprotective influences. Tryptophan and kynurenine correlated with body mass index, suggesting a relationship with obesity. Acute exercise directly affects circulating levels of tryptophan, kynurenine and kynurenic acid, providing a potential mechanism for the anti-depressive effects of exercise. Furthermore, exercise-mediated changes in kynurenine metabolism are preserved in type 2 diabetic patients. Copyright © 2016 John Wiley & Sons, Ltd.

Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites

Metabolites of the kynurenine pathway (KP) of tryptophan (TRP) degradation have been closely linked to the pathogenesis of several neurodegenerative disorders. Recent work has highlighted the therapeutic potential of inhibiting two critical regulatory enzymes in this pathway-kynurenine-3-monooxygenase (KMO) and tryptophan-2,3-dioxygenase (TDO). Much evidence indicates that the efficacy of KMO inhibition arises from normalizing an imbalance between neurotoxic [3-hydroxykynurenine (3-HK); quinolinic acid (QUIN)] and neuroprotective [kynurenic acid (KYNA)] KP metabolites. However, it is not clear if TDO inhibition is protective via a similar mechanism or if this is instead due to increased levels of TRP-the substrate of TDO. Here, we find that increased levels of KYNA relative to 3-HK are likely central to the protection conferred by TDO inhibition in a fruit fly model of Huntington's disease and that TRP treatment strongly reduces neurodegeneration by shifting KP flux toward KYNA synthesis. In fly models of Alzheimer's and Parkinson's disease, we provide genetic evidence that inhibition of TDO or KMO improves locomotor performance and ameliorates shortened life span, as well as reducing neurodegeneration in Alzheimer's model flies. Critically, we find that treatment with a chemical TDO inhibitor is robustly protective in these models. Consequently, our work strongly supports targeting of the KP as a potential treatment strategy for several major neurodegenerative disorders and suggests that alterations in the levels of neuroactive KP metabolites could underlie several therapeutic benefits.

Selected metabolites of kynurenine pathway and response to antipsychotic treatment in schizophrenia

IntroductionDeficit of glutamatergic transmission and aberrant function of kynurenine pathway, with disturbed synthesis of glutamate receptors antagonist, kynurenic acid (KYNA) and neurotoxic metabolite of kynurenine, 3-hydroxykynurenine (3-OH-KYN) have been implicated in the pathogenesis of schizophrenia.ObjectivesDemonstrated by others higher level of KYNA in the brain may cause relative deficiency of glutamate-mediate transmission with resulting behavioural and cognitive changes.AimsSearch for predictors of satisfactory response to antipsychotic treatment based on the analysis of KYNA and 3-OH-KYN serum levels.MethodsFifty-three patients with chronic schizophrenia and 46 healthy individuals were enrolled in the study. Quantitative analyses of KYNA and 3-OH-KYN were performed using high-pressure liquid chromatography (HPLC) and electrochemical detection, respectively. Clinical assessments (PANSS, SANS, SAPS) and blood analyses were conducted at 3 time-points: during the active phase of disease, after 4 weeks of modified pharmacotherapy, and after reaching remission.ResultsIn schizophrenia group, lower levels of KYNA (P = 0.002) and non-altered levels of 3-OH-KYN (p = 0.195), as compared to control, were detected during active phase of disease. Despite clinical improvement, no significant changes in the level of studied metabolites were observed later on. The initial level of 3-OH-KYN correlated negatively (r = –0.368; Spearman's rank) with clinical improvement (negative symptoms) (P < 0.05).Conclusions1. The peripheral dysregulation of kynurenine pathway metabolites in chronic schizophrenia manifests as relative increase in the ratio between neurotoxic 3-OH-KYN and neuroprotective KYNA. 2. The higher serum level of 3-OH-KYN during relapse of schizophrenia seems to predict poor response to antipsychotic treatment.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Inhibition of kynurenine aminotransferase II reduces activity of midbrain dopamine neurons

