scholarly journals Effects of Tranilast on the Urinary Excretion of Kynurenic and Quinolinic Acid under Conditions of L Tryptophan Loading

2013 ◽  
Vol 6 ◽  
pp. IJTR.S12797 ◽  
Author(s):  
Rowland R. Noakes
Keyword(s):  
Urinary Excretion ◽  
Quinolinic Acid ◽  
Kynurenic Acid ◽  
Competitive Inhibitor ◽  
Kynurenine Pathway ◽  
Tryptophan Metabolism ◽  
Autoimmune Response ◽  
Current Therapy ◽  
Indoleamine 2 ◽  
Hydroxyanthranilic Acid

The pathogenesis of morphea and other cutaneous sclerosing disorders remain poorly understood. Although they are considered to be autoimmune disorders, abnormal tryptophan metabolism may be involved. Current therapy is directed to supressing the autoimmune response. Demonstration of a therapeutic response to manipulation of the kynurenine pathway would both support a role for abnormal tryptophan metabolism and offer additional targets for therapy. Tranilast is a 3-hydroxyanthranilic acid derivative known to target the kynurenine pathway. The aim of this study was to see if tranilast lowered the urinary excretion of the kynurenine metabolites kynurenic and quinolinic acid under condition of L tryptophan loading in a volunteer. Mean baseline value for kynurenic acid and quinolinic acid were 1.1 and 2.1 mmol/mol creatinine, respectively. This rose to 5.6 and 3.8 mmol/mol creatinine respectively under conditions of L tryptophan loading 2 grams daily. Adding 1 g of tranilast daily lowered the values to 2.0 and 2.9 mmol/mol creatinine, respectively. These data suggest that tranilast acts as a competitive inhibitor of either indoleamine 2, 3-dioxygenase (IDO), tryptophan 2, 3 di-oxygenase (TDO) or both. As it involved only 1 subject, the results may not be representative of the larger population and must be considered preliminary.

scholarly journals Organ Correlation with Tryptophan Metabolism Obtained by Analyses of TDO-KO and QPRT-KO Mice

2016 ◽  
Vol 9 ◽  
pp. IJTR.S37984 ◽  
Author(s):  
Katsumi Shibata ◽  
Tsutomu Fukuwatari
Keyword(s):  
Quinolinic Acid ◽  
Kynurenic Acid ◽  
Conversion Ratio ◽  
Tryptophan Metabolism ◽  
Limiting Factors ◽  
Xanthurenic Acid ◽  
Wild Type ◽  
Organ Specific ◽  
Hydroxyanthranilic Acid ◽  
Rate Limiting

The aim of this article is to report the organ-specific correlation with tryptophan (Trp) metabolism obtained by analyses of tryptophan 2,3-dioxygenase knockout (TDO-KO) and quinolinic acid phosphoribosyltransferase knockout (QPRT-KO) mice models. We found that TDO-KO mice could biosynthesize the necessary amount of nicotinamide (Nam) from Trp, resulting in the production of key intermediate, 3-hydroxyanthranilic acid. Upstream metabolites, such as kynurenic acid and xanthurenic acid, in the urine were originated from nonhepatic tissues, and not from the liver. In QPRT-KO mice, the Trp to quinolinic acid conversion ratio was 6%; this value was higher than expected. Furthermore, we found that QPRT activity in hetero mice was half of that in wild-type (WT) mice. Urine quinolinic acid levels remain unchanged in both hetero and WT mice, and the conversion ratio of Trp to Nam was also unaffected. Collectively, these findings show that QPRT was not the rate-limiting enzyme in the conversion. In conclusion, the limiting factors in the conversion of Trp to Nam are the substrate amounts of 3-hydroxyanthranilic acid and activity of 3-hydroxyanthranilic acid 3,4-dioxygenase in the liver.

scholarly journals Tryptophan Metabolism in Rat Liver after Administration of Tryptophan, Kynurenine Metabolites, and Kynureninase Inhibitors

2016 ◽  
Vol 9 ◽  
pp. IJTR.S38190 ◽  
Author(s):  
Abdulla A.-B. Badawy ◽  
Samina Bano
Keyword(s):  
Rat Liver ◽  
Immune Activation ◽  
Kynurenic Acid ◽  
Chronic Administration ◽  
Kynurenine Pathway ◽  
Tryptophan Metabolism ◽  
Disease States ◽  
Metabolite Concentrations ◽  
Hydroxyanthranilic Acid ◽  
Stimulation Of

