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Ewa M. Urbanska - One of the best experts on this subject based on the ideXlab platform.
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experimental hypothyroidism raises brain Kynurenic Acid novel aspect of thyroid dysfunction
European Journal of Pharmacology, 2020Co-Authors: Tomasz Tomczyk, Ewa M. UrbanskaAbstract:Abstract Hypothyroidism frequently manifests with altered mood and disturbed cognition. Kynurenic Acid may influence cognition through antagonism of N-methyl-d-aspartate receptors (NMDA) and α7 nicotinic receptors. In here, thyroid hormones effects on Kynurenic Acid synthesis in rat cortical slices and on kynurenine aminotransferases (KATs) activity in semi-purified cortical homogenates were studied. Furthermore, brain Kynurenic Acid levels and KATs activities were evaluated in experimental model of hypothyroidism, induced by chronic administration of 0.05% propylthiouracil in drinking water. In vitro, L-thyroxine (T4) and 3,3,5-triiodothyronine (T3), reduced Kynurenic Acid synthesis and KATs activities (IC50 ~ 50–150 μM). In vivo, propylthiouracil increased cortical, hippocampal and striatal, but not cerebellar Kynurenic Acid content (192%, 142% and 124% of control, respectively), despite uniformly decreased KAT II activity and lower cortical and striatal KAT I activity. T4 application to hypothyroid animals restored Kynurenic Acid levels to control values and reversed enzymatic changes. T4 alone did not change brain Kynurenic Acid levels, despite increased activities of brain KATs. Hence, thyroid hormones modulate Kynurenic Acid levels by two opposing mechanisms, stimulation of KATs activity, most probably transcriptional, and direct, post-translational inhibition of KATs. Lack of correlation between KATs activity and Kynurenic Acid level may reflect the influence of T4 on organic anion transporter and result from impaired removal of Kynurenic Acid from the brain during hypothyroidism. Our data reveal novel mechanism linked with thyroid hormones deficiency and imply the potential involvement of increased brain Kynurenic Acid in the hypothyroidism-related cognitive disturbance.
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Experimental hypothyroidism raises brain Kynurenic Acid – Novel aspect of thyroid dysfunction
European journal of pharmacology, 2020Co-Authors: Tomasz Tomczyk, Ewa M. UrbanskaAbstract:Abstract Hypothyroidism frequently manifests with altered mood and disturbed cognition. Kynurenic Acid may influence cognition through antagonism of N-methyl-d-aspartate receptors (NMDA) and α7 nicotinic receptors. In here, thyroid hormones effects on Kynurenic Acid synthesis in rat cortical slices and on kynurenine aminotransferases (KATs) activity in semi-purified cortical homogenates were studied. Furthermore, brain Kynurenic Acid levels and KATs activities were evaluated in experimental model of hypothyroidism, induced by chronic administration of 0.05% propylthiouracil in drinking water. In vitro, L-thyroxine (T4) and 3,3,5-triiodothyronine (T3), reduced Kynurenic Acid synthesis and KATs activities (IC50 ~ 50–150 μM). In vivo, propylthiouracil increased cortical, hippocampal and striatal, but not cerebellar Kynurenic Acid content (192%, 142% and 124% of control, respectively), despite uniformly decreased KAT II activity and lower cortical and striatal KAT I activity. T4 application to hypothyroid animals restored Kynurenic Acid levels to control values and reversed enzymatic changes. T4 alone did not change brain Kynurenic Acid levels, despite increased activities of brain KATs. Hence, thyroid hormones modulate Kynurenic Acid levels by two opposing mechanisms, stimulation of KATs activity, most probably transcriptional, and direct, post-translational inhibition of KATs. Lack of correlation between KATs activity and Kynurenic Acid level may reflect the influence of T4 on organic anion transporter and result from impaired removal of Kynurenic Acid from the brain during hypothyroidism. Our data reveal novel mechanism linked with thyroid hormones deficiency and imply the potential involvement of increased brain Kynurenic Acid in the hypothyroidism-related cognitive disturbance.
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Memantine increases brain production of Kynurenic Acid via protein kinase A-dependent mechanism.