Kynurenic acid (KYNA), a neuroactive metabolite of tryptophan, is elevated in the brain of patients with psychotic disorders. Therefore, lowering brain KYNA levels might be a novel approach in the treatment of psychotic disorders. The present in vivo electrophysiological study aimed to investigate the effect of an inhibitor of kynurenine aminotransferase (KAT) II, the primary enzyme for KYNA synthesis, on dopamine (DA) neurons in the ventral tegmental area (VTA). Acute administration of the KAT II inhibitor PF-04859989 (5 or 10 mg/kg) was associated with a short-onset, time-dependent decrease in firing rate and burst activity of DA neurons, both parameters reaching a 50% reduction within 45 min. Furthermore, PF-04859989 reduced the number of spontaneously active DA cells as measured 4–6 after administration. Pretreatment with d-cycloserine (30 mg/kg) or CGP-52432 (10 mg/kg) prevented the inhibitory action of PF-04859989 (5 mg/kg) on firing rate and burst firing activity. In contrast, pretreatment with methyllycaconitine (MLA, 4 mg/kg) did not change the response, whereas picrotoxin (4.5 mg/kg) partially prevented the inhibitory effects of PF-04859989 (5 mg/kg, i.v.). Our results show that a specific inhibition of KAT II is associated with a marked reduction in VTA DA firing activity. This effect appears to be specifically executed by NMDA-receptors and mediated indirectly via a GABA(B)-receptor-induced disinhibition of DA neurons. Our findings are in line with the view that endogenous KYNA, by modulation of the NMDA-receptor, exerts important physiological roles in the brain.

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

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.

Alternative kynurenic acid synthesis routes studied in the rat cerebellum.

Kynurenic acid (KYNA), an astrocyte-derived, endogenous antagonist of α7 nicotinic acetylcholine and excitatory amino acid receptors, regulates glutamatergic, GABAergic, cholinergic and dopaminergic neurotransmission in several regions of the rodent brain. Synthesis of KYNA in the brain and elsewhere is generally attributed to the enzymatic conversion of L-kynurenine (L-KYN) by kynurenine aminotransferases (KATs). However, alternative routes, including KYNA formation from D-kynurenine (D-KYN) by D-amino acid oxidase (DAAO) and the direct transformation of kynurenine to KYNA by reactive oxygen species (ROS), have been demonstrated in the rat brain. Using the rat cerebellum, a region of low KAT activity and high DAAO activity, the present experiments were designed to examine KYNA production from L-KYN or D-KYN by KAT and DAAO, respectively, and to investigate the effect of ROS on KYNA synthesis. In chemical combinatorial systems, both L-KYN and D-KYN interacted directly with peroxynitrite (ONOO−) and hydroxyl radicals (OH•), resulting in the formation of KYNA. In tissue homogenates, the non-specific KAT inhibitor aminooxyacetic acid (AOAA; 1 mM) reduced KYNA production from L-KYN and D-KYN by 85.1 ± 1.7% and 27.1 ± 4.5%, respectively. Addition of DAAO inhibitors (benzoic acid, kojic acid or 3-methylpyrazole-5-carboxylic acid; 5 μM each) attenuated KYNA formation from L-KYN and D-KYN by ~35% and ~66%, respectively. ONOO− (25 μM) potentiated KYNA production from both L-KYN and D-KYN, and these effects were reduced by DAAO inhibition. AOAA attenuated KYNA production from L-KYN + ONOO− but not from D-KYN + ONOO−. In vivo, extracellular KYNA levels increased rapidly after perfusion of ONOO− and, more prominently, after subsequent perfusion with L-KYN or D-KYN (100 μM). Taken together, these results suggest that different mechanisms are involved in KYNA production in the rat cerebellum, and that, specifically, DAAO and ROS can function as alternative routes for KYNA production.

Pharmacological Targets for Neurorehabilitation

In respect to the functional activities of D-cycloserine scientists suggested anticonvulsive activities [4,5] and furthermore the application seems to improve memory and cognitive function. Recently we discovered that D-Cycloserine has the ability to block kynurenic acid synthesis [6]. Kynurenic acid, a metabolite along the kynurenine pathway of tryptophan degradation blocks the glycine sites of NMDA glutamatergic receptors [7] and also the nicotine cholinergic receptors [8] and exerts anticonvulsive activities [7].

Experimental diabetes mellitus type 1 increases hippocampal content of kynurenic acid in rats

