scholarly journals Modulation of Hippocampal Synaptic Transmission by the Kynurenine Pathway Member Xanthurenic Acid and Other VGLUT Inhibitors

2013 ◽  
Vol 38 (6) ◽  
pp. 1060-1067 ◽  
Author(s):  
S A Neale ◽  
C S Copeland ◽  
V N Uebele ◽  
F J Thomson ◽  
T E Salt
Keyword(s):  
Synaptic Transmission ◽  
Kynurenine Pathway ◽  
Xanthurenic Acid

scholarly journals Clinical relevance of depressed kynurenine pathway in episodic migraine patients: potential prognostic markers in the peripheral plasma during the interictal period

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Bernadett Tuka ◽  
Aliz Nyári ◽  
Edina Katalin Cseh ◽  
Tamás Körtési ◽  
Dániel Veréb ◽  
...  
Keyword(s):  
Anthranilic Acid ◽  
Clinical Relevance ◽  
Kynurenic Acid ◽  
Picolinic Acid ◽  
Plasma Concentrations ◽  
Episodic Migraine ◽  
Kynurenine Pathway ◽  
Xanthurenic Acid ◽  
Control Subjects ◽  
Healthy Control

Abstract Background Altered glutamatergic neurotransmission and neuropeptide levels play a central role in migraine pathomechanism. Previously, we confirmed that kynurenic acid, an endogenous glutamatergic antagonist, was able to decrease the expression of pituitary adenylate cyclase-activating polypeptide 1–38, a neuropeptide with known migraine-inducing properties. Hence, our aim was to reveal the role of the peripheral kynurenine pathway (KP) in episodic migraineurs. We focused on the complete tryptophan (Trp) catabolism, which comprises the serotonin and melatonin routes in addition to kynurenine metabolites. We investigated the relationship between metabolic alterations and clinical characteristics of migraine patients. Methods Female migraine patients aged between 25 and 50 years (n = 50) and healthy control subjects (n = 34) participated in this study. Blood samples were collected from the cubital veins of subjects (during both the interictal/ictal periods in migraineurs, n = 47/12, respectively). 12 metabolites of Trp pathway were determined by neurochemical measurements (UHPLC-MS/MS). Results Plasma concentrations of the most Trp metabolites were remarkably decreased in the interictal period of migraineurs compared to healthy control subjects, especially in the migraine without aura (MWoA) subgroup: Trp (p < 0.025), L-kynurenine (p < 0.001), kynurenic acid (p < 0.016), anthranilic acid (p < 0.007), picolinic acid (p < 0.03), 5-hydroxy-indoleaceticacid (p < 0.025) and melatonin (p < 0.023). Several metabolites showed a tendency to elevate during the ictal phase, but this was significant only in the cases of anthranilic acid, 5-hydroxy-indoleaceticacid and melatonin in MWoA patients. In the same subgroup, higher interictal kynurenic acid levels were identified in patients whose headache was severe and not related to their menstruation cycle. Negative linear correlation was detected between the interictal levels of xanthurenic acid/melatonin and attack frequency. Positive associations were found between the ictal 3-hydroxykynurenine levels and the beginning of attacks, just as between ictal picolinic acid levels and last attack before ictal sampling. Conclusions Our results suggest that there is a widespread metabolic imbalance in migraineurs, which manifests in a completely depressed peripheral Trp catabolism during the interictal period. It might act as trigger for the migraine attack, contributing to glutamate excess induced neurotoxicity and generalised hyperexcitability. This data can draw attention to the clinical relevance of KP in migraine.

Association of markers of inflammation, the kynurenine pathway and B vitamins with age and mortality, and a signature of inflammaging

2021 ◽  
Author(s):  
Pierre-Antoine Dugué ◽  
Allison M Hodge ◽  
Arve Ulvik ◽  
Per M Ueland ◽  
Øivind Midttun ◽  
...  
Keyword(s):  
Cox Regression ◽  
Kynurenine Pathway ◽  
Health Study ◽  
Xanthurenic Acid ◽  
Markers Of Inflammation ◽  
Par Index ◽  
Vitamin Status ◽  
Melbourne Collaborative Cohort Study ◽  
Index Ratio ◽  
B Vitamin