Neuroscience letters, 2008Co-Authors: Renata Kloc, Marian Wielosz, Elzbieta Luchowska, Björn Owe-larsson, Ewa M. UrbanskaAbstract:Abstract We describe a novel aspect of action of memantine ex vivo , in the brain cortical slices and in vitro , in mixed glial cultures. The drug potently increased the production of Kynurenic Acid, an endogenous tryptophan metabolite blocking N -methyl- d -aspartate (NMDA) and nicotinic α7 receptors. In cortical slices memantine, an open-channel NMDA blocker (100–150 μM), but not the competitive NMDA receptor antagonist, LY235959 increased the production of Kynurenic Acid. Neither SCH23390, D1 receptor antagonist (50 μM) nor raclopride, D2 receptor antagonist (10 μM) changed the memantine-induced effects. Propranolol (100 μM) has partially reduced its action. Selective cAMP-dependent protein kinase (PKA) inhibitor, KT5720 (1 μM), but not selective protein kinase C (PKC) inhibitor, NPC15437 (30 μM) totally reversed the action of memantine. In mixed glial cultures, 2–24 h incubation with memantine (2–50 μM) enhanced the production of Kynurenic Acid. Memantine (up to 0.5 mM) has not affected the activity of Kynurenic Acid biosynthetic enzymes. The obtained data suggest that memantine enhances the production of Kynurenic Acid in PKA-mediated way. This effect may partially contribute to the therapeutic actions of memantine and be of a potential clinical importance.
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Clenbuterol enhances the production of Kynurenic Acid in brain cortical slices and glial cultures.
Pharmacological reports : PR, 2008Co-Authors: Elzbieta Luchowska, Marian Wielosz, Renata Kloc, Sebastian Wnuk, Bartosz Olajossy, Ewa M. UrbanskaAbstract:The effect of a beta(2)-adrenergic agonist, clenbuterol on the production of a glutamate receptor antagonist, Kynurenic Acid was studied in vitro. Clenbuterol enhanced the production of Kynurenic Acid in brain cortical slices (0.1-1.0 mM) and in glial cultures (1-50 muM). Timolol, a non-selective beta-adrenergic antagonist prevented this effect. The presented data indicate a novel mechanism of action of beta(2)-adrenoceptor agonists and suggest that an increased formation of the endogenous glutamate receptor antagonist, Kynurenic Acid could partially contribute to their neuroprotective activity.
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SNAP and SIN-1 increase brain production of Kynurenic Acid.
European Journal of Pharmacology, 2007Co-Authors: Piotr Luchowski, Ewa M. UrbanskaAbstract:The influence of nitric oxide (NO) donors, S-nitroso-N-acetylpenicillamine (SNAP), and 3-morpholinosydnonimine (SIN-1), on the central production of an endogenous glutamate receptor antagonist, Kynurenic Acid, was evaluated in vitro. In cortical slices, SNAP and SIN-1 potently increased the extracellular concentration of Kynurenic Acid. A free radical scavenger, l-ascorbate reversed this effect. Neither SNAP nor SIN-1 altered the activity of Kynurenic Acid biosynthetic enzymes, kynurenine aminotransferases (KAT I and II). These data reveal a novel aspect of the brain response to studied herein NO donors and suggest that in the milieu containing NO-related free radicals the formation of Kynurenic Acid is enhanced.
Robert Schwarcz - One of the best experts on this subject based on the ideXlab platform.
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enzymatic transamination of d kynurenine generates Kynurenic Acid in rat and human brain
Journal of Neurochemistry, 2012Co-Authors: Veronica Perezde La Cruz, Laura Amori, Korrapati V Sathyasaikumar, Xiaodan Wang, Francesca M Notarangelo, Robert SchwarczAbstract:J. Neurochem. (2012) 120, 1026–1035. Abstract 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-aminoAcid 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.
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Metabolic control of Kynurenic Acid formation in the rat brain.