BackgroundDiabetes mellitus (DM) is frequently associated with peripheral and central complications and has recently emerged as a risk factor for cognitive impairment and dementia. Kynurenic acid (KYNA), a unique tryptophan derivative, displays pleiotropic effects including blockade of ionotropic glutamate and α7 nicotinic receptors. Here, the influence of experimental diabetes on KYNA synthesis was studied in rat brain. MethodsDM was induced by i.p. administration of streptozotocin (STZ). Five weeks later, KYNA content and the activity of semi-purified kynurenine aminotransferases (KATs) were measured in frontal cortex, hippocampus and striatum of diabetic and insulin-treated rats, using HPLC-based methods. ResultsHippocampal but not cortical or striatal KYNA concentration was considerably increased during DM, either untreated or treated with insulin (220% and 170% of CTR, respectively). The activity of kynurenine aminotransferase I (KAT I) was not affected by DM in all of the studied structures. KAT II activity was moderately increased in cortex (145% of CTR) and hippocampus (126% of CTR), but not in striatum of diabetic animals. Insulin treatment normalized cortical but not hippocampal KAT II activity. ConclusionsA novel factor potentially implicated in diabetic hippocampal dysfunction has been identified. Observed increase of KYNA level may stem from the activation of endogenous neuroprotection, however, it may also have negative impact on cognition.

Reduction of brain kynurenic acid improves cognitive function.

The elevation of kynurenic acid (KYNA) observed in schizophrenic patients may contribute to core symptoms arising from glutamate hypofunction, including cognitive impairments. Although increased KYNA levels reduce excitatory neurotransmission, KYNA has been proposed to act as an endogenous antagonist at the glycine site of the glutamate NMDA receptor (NMDAR) and as a negative allosteric modulator at the α7 nicotinic acetylcholine receptor. Levels of KYNA are elevated in CSF and the postmortem brain of schizophrenia patients, and these elevated levels of KYNA could contribute to NMDAR hypofunction and the cognitive deficits and negative symptoms associated with this disease. However, the impact of endogenously produced KYNA on brain function and behavior is less well understood due to a paucity of pharmacological tools. To address this issue, we identified PF-04859989, a brain-penetrable inhibitor of kynurenine aminotransferase II (KAT II), the enzyme responsible for most brain KYNA synthesis. In rats, systemic administration of PF-04859989 dose-dependently reduced brain KYNA to as little as 28% of basal levels, and prevented amphetamine- and ketamine-induced disruption of auditory gating and improved performance in a sustained attention task. It also prevented ketamine-induced disruption of performance in a working memory task and a spatial memory task in rodents and nonhuman primates, respectively. Together, these findings support the hypotheses that endogenous KYNA impacts cognitive function and that inhibition of KAT II, and consequent lowering of endogenous brain KYNA levels, improves cognitive performance under conditions considered relevant for schizophrenia.

D-cycloserine lowers kynurenic acid formation—New mechanism of action

d-Cycloserine, known as a partial agonist at the glycine modulatory site of the glutamatergic N-methyl-d-aspartate (NMDA) receptor, exerts anticonvulsive activities and improves cognitive function. The present study evaluates the action of d-cycloserine with respect to the biosynthetic machinery of kynurenic acid (KYNA) synthesis e.g. the activity of enzymes synthesizing KYNA, kynurenine aminotransferases I, kynurenine aminotransferase II and kynurenine aminotransferase III (KAT I, KAT II and KAT III) in the rat liver and brain, and human frontal cortex in the presence of the anti-mycobacterial drug d-cycloserine, in an in vitro study. We found that d-cycloserine blocked dose-dependent and significantly KAT I, II and III activities in rat liver and brain homogenates. Furthermore, the inhibitory effect of KYNA formation was observed in the frontal cortex homogenate of human post mortem tissue, as well. d-Cycloserine, at 63.7µM concentration blocked significantly KAT II, I and III (53.2, 66.1 and 71.3% of control, P<0.001) activities in the human frontal cortex homogenate. Obtained data indicate that d-cycloserine exerts notable biochemical properties to block KYNA synthesis. Lowering of KYNA content due to d-cycloserine inhibition of KATs activities can free up more glycine sites for the actions of d-cycloserine. On the other site, it needs to be clarified, if the postulated mechanism for d-cycloserine to act as a partial agonist at the glycine site of the NMDA receptor could be mainly due to KAT's inhibition. We propose that this mechanism(s) might play a role in the improvement of memory, cognition and/or delusion in Alzheimer's, HIV-1 infected patients and schizophrenia patients.

Ammonia upregulates kynurenine aminotransferase II mRNA expression in rat brain: a role for astrocytic NMDA receptors?