Abstract Background Inflammation is a key feature of aging. We aimed to i) investigate the association of 34 blood markers potentially involved in inflammatory processes with age and mortality, ii) develop a signature of ‘inflammaging’. Methods Thirty-four blood markers relating to inflammation, B vitamin status and the kynurenine pathway were measured in 976 participants in the Melbourne Collaborative Cohort Study at baseline (median age=59 years) and follow-up (median age=70 years). Associations with age and mortality were assessed using linear and Cox regression, respectively. A parsimonious signature of inflammaging was developed and its association with mortality was compared with two marker scores calculated across all markers associated with age and mortality, respectively. Results The majority of markers (30/34) were associated with age, with stronger associations observed for neopterin, cystatin C, IL-6, TNF-α, several markers of the kynurenine pathway and derived indices KTR (kynurenine/tryptophan ratio), PAr index (ratio of 4-pyridoxic acid and the sum of pyridoxal 5´-phosphate and pyridoxal), and HK:XA (3-hydroxykynurenine/xanthurenic acid ratio). Many markers (17/34) showed an association with mortality, in particular IL-6, neopterin, CRP, quinolinic acid, PAr index, and KTR. The inflammaging signature included ten markers and was strongly associated of mortality (HR per SD=1.40, 95%CI:1.24-1.57, P=2x10 -8), similar to scores based on all age-associated (HR=1.38, 95%CI:1.23-1.55, P=4x10 -8) and mortality-associated markers (HR=1.43, 95%CI:1.28-1.60, P=1x10 -10), respectively. Strong evidence of replication of the inflammaging signature association with mortality was found in the Hordaland Health Study. Conclusion Our study highlights the key role of the kynurenine pathway and vitamin B6 catabolism in aging, along with other well-established inflammation-related markers. A signature of inflammaging based on ten markers was strongly associated with mortality.

scholarly journals Metabolic dysfunctions in the kynurenine pathway, noradrenergic and purine metabolism in schizophrenia and bipolar disorders

2019 ◽  
Vol 50 (4) ◽  
pp. 595-606 ◽  
Author(s):  
Nils Eiel Steen ◽  
Ingrid Dieset ◽  
Sigrun Hope ◽  
Trude S.J. Vedal ◽  
Olav B. Smeland ◽  
...  
Keyword(s):  
Psychotic Disorders ◽  
Plasma Concentrations ◽  
Bipolar Disorders ◽  
Kynurenine Pathway ◽  
Xanthurenic Acid ◽  
Vanillylmandelic Acid ◽  
Healthy Controls ◽  
Schizophrenia Spectrum Disorders ◽  
Schizophrenia Spectrum ◽  
Metabolic Dysfunctions

AbstractBackgroundWe aimed at exploring potential pathophysiological processes across psychotic disorders, applying metabolomics in a large and well-characterized sample of patients and healthy controls.MethodsPatients with schizophrenia and bipolar disorders (N = 212) and healthy controls (N = 68) had blood sampling with subsequent metabolomics analyses using electrochemical coulometric array detection. Concentrations of 52 metabolites including tyrosine, tryptophan and purine pathways were compared between patients and controls while controlling for demographic and clinical characteristics. Significant findings were further tested in medication-free subsamples.ResultsSignificantly decreased plasma concentrations in patients compared to healthy controls were found for 3-hydroxykynurenine (3OHKY, p = 0.0008), xanthurenic acid (XANU, p = 1.5×10−5), vanillylmandelic acid (VMA, p = 4.5×10−5) and metanephrine (MN, p = 0.0001). Plasma concentration of xanthine (XAN) was increased in the patient group (p = 3.5×10−5). Differences of 3OHKY, XANU, VMA and XAN were replicated across schizophrenia spectrum disorders and bipolar disorders subsamples of medication-free individuals.ConclusionsAlthough prone to residual confounding, the present results suggest the kynurenine pathway of tryptophan metabolism, noradrenergic and purinergic system dysfunction as trait factors in schizophrenia spectrum and bipolar disorders. Of special interest is XANU, a metabolite previously not found to be associated with bipolar disorders.

scholarly journals 876Association of blood markers of inflammation, vitamin status and the kynurenine pathway with age and all-cause mortality