Rat liver tryptophan (Trp), kynurenine pathway metabolites, and enzymes deduced from product/substrate ratios were assessed following acute and/or chronic administration of kynurenic acid (KA), 3-hydroxykynurenine (3-HK), 3-hydroxyanthranilic acid (3-HAA), Trp, and the kynureninase inhibitors benserazide (BSZ) and carbidopa (CBD). KA activated Trp 2,3-dioxygenase (TDO), possibly by increasing liver 3-HAA, but inhibited kynurenine aminotransferase (KAT) and kynureninase activities with 3-HK as substrate. 3-HK inhibited kynureninase activity from 3-HK. 3-HAA stimulated TDO, but inhibited kynureninase activity from K and 3-HK. Trp (50 mg/kg) increased kynurenine metabolite concentrations and KAT from K, and exerted a temporary stimulation of TDO. The kynureninase inhibitors BSZ and CBD also inhibited KAT, but stimulated TDO. BSZ abolished or strongly inhibited the Trp-induced increases in liver Trp and kynurenine metabolites. The potential effects of these changes in conditions of immune activation, schizophrenia, and other disease states are discussed.

Effect of Nicotinamide Administration on the Tryptophan-Nicotinamide Pathway in Humans

2007 ◽  
Vol 77 (4) ◽  
pp. 255-262 ◽  
Author(s):  
Fukuwatari ◽  
Shibata
Keyword(s):  
Urinary Excretion ◽  
Young Women ◽  
Quinolinic Acid ◽  
Kynurenic Acid ◽  
De Novo ◽  
Conversion Ratio ◽  
Xanthurenic Acid ◽  
Dependent Manner ◽  
Hydroxyanthranilic Acid ◽  
Dose Dependent

The vitamin nicotinamide is synthesized in the liver from tryptophan, and distributed to non-hepatic tissues. Although it is generally accepted that 60 mg tryptophan is equivalent to 1 mg nicotinamide in humans, the conversion ratio of tryptophan to nicotinamide is changeable. To determine if de novo nicotinamide synthesis from tryptophan is influenced by nicotinamide intake itself, six young women consumed controlled diets containing 30.4 or 24.8 mg niacin-equivalent nicotinamide supplements with 0, 89, 310, or 562 μmol/day (0, 10.9, 37.8, or 68.6 mg/day, respectively), and urinary excretion of intermediates and metabolites of the tryptophan-nicotinamide pathway were measured. Urinary excretion of nicotinamide metabolites increased linearly in a dose-dependent manner. None of the intermediates, including anthranilic acid, kynurenic acid, xanthurenic acid, 3-hydroxyanthranilic acid, and quinolinic acid, changed at all, even when up to 562 μmol/day nicotinamide was given. That is, exogenous nicotinamide did not affect de novo nicotinamide synthesis. Therefore, when niacin equivalent is calculated, the intake of nicotinamide itself need not be considered as a factor that changes the tryptophan-nicotinamide conversion ratio.

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

2016 ◽  
Vol 113 (19) ◽  
pp. 5435-5440 ◽  
Author(s):  
Carlo Breda ◽  
Korrapati V. Sathyasaikumar ◽  
Shama Sograte Idrissi ◽  
Francesca M. Notarangelo ◽  
Jasper G. Estranero ◽  
...  
Keyword(s):  
Quinolinic Acid ◽  
Neurodegenerative Disorders ◽  
Kynurenic Acid ◽  
Therapeutic Potential ◽  
Fruit Fly ◽  
Kynurenine Pathway ◽  
Locomotor Performance ◽  
Potential Treatment ◽  
Regulatory Enzymes ◽  
Therapeutic Benefits

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.

ROLE OF KYNURENINE PATHWAY METABOLITES IN DEPRESSION-A REVIEW

2020 ◽  
pp. 1-6
Author(s):  
Priyadarshini Soni ◽  
Lubhan Singh ◽  
Prabhat Singh ◽  
Sokindra Kumar
Keyword(s):  
Amino Acid ◽  
Kynurenic Acid ◽  
Kynurenine Pathway ◽  
World Health ◽  
The World ◽  
Important Pathway ◽  
Hydroxyanthranilic Acid ◽  
Health Organization

Today most common psychiatric problem across the world is depression and stress is main source of ailment. According to World health organization, it will be the main cause of morbidity by 2020 in the world. Depression can critically affects the quality of life  as it is characterized by many symptoms like unhappy feeling, lack of interest and pleasure, down energy, inadequacy, regret feeling, slow-down of thoughts or reduction in physical movement, speech can affects, altered appetite or sleep, sad,  and increase the risk of suicide. Human body is inadequate to produce tryptophan which is a crucial amino acid; therefore it must be required from diet. After absorption, L-tryptophan crosses the BBB (Blood brain barrier) by non-specific L-type amino acid transporter and act as precursor to various metabolic pathways in central nervous system (CNS). Kynurenine is an important pathway that is associated with tryptophan (TRP) metabolism, where it develops a lot of metabolites such as 3-hydroxykynurenine (3HK), anthranilic acid (AA), kynurenic acid (KYNA), 3-hydroxyanthranilic acid (3HAA) and quinolinic acid (QUIN) known as kynurenines. It is already reported previously that disturbance in neuroprotective and neurotoxic metabolites leads to many psychiatric disorders. This review summarizes the role of kynurenine pathway metabolites in depression.   