Developmental neuroscience, 1998Co-Authors: Paul S. Hodgkins, Robert SchwarczAbstract:Excitotoxic neuronal loss can be precipitated by defects in cerebral energy metabolism. Antagonists of excitatory amino Acid receptors, such as the endogenous metabolite Kynurenic Acid, can effectively block excitotoxic lesions. Using brain tissue slices, the present study was designed to examine a potential link between metabolic status and cerebral Kynurenic Acid formation in adult rats. The results demonstrate that fluctuations in cerebral energy metabolism are closely associated with changes in Kynurenic Acid synthesis. Taken together, the data are compatible with the idea that the production of Kynurenic Acid in the brain is critically affected by the availability of pyruvate or other 2-oxoAcids (i.e. co-substrates for the enzymatic transamination of the bioprecursor of Kynurenic Acid, L-kynurenine). Such metabolic control of Kynurenic Acid function may play a role in excitotoxic brain diseases
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(R,S)-3,4-dichlorobenzoylalanine (FCE 28833A) causes a large and persistent increase in brain Kynurenic Acid levels in rats
European journal of pharmacology, 1996Co-Authors: Carmela Speciale, Massimo Cini, Marina Marconi, Mario Varasi, Robert SchwarczAbstract:Kynurenic Acid is an endogenous excitatory amino-Acid receptor antagonist with neuroprotective and anticonvulsant properties. We demonstrate here that systemic administration of the new and potent kynurenine 3-hydroxylase inhibitor (R,S)-3,4-dichlorobenzoylalanine (FCE 28833A) causes a dose-dependent elevation in endogenous kynurenine and Kynurenic Acid levels in rat brain tissue. In hippocampal microdialysates, peak increases of 10- and 80-fold above basal Kynurenic Acid concentrations, respectively, were obtained after a single oral or intraperitoneal administration of 400 mg/kg FCE 28833A. After intraperitoneal treatment with FCE 28833A, extracellular brain Kynurenic Acid levels remained significantly elevated for at least 22 h, rendering this compound a far more effective enhancer of Kynurenic Acid levels than the previously described kynurenine 3-hydroxylase blocker m-nitrobenzoylalanine. FCE 28833A and similar molecules may have therapeutic value in diseases which are linked to a hyperfunction of excitatory amino-Acid receptors.
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l-α-Aminoadipic Acid as a regulator of Kynurenic Acid production in the hippocampus: a microdialysis study in freely moving rats
European journal of pharmacology, 1995Co-Authors: Urban Ungerstedt, Robert SchwarczAbstract:Abstract l -α-Aminoadipic Acid is a lysine metabolite with neuroexcitatory properties, and has previously been shown to inhibit the production of the broad spectrum excitatory amino Acid receptor antagonist Kynurenic Acid in brain tissue slices. The effects of l -α-aminoadipic Acid on the levels of extracellular Kynurenic Acid were now studied by microdialysis in the dorsal hippocampus of freely moving rats. Application of l -α-aminoadipic Acid through the microdialysis probe dose dependently decreased both the concentration of endogenous Kynurenic Acid and of Kynurenic Acid which was produced de novo from its bioprecursor l -kynurenine (500 μM applied through the probe). 500 μM l -α-aminoadipic Acid lowered the Kynurenic Acid concentration in the dialysate by 47% and 28% with and without precursor loading, respectively, whereas d -α-aminoadipic Acid was without effect. Co-administration of 500 μM l -α-aminoadipic Acid with 50 μM veratridine, which by itself produces a substantial decrease in the levels of extracellular Kynurenic Acid, did not result in a further reduction in Kynurenic Acid concentrations. Extensive neuronal degeneration caused by an intrahippocampal injection of quinolinic Acid (120 nmol) did not interfere with the effect of l -α-aminoadipic Acid. Taken together, these data suggest that the effect of l -α-aminoadipic Acid on extracellular Kynurenic Acid levels is likely due to its direct action on astrocytes, which are known to harbor Kynurenic Acid's biosynthetic enzyme, kynurenine aminotransferase. l -α-Aminoadipic Acid may modulate Kynurenic Acid function in the brain and thus play a role in the pathogenesis of neurodegenerative and seizure disorders.
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Regulation of Kynurenic Acid synthesis studied by microdialysis in the dorsal hippocampus of unanesthetized rats.