Kynurenine aminotransferase II (KAT-II) is the astrocytic enzyme catalyzing the synthesis of kynurenic acid (KYNA), an endogenous inhibitor of the α7-nicotinic receptor and the NMDA receptor (NMDAr). A previous study demonstrated an increase of KYNA synthesis in the brain of rats with thioacetamide (TAA)-induced acute liver failure. Here we show that TAA administration increases KAT-II expression in the rat cerebral cortex and the effect is mimicked in cerebral cortical astrocytes in culture treated with high (5mM) concentration of ammonia. KAT-II expression in control and TAA-treated rats was increased by NMDAr antagonist memantine, and the effects of TAA and memantine appeared additive. In astrocytes, the NMDAr antagonist MK-801 raised KAT-II expression as well, while NMDA added alone had no effect. Glutamate decreased KAT-II mRNA level, which was attenuated by MK-801. The results suggest that stimulation of KAT-II expression during hepatic encephalopathy may be associated with a partial inactivation of astrocytic NMDAr by ammonia.

Pre‐ and postnatal exposure to kynurenine causes cognitive deficits in adulthood

Levels of kynurenic acid (KYNA), an endogenous product of tryptophan degradation, are elevated in the brain and cerebrospinal fluid of individuals with schizophrenia (SZ). This increase has been implicated in the cognitive dysfunctions seen in the disease, as KYNA is an antagonist of the α7 nicotinic acetylcholine receptor and the N-methyl-d-aspartate receptor, both of which are critically involved in cognitive processes and in a defining neurodevelopmental period in the pathophysiology of SZ. We tested the hypothesis that early developmental increases in brain KYNA synthesis might cause biochemical and functional impairments in adulthood. To this end, we stimulated KYNA formation by adding the KYNA precursor kynurenine (100 mg/day) to the chow fed to rat dams from gestational day 15 to postnatal day 21 (PD 21). This treatment raised brain KYNA levels in the offspring by 341% on PD 2 and 210% on PD 21. Rats were then fed normal chow until adulthood (PD 56-80). In the adult animals, basal levels of extracellular KYNA, measured in the hippocampus by in vivo microdialysis, were elevated (+12%), whereas extracellular glutamate levels were significantly reduced (-13%). In separate adult animals, early kynurenine treatment was shown to impair performance in two behavioral tasks linked to hippocampal function, the passive avoidance test and the Morris water maze test. Collectively, these studies introduce a novel, naturalistic rat model of SZ, and also suggest that increases in brain KYNA during a vulnerable period in brain development may play a significant role in the pathophysiology of the disease.

Kynurenic acid and 3-hydroxykynurenine production from d-kynurenine in mice

Kynurenic acid (KYNA), an antagonist of the α7 nicotinic acetylcholine receptor and the N-methyl-d-aspartate receptor, and 3-hydroxykynurenine (3-HK), a generator of reactive oxygen species, are neuroactive metabolites of the kynurenine pathway of tryptophan degradation. In the mammalian brain as elsewhere, both compounds derive from a common bioprecursor, l-kynurenine (l-KYN). Recent studies in rats demonstrated that d-kynurenine (d-KYN), a metabolite of the bacterial amino acid d-tryptophan, can also function as a bioprecursor of brain KYNA. We now investigated the conversion of systemically administered d-KYN to KYNA in mice and also explored the possible production of 3-HK in the same animals. Thirty min after an injection of d-KYN or l-KYN (30mg/kg, i.p.), newly produced KYNA and 3-HK were recovered from plasma, liver, forebrain and cerebellum in all cases. Using a new chiral separation method, 3-HK produced from d-KYN was positively identified as D-3-HK. l-KYN was the more effective precursor of KYNA in all tissues and also exceeded d-KYN as a precursor of brain 3-HK. In contrast, d-KYN was more potent as a precursor of 3-HK in the liver. The production of both KYNA and 3-HK from d-KYN was rapid in all tissues, peaking at 15–30min following a systemic injection of d-KYN. These results show that biosynthetic routes other than those classically ascribed to l-KYN can account for the synthesis of both KYNA and 3-HK in vivo. This new insight may be of significant physiological or pathological relevance.

Enzymatic transamination of d‐kynurenine generates kynurenic acid in rat and human brain