URINARY EXCRETION OF TRYPTOPHAN METABOLITES IN THE HEALTHY INFANT

PEDIATRICS ◽  
1962 ◽  
Vol 30 (4) ◽  
pp. 585-591
Author(s):  
Franco Vassella ◽  
Bo Hellström ◽  
Bo Wengle
Keyword(s):  
Body Weight ◽  
Urinary Excretion ◽  
Paper Chromatography ◽  
Kynurenic Acid ◽  
Healthy Infant ◽  
Xanthurenic Acid ◽  
Two Dimensional ◽  
Healthy Infants ◽  
Tryptophan Metabolites ◽  
Hydroxyanthranilic Acid

Urinary excretion of tryptophan metabolites was studied qualitatively by two-dimensional paper chromatography in a group of 50 healthy infants with no tryptophan supplementation. Twenty-two infants of this group were given 100 mg of L-tryptophan per kilogram of body-weight, and the 24-hour urinary excretions of kynurenine, kynurenic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, and xanthurenic acid were estimated by quantitative paper chromatography. A high excretion of kynurenine was found to be a distinguishing feature. Various possibilities to explain this difference as compared to adults are discussed.

scholarly journals Effects of Sleep Deprivation on the Tryptophan Metabolism

2020 ◽  
Vol 13 ◽  
pp. 117864692097090
Author(s):  
Abid Bhat ◽  
Ananda Staats Pires ◽  
Vanessa Tan ◽  
Saravana Babu Chidambaram ◽  
Gilles J Guillemin
Keyword(s):  
Sleep Deprivation ◽  
Kynurenic Acid ◽  
Second Messengers ◽  
Sleep Time ◽  
Kynurenine Pathway ◽  
Tryptophan Metabolism ◽  
Cellular Functions ◽  
Intracellular Second Messengers ◽  
The Impact ◽  
The Brain

Sleep has a regulatory role in maintaining metabolic homeostasis and cellular functions. Inadequate sleep time and sleep disorders have become more prevalent in the modern lifestyle. Fragmentation of sleep pattern alters critical intracellular second messengers and neurotransmitters which have key functions in brain development and behavioral functions. Tryptophan metabolism has also been found to get altered in SD and it is linked to various neurodegenerative diseases. The kynurenine pathway is a major regulator of the immune response. Adequate sleep alleviates neuroinflammation and facilitates the cellular clearance of metabolic toxins produced within the brain, while sleep deprivation activates the enzymatic degradation of tryptophan via the kynurenine pathway, which results in an increased accumulation of neurotoxic metabolites. SD causes increased production and accumulation of kynurenic acid in various regions of the brain. Higher levels of kynurenic acid have been found to trigger apoptosis, leads to cognitive decline, and inhibit neurogenesis. This review aims to link the impact of sleep deprivation on tryptophan metabolism and associated complication in the brain.

scholarly journals Imbalanced Kynurenine Pathway in Schizophrenia

2014 ◽  
Vol 7 ◽  
pp. IJTR.S16800 ◽  
Author(s):  
Magdalena E. Kegel ◽  
Maria Bhat ◽  
Elisabeth Skogh ◽  
Martin Samuelsson ◽  
Kristina Lundberg ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Cerebrospinal Fluid ◽  
Liquid Chromatography ◽  
Quinolinic Acid ◽  
Kynurenic Acid ◽  
Kynurenine Pathway ◽  
The Other ◽  
Healthy Controls ◽  
Liquid Chromatography Mass Spectrometry ◽  
Csf Levels

Several studies suggest a role for kynurenic acid (KYNA) in the pathophysiology of schizophrenia. It has been proposed that increased brain KYNA levels in schizophrenia result from a pathological shift in the kynurenine pathway toward enhanced KYNA formation, away from the other branch of the pathway leading to quinolinic acid (QUIN). Here we investigate the levels of QUIN in cerebrospinal fluid (CSF) of patients with schizophrenia and healthy controls, and relate those to CSF levels of KYNA and other kynurenine metabolites from the same individuals. CSF QUIN levels from stable outpatients treated with olanzapine (n = 22) and those of controls (n = 26) were analyzed using liquid chromatography-mass spectrometry. No difference in CSF QUIN levels between patients and controls was observed (20.6 ± 1.5 nM vs. 18.2 ± 1.1 nM, P = 0.36). CSF QUIN was positively correlated to CSF kynurenine and CSF KYNA in patients but not in controls. The CSF QUIN/KYNA ratio was lower in patients than in controls ( P = 0.027). In summary, the present study offers support for an over-activated and imbalanced kynurenine pathway, favoring the production of KYNA over QUIN in patients with schizophrenia.

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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