European journal of pharmacology, 1992Co-Authors: Urban Ungerstedt, Robert SchwarczAbstract:The production of the broad spectrum excitatory amino Acid receptor antagonist Kynurenic Acid was assessed by hippocampal microdialysis in freely moving rats. Extracellular Kynurenic Acid, determined spectrophotometrically, was measured following the perfusion of its bioprecursor L-kynurenine (500 microM) through the dialysis probe. In this paradigm, the concentration of Kynurenic Acid reached plateau levels within 2 h. These steady state levels were more than doubled in gliotic quinolinate-lesioned tissue. The non-specific inhibitor of kynurenine aminotransferase, aminooxyacetic Acid (300 microM), and the depolarizing agent veratridine (50 microM), introduced through the dialysis membrane, caused a 69 and 57% decrease, respectively, in extracellular Kynurenic Acid. The effect of veratridine was rapidly reversible and was blocked by 5 microM tetrodotoxin or in the quinolinate-lesioned hippocampus. In contrast, the effect of aminooxyacetic Acid was longer lasting upon drug discontinuation, and was not reversed by tetrodotoxin or in lesioned tissue. These data demonstrate that hippocampal Kynurenic Acid can be regulated by direct interference with its biosynthetic enzyme and by a distinct process involving neuron-glia interactions.
Laszlo Vecsei - One of the best experts on this subject based on the ideXlab platform.
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Protective effects of glucosamine-Kynurenic Acid after compression-induced spinal cord injury in the rat
Open Life Sciences, 2012Co-Authors: Andrea Korimová, Laszlo Vecsei, József Toldi, Dáša Čížková, Ivo VanickýAbstract:Kynurenic Acid (KYNA), a metabolite of the essential amino Acid L-tryptophan, is a broad spectrum antagonist of excitatory amino Acid receptors, which have also anticonvulsant and neuroprotective properties. After spinal cord injury (SCI), excitotoxicity is considered to play a significant role in the processes of secondary tissue destruction in both grey and white matter of the spinal cord. In this study, we have tested the potential therapeutic effect of glucosamine-Kynurenic Acid, administered after experimental compression-induced SCI in the rat. Spinal application of glucosamine-Kynurenic Acid continually for 24 hr after experimental SCI resulted in improved motor function recovery, beginning from the first week of evaluation and continuing until the end of the study (4 weeks). After 4 weeks’ survival, quantitative morphometric analysis of the spinal cord showed that glucosamine-Kynurenic Acid treatment was associated with improved tissue preservation at the lesion site. These findings indicate that spinal application of glucosamineKynurenic Acid is neuroprotective and improves the outcome even when administered after spinal trauma. Our results suggest that the treatments initiated in early posttraumatic period can alleviate secondary injury and improve the final outcome after SCI.
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Manipulating Kynurenic Acid levels in the brain - on the edge between neuroprotection and cognitive dysfunction.
Current topics in medicinal chemistry, 2012Co-Authors: Levente Szalárdy, József Toldi, Ferenc Fülöp, Dénes Zádori, Péter Klivényi, Laszlo VecseiAbstract:A number of neurodegenerative diseases have been associated with potentially neurotoxic alterations in the kynurenine pathway. Due to the potent inhibitory effect of Kynurenic Acid on glutamate receptor function, the potential use of the elevation of its concentrations in the brain in the protection against excitotoxic injury has earned an ever greater interest. The first strong preclinical achievements of protection in transgenic murine models of chronic neurodegenerative diseases by kynurenergic approaches have recently been published. Despite the remarkable neuroprotection provided by these molecules, the potential risk of interfering with cognitive functions when dealing with molecules capable of impairing glutamatergic and cholinergic transmission should always be considered. This issue is of particular interest in light of the high affinity of Kynurenic Acid towards the glycine site of NMDA receptors, the antagonism of which is known to recapitulate key behavioral features of schizophrenia. In the past decade, however, a number of other sites of action have been revealed, most of them being possible contributors of either the neuroprotective or the cognitive deteriorating effects of Kynurenic Acid. This paper reviews the current understanding about how Kynurenic Acid can influence cognitive functions in experimental animals, and discusses the possibility of exploiting the neuroprotective potential of Kynurenic Acid without impairing cognitive functions.
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A novel Kynurenic Acid analogue: a comparison with Kynurenic Acid. An in vitro electrophysiological study.