2021 ◽  
Vol 50 (Supplement_1) ◽  
Author(s):  
Pierre-antoine Dugué ◽  
Allison Hodge ◽  
Per Ueland ◽  
Øivind Midttun ◽  
Arve Ulvik ◽  
...  
Keyword(s):  
Quinolinic Acid ◽  
Cox Regression ◽  
Strong Association ◽  
Kynurenine Pathway ◽  
Xanthurenic Acid ◽  
Lasso Regression ◽  
Markers Of Inflammation ◽  
Par Index ◽  
Vitamin Status ◽  
All Cause Mortality

Abstract Background Inflammation is a key feature of aging and a cause of numerous diseases. We investigated the association of 35 blood markers involved in inflammatory processes with age and mortality and developed a signature of ‘inflammaging’. Methods Thirty-five blood markers relating to the kynurenine pathway, vitamin status, and inflammation were measured in 976 participants in the Melbourne Collaborative Cohort Study at baseline (1990-1994, median age 59 years) and follow-up (2003-2007, median age 70 years). Associations of each marker with age and all-cause mortality were assessed using linear and Cox regression, respectively. A signature of inflammaging was obtained via Lasso regression of age on the markers and tested for association with mortality; we compared mortality associations for this signature and two weighted scores across all markers associated with age and mortality, respectively. Results Most markers (29/35) were associated with age, with strongest associations observed for cystatin C, neopterin, quinolinic acid, and the kynurenine/tryptophan ratio, PAr index, and 3-hydroxykynurenine/xanthurenic acid ratio. Many markers (14/35) showed strong associations with mortality in particular neopterin, quinolinic acid, HK/XA, PAr index, CRP, IL-6 and KTr. The inflammaging signature included six markers and showed strong association with mortality (HR = 1.5, 95%CI: 1.3-1.7), almost as strong as the association of weighted scores combining all measured markers. Conclusions Our study highlights the key role played by markers of the kynurenine pathway and vitamin B6 catabolism in aging, along with other well-established inflammation-related markers. Key messages A signature of ‘inflammaging’ based on 6 markers may be useful to better predict mortality.

scholarly journals The impact of bariatric surgery on serum tryptophan–kynurenine pathway metabolites

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Kai Tai Derek Yeung ◽  
Nicholas Penney ◽  
Luke Whiley ◽  
Hutan Ashrafian ◽  
Matthew R. Lewis ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Bariatric Surgery ◽  
Serum Levels ◽  
Kynurenine Pathway ◽  
Xanthurenic Acid ◽  
Liquid Chromatography Tandem Mass ◽  
Post Operation ◽  
Ultrahigh Performance Liquid Chromatography ◽  
The Impact

AbstractThis study aims to explore the immediate effects of bariatric surgery on serum tryptophan–kynurenine pathway metabolites in individuals with type 2 diabetes and BMI > 30. With the goal of providing insight into the link between tryptophan pathway metabolites, type 2 diabetes, and chronic obesity-induced inflammation. This longitudinal study included 20 participants. Half were diagnosed with type 2 diabetes. 11 and 9 underwent RYGB and SG respectively. Blood samples were obtained at pre-operative and 3 months post-operative timepoints. Tryptophan and downstream metabolites of the kynurenine pathway were quantified with an ultrahigh-performance liquid chromatography tandem mass spectrometry with electrospray ionisation method. At 3 months post-operation, RYGB led to significant reductions in tryptophan, kynurenic acid and xanthurenic acid levels when compared to baseline. Significant reductions of the same metabolites after surgery were also observed in individuals with T2D irrespective of surgical procedure. These metabolites were significantly correlated with serum HbA1c levels and BMI. Bariatric surgery, in particular RYGB reduces serum levels of tryptophan and its downstream kynurenine metabolites. These metabolites are associated with T2D and thought to be potentially mechanistic in the systemic processes of obesity induced inflammation leading to insulin resistance. Its reduction after surgery is associated with an improvement in glycaemic control (HbA1c).

scholarly journals Changes in synaptic transmission and protein expression in the brains of adult offspring after prenatal inhibition of the kynurenine pathway

Neuroscience ◽  
2013 ◽  
Vol 254 ◽  
pp. 241-259 ◽  
Author(s):  
C.M. Forrest ◽  
O.S. Khalil ◽  
M. Pisar ◽  
K. McNair ◽  
E. Kornisiuk ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Protein Expression ◽  
Kynurenine Pathway ◽  
Adult Offspring

scholarly journals Vitamins B2and B6as determinants of kynurenines and related markers of interferon-γ-mediated immune activation in the community-based Hordaland Health Study

