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.

Relationship between Serum Tryptophan and Tryptophan Metabolite Levels after Tryptophan Ingestion in Normal Subjects and Age-Related Cataract Patients

1995 ◽  
Vol 89 (6) ◽  
pp. 591-599 ◽  
Author(s):  
Roger J. W. Truscott ◽  
Anthony J. Elderfield
Keyword(s):  
Anthranilic Acid ◽  
Kynurenic Acid ◽  
Normal Subjects ◽  
Serum Levels ◽  
Xanthurenic Acid ◽  
Control Subjects ◽  
Age Related ◽  
Hydroxyanthranilic Acid ◽  
And Control ◽  
Cataract Patients

1. Cataract is the single major cause of blindness worldwide; however, the reasons for the development of this condition remain unknown. It has been suggested that the essential amino acid tryptophan may be implicated in the aetiology but definitive evidence has been lacking. 2. The serum levels of tryptophan and seven of its metabolites have been measured in both cataract patients and control subjects, after administration of tryptophan, in order to determine the typical response profile and to discover whether differences could be found in tryptophan metabolism in the two groups. 3. Tryptophan, kynurenine, kynurenic acid, xanthurenic acid, 3-hydroxyanthranilic acid, 5-hydroxyanthranilic acid, 5-hydroxytryptophan and anthranilic acid were measured by HPLC with dual electrochemical and programmable wavelength fluorescence detection. Fasting cataract patients (n = 42) and control subjects (n = 37) were given an oral dose of l-tryptophan and sera were sampled at 0, 1, 2, 4 and 6 h. 4. Statistically significant differences in the distribution of data between the two groups were observed. The responses of kynurenine and 5-hydroxyanthranilic acid were higher in cataract patients, but those of kynurenic acid and total tryptophan were lower than in control subjects. No statistically significant differences in free tryptophan, anthranilic acid, 3-hydroxyanthranilic acid, xanthurenic acid or 5-hydroxytryptophan levels were noted. 5. We conclude that there is a major subgroup of age-related cataract patients with a dysfunction in the metabolism of tryptophan. This may be related to the onset of cataract. The mechanism remains to be established but may operate via the action of tryptophan metabolites, such as 5-hydroxyanthranilic acid, which become reactive towards protein upon oxidation.

Similarity Between the Action of Pteridines and Tryptophan Metabolites on Lipid Metabolism

Pteridines ◽  
1999 ◽  
Vol 10 (3) ◽  
pp. 133-140 ◽  
Author(s):  
Vera Rudzite ◽  
Edite Jurika ◽  
Bernhard Widner ◽  
Dietmar Fuchs
Keyword(s):  
Fatty Acids ◽  
Nicotinic Acid ◽  
Anthranilic Acid ◽  
Kynurenic Acid ◽  
Picolinic Acid ◽  
Test System ◽  
Xanthurenic Acid ◽  
Phospholipid Biosynthesis ◽  
Wet Weight

Abstract Incorporation of fatty acids into phospholipids has been investigated using samples of rat liver tissue homogenate, Krebs-Ringer-phosphate buffer (pH=7.4) containing 0.3% albumin, fatty acid mixture and glycerol. The addition of anthranilic acid (2.2 and 4 nmol/g wet weight), kynurenic acid (4 and 40 nmol/ g wet weight), xanthurenic acid (4 and 40 nmol/g wet weight), picolinic acid (0.2 and 2 nmol/g wet weight) induced an increase of saturated and a decrease of polyunsaturated fatty acids incorporation into phospholipids as well as an eleyation of choksterol concentration in samples used for phospholipid biosynthesis in vitro. These changes were similar to those observed after addition of kynurenine and neopterin to the same test system, An inverse relationship has been observed after addition of nicotinic acid to samples used for phospholipid biosynthesis in vitro. Nicrotinic acid induced .1 decrease of saturated and an increase of unsaturated fatty acids incorporation into phospholipids as well as decrease of cholesterol concentration in samples, These changes were similar to those observed after addition of 3-hydroxykynurenine, 3-hydroxyanthranilic acid, quinolinic, acid, 5,6],8-tetrahydrobiopterin and its precursors to the same test system used rex phospholipid biosynthesis in vitro. In parallel anthranilic acid, kynurenic acid, xanthurenic acid and picolinic acid decrease while nicotinic acid increases membrane fluidity in the studied concentrations.

scholarly journals Intravenous administration of LPS activates the kynurenine pathway in healthy male human subjects: a prospective placebo-controlled cross-over trial

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Vincent Millischer ◽  
Matthias Heinzl ◽  
Anthi Faka ◽  
Michael Resl ◽  
Ada Trepci ◽  
...  
Keyword(s):  
Human Subjects ◽  
Picolinic Acid ◽  
Plasma Concentrations ◽  
Experimental Studies ◽  
Placebo Treatment ◽  
Kynurenine Pathway ◽  
Healthy Male ◽  
Systemic Injection ◽  
Plasma Tryptophan ◽  
Endotoxemia Model