Journal of neural transmission (Vienna Austria : 1996), 2009Co-Authors: Máté Marosi, Laszlo Vecsei, Éva Rózsa, Hermina Robotka, Dávid Nagy, Tamás Farkas, Zsolt Kis, Ferenc Fülöp, József ToldiAbstract:Kynurenic Acid is an endogenous product of the tryptophan metabolism, and as a broad-spectrum antagonist of excitatory amino Acid receptors may serve as a protective agent in neurological disorders. The use of Kynurenic Acid as a neuroprotective agent is rather limited, however, because it has only restricted ability to cross the blood–brain barrier. Accordingly, new Kynurenic Acid analogues which can readily cross the blood–brain barrier and exert their complex anti-excitotoxic activity are greatly needed. Such a novel analogue, 2-(2-N,N-dimethylaminoethylamine-1-carbonyl)-1H-quinolin-4-one hydrochloride, has been developed and tested. In an in vitro electrophysiological study, in which its properties were compared with those of Kynurenic Acid, the new analogue behaved quite similarly to Kynurenic Acid: in the micromolar range, its administration led to a decrease in the amplitudes of the field excitatory postsynaptic potentials in the CA1 region of the hippocampus, while in nanomolar concentrations it did not give rise to inhibition, but, in fact, facilitated the field excitatory postsynaptic potentials. Moreover, the new analogue demonstrated similar protective action against PTZ-induced facilitation to that observed after Kynurenic Acid administration. The findings strongly suggest that the neuroactive effects of the new analogue are comparable with those of Kynurenic Acid, but, in contrast with Kynurenic Acid, it readily crosses the blood–brain barrier. The new analogue may therefore be considered a promising candidate for clinical studies.
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Syntheses, transformations and pharmaceutical applications of Kynurenic Acid derivatives.
Current Medicinal Chemistry, 2009Co-Authors: Ferenc Fülöp, József Toldi, Istvan Szatmari, Eniko Vamos, Dénes Zádori, Laszlo VecseiAbstract:The syntheses and transformations of 4-hydroxyquinoline-2-carboxylic Acid, Kynurenic Acid, are reviewed, and special attention is paid to the pharmacological activities and pharmaceutical applications of its derivatives.
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The Janus-face Kynurenic Acid
Journal of Neural Transmission, 2008Co-Authors: Éva Rózsa, Laszlo Vecsei, Hermina Robotka, József ToldiAbstract:Kynurenic Acid is an endogenous product of the tryptophan metabolism. Studies on the mechanism of its action have revealed that Kynurenic Acid at high concentrations is a competitive antagonist of the N -methyl- d -aspartate receptor and acts as a neuroprotectant in different neurological disorders. This in vitro investigation was designed to show that Kynurenic Acid acts differently at low concentrations. In vitro electrophysiological examinations on the young rat hippocampus confirmed the well-known finding that Kynurenic Acid in micromolar concentrations exerts an inhibitory effect. However, in nanomolar concentrations, Kynurenic Acid does not give rise to inhibition, but in fact facilitates the field excitatory postsynaptic potentials. The results available so far are compatible with the idea that Kynurenic Acid in the concentration range between a few hundred nanomolar and micromolar displays different effects. Its probable action on different receptors, inducing the different mechanisms, is discussed. The findings strongly suggest the neuromodulatory role of Kynurenic Acid under both physiological and pathological circumstances.
József Toldi - One of the best experts on this subject based on the ideXlab platform.
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Protective effects of glucosamine-Kynurenic Acid after compression-induced spinal cord injury in the rat
Open Life Sciences, 2012Co-Authors: Andrea Korimová, Laszlo Vecsei, József Toldi, Dáša Čížková, Ivo VanickýAbstract:Kynurenic Acid (KYNA), a metabolite of the essential amino Acid L-tryptophan, is a broad spectrum antagonist of excitatory amino Acid receptors, which have also anticonvulsant and neuroprotective properties. After spinal cord injury (SCI), excitotoxicity is considered to play a significant role in the processes of secondary tissue destruction in both grey and white matter of the spinal cord. In this study, we have tested the potential therapeutic effect of glucosamine-Kynurenic Acid, administered after experimental compression-induced SCI in the rat. Spinal application of glucosamine-Kynurenic Acid continually for 24 hr after experimental SCI resulted in improved motor function recovery, beginning from the first week of evaluation and continuing until the end of the study (4 weeks). After 4 weeks’ survival, quantitative morphometric analysis of the spinal cord showed that glucosamine-Kynurenic Acid treatment was associated with improved tissue preservation at the lesion site. These findings indicate that spinal application of glucosamineKynurenic Acid is neuroprotective and improves the outcome even when administered after spinal trauma. Our results suggest that the treatments initiated in early posttraumatic period can alleviate secondary injury and improve the final outcome after SCI.