2014 ◽  
Vol 112 (7) ◽  
pp. 1065-1072 ◽  
Author(s):  
Despoina Theofylaktopoulou ◽  
Arve Ulvik ◽  
Øivind Midttun ◽  
Per Magne Ueland ◽  
Stein Emil Vollset ◽  
...  
Keyword(s):  
Immune Activation ◽  
Plasma Concentrations ◽  
Correlation Coefficients ◽  
Interferon Γ ◽  
Kynurenine Pathway ◽  
Additive Models ◽  
B Vitamins ◽  
Health Study ◽  
Xanthurenic Acid ◽  
Hydroxyanthranilic Acid

Vitamins B2and B6are cofactors in the kynurenine pathway. Many of the kynurenines are neuroactive compounds with immunomodulatory effects. In the present study, we aimed to investigate plasma concentrations of vitamins B2and B6as determinants of kynurenines and two markers of interferon-γ-mediated immune activation (kynurenine:tryptophan ratio (KTR) and neopterin). We measured the concentrations of vitamins B2and B6vitamers, neopterin, tryptophan and six kynurenines (i.e. kynurenine, anthranilic acid, kynurenic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid and xanthurenic acid) in plasma from 7051 individuals. Dietary intake of vitamins B2and B6was assessed using a validated FFQ. Associations were investigated using partial Spearman's correlations, generalised additive models, and segmented or multiple linear regression. The B2vitamer, riboflavin, was positively associated with 3-hydroxyanthranilic acid and xanthurenic acid, with correlation coefficients, as obtained by segmented regression, of 0·20 (95 % CI 0·16, 0·23) and 0·24 (95 % CI 0·19, 0·28), at riboflavin concentrations below the median value (13·0 nmol/l). The vitamin B6vitamer, pyridoxal 5′-phosphate (PLP), was positively associated with most kynurenines at PLP concentrations < 39·3–47·0 nmol/l, and inversely associated with 3-hydroxykynurenine with the association being more prominent at PLP concentrations < 18·9 nmol/l. Riboflavin and PLP were associated with xanthurenic acid only at relatively low, but normal concentrations of both vitamers. Lastly, PLP was negatively correlated with neopterin and KTR. These results demonstrate the significant and complex determination of kynurenine metabolism by vitamin status. Future studies on B-vitamins and kynurenines in relation to chronic diseases should therefore integrate data on relevant biomarkers related to B-vitamins status and tryptophan metabolism.

scholarly journals Coordination Complex Formation and Redox Properties of Kynurenic and Xanthurenic Acid Can Affect Brain Tissue Homeodynamics

Antioxidants ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 476 ◽  
Author(s):  
Lenka Kubicova ◽  
Franz Hadacek ◽  
Gert Bachmann ◽  
Wolfram Weckwerth ◽  
Vladimir Chobot
Keyword(s):  
Complex Formation ◽  
Neurodegenerative Diseases ◽  
Antioxidant Activities ◽  
Differential Pulse ◽  
Coordination Complexes ◽  
Kynurenine Pathway ◽  
Coordination Complex ◽  
Xanthurenic Acid ◽  
Ros Scavenging ◽  
Deoxyribose Degradation

Reactive oxygen species (ROS) are known for their participation in various physiological and pathological processes in organisms, including ageing or degeneration. Kynurenine pathway metabolites, such as kynurenic (KYNA) or xanthurenic (XA) acid, can affect neurodegenerative diseases due to their ROS scavenging and Fe ion coordination complex formation but insights are still incomplete. Therefore, we investigated the formation and antioxidant capabilities of KYNA– and XA–Fe complexes by nano-electrospray−mass spectrometry, differential pulse voltammetry, deoxyribose degradation and FeII autoxidation assays. XA formed coordination complexes with FeII or FeIII ions and was an effective antioxidant. By contrast, only FeII–KYNA complexes could be detected. Moreover, KYNA showed no antioxidant effects in the FeCl3/ascorbic acid deoxyribose degradation assay variant and only negligible activities in the FeII autoxidation assay. Coordination complexes of Fe ions with KYNA probably stabilize KYNA in its keto tautomer form. Nevertheless, both KYNA and XA exhibited sufficient antioxidant activities in some of the employed assay variants. The results provide evidence that both have the potential to alleviate neurodegenerative diseases by helping to maintain tissue redox homeodynamics.