Abstract Background Administration of lipopolysaccharide (LPS) from Gram-negative bacteria, also known as the human endotoxemia model, is a standardized and safe model of human inflammation. Experimental studies have revealed that peripheral administration of LPS leads to induction of the kynurenine pathway followed by depressive-like behavior and cognitive dysfunction in animals. The aim of the present study is to investigate how acute intravenous LPS administration affects the kynurenine pathway in healthy male human subjects. Methods The present study is a prospective, single-blinded, randomized, placebo-controlled cross-over study to investigate the effects of intravenously administered LPS (Escherichia coli O113, 2 ng/kg) on tryptophan and kynurenine metabolites over 48 h and their association with interleukin-6 (IL-6) and C-reactive protein (CRP). The study included 10 healthy, non-smoking men (18–40 years) free from medication. Statistical differences in tryptophan and kynurenine metabolites as well as associations with IL-6 and CRP in LPS and placebo treated subjects were assessed with linear mixed-effects models. Results Systemic injection of LPS was associated with significantly lower concentrations of plasma tryptophan and kynurenine after 4 h, as well as higher concentrations of quinolinic acid (QUIN) after 48 h compared to the placebo injection. No differences were found in kynurenic acid (KYNA) or picolinic acid plasma concentrations between LPS or placebo treatment. The KYNA/kynurenine ratio peaked at 6 h post LPS injection while QUIN/kynurenine maintained significantly higher from 3 h post LPS injection until 24 h. The kynurenine/tryptophan ratio was higher at 24 h and 48 h post LPS treatment. Finally, we report an association between the kynurenine/tryptophan ratio and CRP. Conclusions Our findings strongly support the concept that an inflammatory challenge with LPS induces the kynurenine pathway in humans, activating both the neurotoxic (QUIN) and neuroprotective (KYNA) branch of the kynurenine pathway. Trial registration This study is based on a study registered at ClinicalTrials.gov, NCT03392701. Registered 21 December 2017.

Modified enzyme-based colorimetric assay of urinary and plasma oxalate with improved sensitivity and no ascorbate interference: reference values and sample handling procedures

1991 ◽  
Vol 37 (7) ◽  
pp. 1229-1235 ◽  
Author(s):  
David M Wilson ◽  
Robert R Liedtke
Keyword(s):  
Reference Values ◽  
Colorimetric Assay ◽  
Plasma Concentrations ◽  
Urinary Oxalate ◽  
Sample Handling ◽  
Control Subjects ◽  
Analytical Recovery ◽  
Healthy Control ◽  
Excretion Rates ◽  
Urinary Oxalate Excretion

Abstract The measurement of oxalate in urine and plasma continues to be difficult, particularly in the presence of ascorbate. We have modified and validated a colorimetric assay involving the use of oxalate oxidase (EC 1.2.3.4). Modification of an HPLC spectrophotometric detector improved sensitivity (to as much as 1000-fold that of conventional spectrophotometers) and allowed measurement of oxalate concentrations less than 1 mumol/L. This provided more than enough sensitivity for measurement of normal concentrations of plasma oxalate. We established reference values for oxalate concentrations in urine and plasma, studied sample handling, and established conditions to avoid ascorbate interference in urine and plasma measurements. Mean analytical recovery of [14C]oxalate from plasma to the filtrate was 86 (SD 10)%; recovery of unlabeled oxalate from filtrate was 87 (SD 9)%. Urinary oxalate excretion rates in apparently healthy controls were 0.11-0.46 mmol/24 h. Plasma concentrations in control subjects were 2.5 (SD 0.7) mumol/L, similar to concentrations determined by recent gas chromatographic and isotope dilution methods. Frozen and acidified urine samples showed no interference from ascorbate when excess ascorbate was avoided. Ingestion of 2 g of ascorbate daily did not increase urinary oxalate in healthy control subjects, but during storage ascorbate was converted to oxalate in all conditions tested.