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Manipulating Kynurenic Acid levels in the brain - on the edge between neuroprotection and cognitive dysfunction.
Current topics in medicinal chemistry, 2012Co-Authors: Levente Szalárdy, József Toldi, Ferenc Fülöp, Dénes Zádori, Péter Klivényi, Laszlo VecseiAbstract:A number of neurodegenerative diseases have been associated with potentially neurotoxic alterations in the kynurenine pathway. Due to the potent inhibitory effect of Kynurenic Acid on glutamate receptor function, the potential use of the elevation of its concentrations in the brain in the protection against excitotoxic injury has earned an ever greater interest. The first strong preclinical achievements of protection in transgenic murine models of chronic neurodegenerative diseases by kynurenergic approaches have recently been published. Despite the remarkable neuroprotection provided by these molecules, the potential risk of interfering with cognitive functions when dealing with molecules capable of impairing glutamatergic and cholinergic transmission should always be considered. This issue is of particular interest in light of the high affinity of Kynurenic Acid towards the glycine site of NMDA receptors, the antagonism of which is known to recapitulate key behavioral features of schizophrenia. In the past decade, however, a number of other sites of action have been revealed, most of them being possible contributors of either the neuroprotective or the cognitive deteriorating effects of Kynurenic Acid. This paper reviews the current understanding about how Kynurenic Acid can influence cognitive functions in experimental animals, and discusses the possibility of exploiting the neuroprotective potential of Kynurenic Acid without impairing cognitive functions.
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A novel Kynurenic Acid analogue: a comparison with Kynurenic Acid. An in vitro electrophysiological study.
Journal of neural transmission (Vienna Austria : 1996), 2009Co-Authors: Máté Marosi, Laszlo Vecsei, Éva Rózsa, Hermina Robotka, Dávid Nagy, Tamás Farkas, Zsolt Kis, Ferenc Fülöp, József ToldiAbstract:Kynurenic Acid is an endogenous product of the tryptophan metabolism, and as a broad-spectrum antagonist of excitatory amino Acid receptors may serve as a protective agent in neurological disorders. The use of Kynurenic Acid as a neuroprotective agent is rather limited, however, because it has only restricted ability to cross the blood–brain barrier. Accordingly, new Kynurenic Acid analogues which can readily cross the blood–brain barrier and exert their complex anti-excitotoxic activity are greatly needed. Such a novel analogue, 2-(2-N,N-dimethylaminoethylamine-1-carbonyl)-1H-quinolin-4-one hydrochloride, has been developed and tested. In an in vitro electrophysiological study, in which its properties were compared with those of Kynurenic Acid, the new analogue behaved quite similarly to Kynurenic Acid: in the micromolar range, its administration led to a decrease in the amplitudes of the field excitatory postsynaptic potentials in the CA1 region of the hippocampus, while in nanomolar concentrations it did not give rise to inhibition, but, in fact, facilitated the field excitatory postsynaptic potentials. Moreover, the new analogue demonstrated similar protective action against PTZ-induced facilitation to that observed after Kynurenic Acid administration. The findings strongly suggest that the neuroactive effects of the new analogue are comparable with those of Kynurenic Acid, but, in contrast with Kynurenic Acid, it readily crosses the blood–brain barrier. The new analogue may therefore be considered a promising candidate for clinical studies.
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Syntheses, transformations and pharmaceutical applications of Kynurenic Acid derivatives.
Current Medicinal Chemistry, 2009Co-Authors: Ferenc Fülöp, József Toldi, Istvan Szatmari, Eniko Vamos, Dénes Zádori, Laszlo VecseiAbstract:The syntheses and transformations of 4-hydroxyquinoline-2-carboxylic Acid, Kynurenic Acid, are reviewed, and special attention is paid to the pharmacological activities and pharmaceutical applications of its derivatives.