scholarly journals Postpartum corticosterone and fluoxetine shift the tryptophan-kynurenine pathway in dams

2021 ◽  
Author(s):  
Wansu Qiu ◽  
Kimberly A. Go ◽  
Yvonne Lamers ◽  
Liisa A. M. Galea
Keyword(s):  
Selective Serotonin Reuptake Inhibitors ◽  
De Novo ◽  
Kynurenine Pathway ◽  
Xanthurenic Acid ◽  
Plasma Tryptophan ◽  
Limited Efficacy ◽  
Metabolite Concentrations ◽  
Antidepressant Efficacy ◽  
Enzyme Cofactors ◽  
Hydroxyanthranilic Acid

AbstractPerinatal depression (PND) affects 15% of mothers. Selective serotonin reuptake inhibitors (SSRIs) are currently the first-line of treatment for PND, but are not always efficacious. Previously, we found significant reductions in plasma tryptophan concentrations and higher hippocampal proinflammatory cytokine, IL-1β levels, due to maternal SSRI treatment. Both inflammation and tryptophan-kynurenine metabolic pathway (TKP) are associated with SSRI efficacy in individuals with major depressive disorder (MDD). TKP is divided into neuroprotective and neurotoxic pathways. Higher metabolite concentrations of the neurotoxic pathway are associated with depression onset and implicated in SSRI efficacy. Metabolites in TKP were investigated in a rodent model of de novo postpartum depression (PPD) given treatment with the SSRI, fluoxetine (FLX). Dams were administered corticosterone (CORT) (40mg/kg, s.c.), and treated with the SSRI, fluoxetine (FLX) (10mg/kg, s.c.), during the postpartum for 22 days after parturition. Plasma TKP metabolite concentrations were quantified on the last day of treatment. Maternal postpartum CORT increased neurotoxic metabolites and co-enzyme/cofactors in dams (3-hydroxykynurenine, 3-hydroxyanthranilic acid, vitamin B2, flavin adenine dinucleotide). The combination of both CORT and FLX shifted the neuroprotective-to-neurotoxic ratio towards neurotoxicity. Postpartum FLX decreased plasma xanthurenic acid concentrations. Together, our data indicate higher neurotoxic TKP expression due to maternal postpartum CORT treatment, similar to clinical presentation of MDD. Moreover, maternal FLX treatment showed limited efficacy to influence TKP metabolites, which may correspond to its limited efficacy to treat depressive-like endophenotypes. Overall suggesting changes in TKP may be used as a biomarker of de novo PPD and antidepressant efficacy and targeting this pathway may serve as a potential therapeutic target.

Niacin Depletion in Parkinsonian Patients Treated with L-dopa, Benserazide and Carbidopa

1979 ◽  
Vol 56 (1) ◽  
pp. 89-93 ◽  
Author(s):  
D. A. Bender ◽  
C. J. Earl ◽  
A. J. Lees
Keyword(s):  
Vitamin B6 ◽  
Kynurenine Pathway ◽  
Nucleotide Metabolism ◽  
Xanthurenic Acid ◽  
Control Value ◽  
Decarboxylase Inhibitors ◽  
Vitamin B6 Deficiency ◽  
Nicotinamide Coenzymes ◽  
Niacin Deficiency ◽  
Endogenous Synthesis

1. Benserazide and carbidopa, decarboxylase inhibitors used in the treatment of Parkinson's disease, have been shown to inhibit the enzyme kynurenine hydrolase in rat and mouse liver. This results in reduced synthesis of nicotinamide coenzymes from tryptophan, and hence an increased reliance on dietary niacin. 2. Pellagra might be expected as a result of this inhibition of endogenous synthesis of nicotinamide nucleotides, but has not been reported in patients treated with either drug. 3. The urinary excretion of N1-methylnicotinamide, a product of nicotinamide nucleotide metabolism, is considerably reduced in patients treated with dopa alone or in combination with an inhibitor of peripheral dopa decarboxylase, to as low as 40% of the control value. This means that many of these patients could be classified as ‘at risk’ of niacin deficiency, even if not frankly deficient. 4. Patients treated with dopa plus a decarboxylase inhibitor, but not those treated with dopa alone, also show a reduced excretion of xanthurenic acid, and an increased excretion of kynurenine, as would be expected after inhibition of the kynurenine pathway, and possibly indicative of marginal vitamin B6 deficiency.

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