In the mammalian brain, the α7 nicotinic and NMDA receptor antagonist kynurenic acid is synthesized by irreversible enzymatic transamination of the tryptophan metabolite l-kynurenine. d-kynurenine, too, serves as a bioprecursor of kynurenic acid in several organs including the brain, but the conversion is reportedly catalyzed through oxidative deamination by d-amino acid oxidase. Using brain and liver tissue homogenates from rats and humans, and conventional incubation conditions for kynurenine aminotransferases, we show here that kynurenic acid production from d-kynurenine, like the more efficient kynurenic acid synthesis from l-kynurenine, is blocked by the aminotransferase inhibitor amino-oxyacetic acid. In vivo, focal application of 100 μM d-kynurenine by reverse microdialysis led to a steady rise in extracellular kynurenic acid in the rat striatum, causing a 4-fold elevation after 2 h. Attesting to functional significance, this increase was accompanied by a 36% reduction in extracellular dopamine. Both of these effects were duplicated by perfusion of 2 μM l-kynurenine. Co-infusion of amino-oxyacetic acid (2 mM) significantly attenuated the in vivo effects of d-kynurenine and essentially eliminated the effects of l-kynurenine. Thus, enzymatic transamination accounts in part for kynurenic acid synthesis from d-kynurenine in the brain. These results are discussed with regard to implications for brain physiology and pathology.

The role of kynurenines in the pathomechanism of amyotrophic lateral sclerosis and multiple sclerosis: therapeutic implications

Tryptophan is one of the essential amino acids, 80% of which is catabolised in the extrahepatic tissues by indoleamine-2,3-dioxygenase (IDO), the rate-limiting enzyme of the kynurenine pathway. Metabolites along the kynurenine pathway have been implicated to play a role in the pathomechanism of neuroinflammatory and neurodegenerative disorders. Changes in the concentration levels of kynurenines can shift the balance to pathological conditions. The ability to influence the metabolism towards the neuroprotective branch of the kynurenine pathway, i.e. towards kynurenic acid (KYNA) synthesis, may be one option in preventing neurodegenerative diseases. Three potential therapeutic strategies could be feasible to develop drugs to live up to expectations: (1) chemically related drugs with better bioavailability and higher affinity to the binding sites of excitatory receptors; (2) prodrugs of KYNA, which easily cross the blood-brain barrier combined with an inhibitor of organic acid transport for enhancement of the brain KYNA concentration; (3) inhibitors of enzymes of the kynurenine pathway. In this review, we focus on aspects of the pathomechanism and therapeutic possibilities of amyotrophic lateral sclerosis and multiple sclerosis that may be influenced by kynurenines.

Kynurenine 3-monooxygenase polymorphisms: relevance for kynurenic acid synthesis in patients with schizophrenia and healthy controls

Patients with schizophrenia show increased brain and cerebrospinal fluid (CSF) concentrations of the endogenous N-methyl-D-aspartate receptor antagonist kynurenic acid (KYNA). This compound is an end-metabolite of the kynurenine pathway, and its formation indirectly depends on the activity of kynurenine 3-monooxygenase (KMO), the enzyme converting kynurenine to 3-hydroxykynurenine. We analyzed the association between KMO gene polymorphisms and CSF concentrations of KYNA in patients with schizophrenia and healthy controls. Fifteen single nucleotide polymorphisms (SNPs) were selected covering KMO and were analyzed in UNPHASED. We included 17 patients with schizophrenia and 33 controls in our study. We found an association between a KMO SNP (rs1053230), encoding an amino acid change of potential importance for substrate interaction, and CSF concentrations of KYNA. Given the limited sample size, the results are tentative until replication. Our results suggest that the nonsynonymous KMO SNP rs1053230 influences CSF concentrations of KYNA.

High tryptophan diet reduces extracellular dopamine release via kynurenic acid production in rat striatum

At endogenous brain concentrations, the neuroinhibitory tryptophan metabolite kynurenic acid (KYNA) is a preferential antagonist of the α7 nicotinic acetylcholine receptor (α7nAChR). In the present study, male Wistar rats were fed a high tryptophan diet (adding 0.1-1.5% tryptophan) for 24 h to examine (i) the effect of increased tryptophan on extracellular dopamine (DA) and KYNA levels and (ii) to determine any possible interactions between DA and KYNA. Brain KYNA levels were dose-dependently increased by tryptophan intake, and these increase were consistent with kynurenine (KYN), the precursor to KYNA, levels in the brain, plasma and liver. Administration of the 1.5% tryptophan added diet reduced the extracellular DA level to 60%, and increased the extracellular KYNA to 320% in the striatum. The DA reduction was attenuated through inhibiting KYNA synthesis with 2-aminoadipic acid. These results indicate that a high tryptophan diet can induce KYNA production and suppress DA release. One possible mechanism is that as more KYN is metabolized from the high doses of tryptophan in the liver and released into the blood stream, KYNA production in astrocytes is enhanced and the increased extracellular KYNA inhibits DA release by blocking α7nAChRs. Dietary manipulation of KYNA formation in astrocytes may offer a unique strategy to modulate DA.