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The Janus-face Kynurenic Acid
Journal of Neural Transmission, 2008Co-Authors: Éva Rózsa, Laszlo Vecsei, Hermina Robotka, József ToldiAbstract:Kynurenic Acid is an endogenous product of the tryptophan metabolism. Studies on the mechanism of its action have revealed that Kynurenic Acid at high concentrations is a competitive antagonist of the N -methyl- d -aspartate receptor and acts as a neuroprotectant in different neurological disorders. This in vitro investigation was designed to show that Kynurenic Acid acts differently at low concentrations. In vitro electrophysiological examinations on the young rat hippocampus confirmed the well-known finding that Kynurenic Acid in micromolar concentrations exerts an inhibitory effect. However, in nanomolar concentrations, Kynurenic Acid does not give rise to inhibition, but in fact facilitates the field excitatory postsynaptic potentials. The results available so far are compatible with the idea that Kynurenic Acid in the concentration range between a few hundred nanomolar and micromolar displays different effects. Its probable action on different receptors, inducing the different mechanisms, is discussed. The findings strongly suggest the neuromodulatory role of Kynurenic Acid under both physiological and pathological circumstances.
Waldemar A. Turski - One of the best experts on this subject based on the ideXlab platform.
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Kynurenic Acid and Neuroprotective Activity of the Ketogenic Diet in the Eye
Current Medicinal Chemistry, 2017Co-Authors: Tomasz Zarnowski, Iwona Zarnowska, Maria Tulidowicz-bielak, Krystyna Mitosek-szewczyk, Artur Wnorowski, Krzysztof Jozwiak, Maciej Gasior, Waldemar A. TurskiAbstract:Background There is growing evidence of the involvement of the kynurenine metabolic pathway and the enhancement of Kynurenic Acid production in the neuroprotective effects of the ketogenic diet. Objective Here, we review evidence implicating Kynurenic Acid in the efficacy of ketogenic diet in eye diseases associated with neurodegeneration. Findings Ketogenic diet and ketone bodies that are elevated during exposure to the ketogenic diet each have a neuroprotective effect on retinal ganglion cells in a rat model of Nmethyl- D-aspartate induced neuronal damage. Chronic exposure to ketogenic diet also increases Kynurenic Acid concentrations in discrete rat brain structures. A non-selective glutamate receptor agonist, glutamate, also decreases the production of Kynurenic Acid in bovine retinal slices; this effect is attenuated by acetoacetate and β-hydroxybutyrate, two of three ketone bodies overproduced during ketogenic diet. Perspective Whether ketogenic diet induced enhancement of Kynurenic Acid production would translate into a clinically significant improvement in certain eye diseases like glaucoma and retinal neurodegenerations awaits further experimental and clinical verification.
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Effects of tryptophan, kynurenine and Kynurenic Acid exerted on human reconstructed corneal epithelium in vitro.
Pharmacological reports : PR, 2017Co-Authors: Anna Matysik-woźniak, Waldemar A. Turski, Roman Paduch, Ryszard Maciejewski, Anselm G. Jünemann, Robert RejdakAbstract:Abstract Background Tryptophan metabolites formed along kynurenine pathway may affect cell proliferation and tissue function. This pathway presents potential sites for drug discovery. Tryptophan and its metabolites kynurenine and Kynurenic Acid may be involved in the physiology and pathology of the ocular surface. The purpose of this work is to investigate the effect exerted by tryptophan, kynurenine and Kynurenic Acid upon corneal epithelium. Methods A SkinEthic™ HCE human reconstructed corneal epithelium model was used. WST-1 test was used to examine cell proliferation and viability, and the Griess reaction for nitric oxide determination. The levels of IL-6 and IL-10 were measured by means of ELISA assay. All analyses were carried out after the cells were exposed to tryptophan, kynurenine and Kynurenic Acid at concentrations of 5, 50 or 100 μM for 0–24 h and 24–48 h. Results Tryptophan (100 μM), kynurenine (100 μM) and Kynurenic Acid (5–100 μM) slightly increased the viability and proliferation of corneal epithelium. All of the tested compounds decreased cellular NO release. Kynurenine (50–100 μM) and tryptophan (50–100 μM) decreased while tryptophan (5 μM) and Kynurenic Acid (100 μM) increased the release of IL-6. All of the tested substances increased the level of IL-10 and decreased the IL-6 to IL-10 ratio. Conclusions Tryptophan, kynurenine and Kynurenic Acid affect physiological processes in corneal epithelium and therefore may play a significant role in the physiology and pathology of the ocular surface. Our results indicate that the use of these compounds may be considered in the treatment of ocular surface diseases.