Quantitative Determination of Tryptophan Metabolites (via Kynurenine) in Biologic Fluids

1959 ◽  
Vol 5 (5) ◽  
pp. 391-401 ◽  
Author(s):  
D Coppini ◽  
C A Benassi ◽  
M Montorsi
Keyword(s):  
Quantitative Determination ◽  
Rapid Method ◽  
Methyl Ether ◽  
Anthranilic Acid ◽  
Kynurenic Acid ◽  
Large Range ◽  
Xanthurenic Acid ◽  
Two Dimensional ◽  
Tryptophan Metabolites

Abstract A simple and rapid method for the quantitative determination of eight tryptophan (via kynurenine) metabolites is described. The following compounds can be determined even when present in the same sample of urine, blood or spinal fluid: kynurenine, 3-hydroxykynurenine, Nα-acetylkynurenine, anthranilic and 3-hydroxyanthranilic acids, kynurenic and xanthurenic acids, 8-methyl ether of the xanthurenic acid. The compounds are separated by means of two-dimensional chromatography. Spots of kynurenic acid, Nα-acetylkynurenine and xanthurenic acid 8-methyl ether are eluted with ethanol and the absorbancies are read in the ultraviolet. An acetic solution of p-dimethylaminobenzaldehyde serves as eluent and chromogenic reagent for the spots of kynurenine and anthranilic acid. Spots corresponding to 3-hydroxykynurenine, xanthurenic and 3-hydroxyanthranilic acids are eluted with water and determined by means of the color developed with a diazo reagent. Kynurenic and xanthurenic acids can also be determined conveniently by means of a spectrophotofluorometric procedure. The reproducibility of the results is satisfactory over a large range, and very good for amounts of 1 to 5 µg.

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.

Kynurenic acid in brain function and dysfunction

2020 ◽  
pp. 323-332
Author(s):  
Robert Schwarcz ◽  
Sophie Erhardt
Keyword(s):  
Kynurenic Acid ◽  
Kynurenine Pathway ◽  
Psychotic Symptoms ◽  
Gabaergic Neurotransmission ◽  
Novel Approach ◽  
Healthy Control ◽  
Amino Acid Tryptophan ◽  
Persons With Schizophrenia ◽  
And Function ◽  
The Brain

The essential amino acid tryptophan is degraded primarily by the kynurenine pathway, a cascade of enzymatic steps leading to the generation of several neuroactive compounds. Of those, kynurenic acid (KYNA), an antagonist at N-methyl-D-aspartate (NMDA) and alpha7-nicotinic receptors, has gained much attention in schizophrenia research. The concentrations of both KYNA and its precursor, kynurenine, have been repeatedly found significantly elevated both in the postmortem cerebral cortex and in the cerebrospinal fluid of schizophrenia persons as compared to healthy control subjects. Studies in experimental animals have demonstrated that KYNA tightly controls dopaminergic, cholinergic, glutamatergic, and GABAergic neurotransmission, and elevated brain levels appear related to psychotic symptoms and cognitive impairments. The kyurenine pathway is highly inducible by immune activation, and studies have shown that the pro-inflammatory cytokines interleukin (IL)-1β‎ and IL-6 are elevated in schizophrenia and stimulate the production of KYNA. Another mechanism that may account for the abnormally high central kynurenine and KYNA levels seen in schizophrenia might be the observed reduced expression and activity of the enzyme kynurenine 3-monooxygenase (KMO), shunting the synthesis of kynurenine toward KYNA. In line with these studies and concepts, preclinical results suggest that inhibition of kynurenine aminotransferase (KAT) II, by reducing the synthesis and function of KYNA in the brain, offers a novel approach to ameliorate psychosis and to improve cognitive performance in persons with schizophrenia.

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 Kynurenines in the Pathogenesis of Multiple Sclerosis: Therapeutic Perspectives

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1564 ◽  
Author(s):  
Tamás Biernacki ◽  
Dániel Sandi ◽  
Krisztina Bencsik ◽  
László Vécsei
Keyword(s):  
Multiple Sclerosis ◽  
Immune System ◽  
Quinolinic Acid ◽  
Nicotinamide Adenine Dinucleotide ◽  
Kynurenic Acid ◽  
Picolinic Acid ◽  
Kynurenine Pathway ◽  
Current Evidence ◽  
Therapeutic Approaches ◽  
The Past

Over the past years, an increasing amount of evidence has emerged in support of the kynurenine pathway’s (KP) pivotal role in the pathogenesis of several neurodegenerative, psychiatric, vascular and autoimmune diseases. Different neuroactive metabolites of the KP are known to exert opposite effects on neurons, some being neuroprotective (e.g., picolinic acid, kynurenic acid, and the cofactor nicotinamide adenine dinucleotide), while others are toxic to neurons (e.g., 3-hydroxykynurenine, quinolinic acid). Not only the alterations in the levels of the metabolites but also disturbances in their ratio (quinolinic acid/kynurenic acid) have been reported in several diseases. In addition to the metabolites, the enzymes participating in the KP have been unearthed to be involved in modulation of the immune system, the energetic upkeep of neurons and have been shown to influence redox processes and inflammatory cascades, revealing a sophisticated, intertwined system. This review considers various methods through which enzymes and metabolites of the kynurenine pathway influence the immune system, the roles they play in the pathogenesis of neuroinflammatory diseases based on current evidence with a focus on their involvement in multiple sclerosis, as well as therapeutic approaches.

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