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the in vitro effect of Kynurenic Acid on the rainbow trout oncorhynchus mykiss leukocyte and splenocyte activity
Polish Journal of Veterinary Sciences, 2014Co-Authors: J Malaczewska, Waldemar A. Turski, A K Siwicki, Roman Wojcik, Edyta KaczorekAbstract:Kynurenic Acid (KYNA), an endogenous neuroprotectant formed along the kynurenine pathway of tryptophan degradation, is a selective ligand of the GPR35 receptor, which can be found on the surface of various populations of human immune cells. In infections and inflammations, KYNA produces an anti-inflammatory effect through this receptor, by depressing the synthesis of reactive oxygen species and pro-inflammatory cytokines. However, it is still unrecognized whether receptors for Kynurenic Acid are also localized on immune cells of poikilothermic animals, or whether KYNA is able to affect these cells. The objective of this study has been to determine the effect of different concentrations of Kynurenic Acid (12.5 microM to 10 mM) on the viability and mitogenic response of lymphocytes and on the activity of phagocytic cells isolated from blood and the spleen of rainbow trout. The results imply low toxicity of Kynurenic Acid towards fish immune cells, and the proliferative effect observed at the two lowest concentrations of KYNA (12.5 microM and 25 microM) seems indicative of endogenous Kynurenic Acid being capable of activating fish lymphocytes. Non-toxic, micromole concentrations of KYNA, however, had no influence on the mitogenic response of lymphocytes nor on the activity of phagocytes in rainbow trout under in vitro conditions. There is some likelihood that such an effect could be observed at lower, nanomole concentrations of KYNA.
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high concentration of Kynurenic Acid in bile and pancreatic juice
Amino Acids, 2009Co-Authors: Piotr Paluszkiewicz, Wojciech Zgrajka, Tomasz Saran, Janusz Schabowski, Jose Luis Valverde Piedra, Olexandr Fedkiv, Sofia Rengman, Stefan Pierzynowski, Waldemar A. TurskiAbstract:Kynurenic Acid (KYNA) is an agonist of the G-protein-coupled receptor GPR35, which is predominantly expressed in gastrointestinal tissues. The aim of this study was to determine the content of KYNA in gastric juice, bile and pancreatic juice and intestinal content. KYNA was determined by means of high performance liquid chromatography. The mean concentrations of KYNA in human gastric juice is 9.91 ± 0.71 nM in contrast to human bile (832.5 ± 204.1 and 306.8 ± 35.2 nM) obtained from patients with cholecystolithiasis and obstructive jaundice, respectively. In pigs, the KYNA levels in bile and pancreatic juice are 1,113.3 ± 63.34 and 757.0 ± 394.4 nM, respectively. The KYNA concentration increases along the digestive system, reaching 1,638 nM in the colon content. We suggest that the liver and pancreas affect the content of Kynurenic Acid in the lumen of the digestive tract.
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Micromolar concentration of Kynurenic Acid in rat small intestine.
Amino acids, 2008Co-Authors: Damian Kuc, Wojciech Zgrajka, Jolanta Parada-turska, Teresa Urbanik-sypniewska, Waldemar A. TurskiAbstract:Kynurenic Acid is an antagonist of glutamate and alpha-7 nicotinic acetylcholine receptors and an agonist of the g-protein-coupled receptor GPR35, which is predominantly expressed in immune and gastrointestinal tissues. In this study, we report that Kynurenic Acid is present in the lumen of rat small intestine in micromolar concentration sufficient to affect the GPR35 receptor. Moreover, we show that Kynurenic Acid can be produced by Escherichia coli. We suggest that Kynurenic Acid may modulate gastrointestinal function and integrity.
