Cited by 169Tryptophan and brain disordersAmino Acid Enzymes and MetabolismNeuroscience and Neuropharmacology Research

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Role of Kynurenines in the Central and Peripherial Nervous Systems

Nemeth, Hajnalka, Toldi, Jozsef, Vecsei, Laszlo·2005·Current Neurovascular Research

DOI 10.2174/1567202054368326

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Abstract

Kynurenine (KYN) is an intermediate in the pathway of the metabolism of tryptophan to nicotinic acid. KYN is formed in the mammalian brain (40%) and is taken up from the periphery (60%), indicating that it can be transported across the blood-brain barrier (BBB). In the brain, KYN can be converted to two other components of the pathway: the neurotoxic quinolinic acid (QUIN) and the neuroprotective kynurenic acid (KYNA). QUIN is probably the most widely studied metabolite of KYN, because it may cause excitotoxic neuronal cell loss and convulsions by interacting with the N-methyl-D-aspartate (NMDA) receptor complex, a type of glutamate receptor. KYNA is another metabolite of KYN; its synthesis is catalysed by KYN aminotransferases. This is the only known endogenous NMDA receptor inhibitor, which can act at the glycine site on the receptor complex. Furthermore, KYNA non-competitively inhibits alpha7 nicotinic acetylcholine presynaptic receptors (nAChRs), inhibiting glutamate release, and regulates the expression of alpha4beta2 nAChR. It is well-known that the activation of excitatory amino acid (EAA) receptors can play a role in a number of neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, stroke and epilepsy. Various studies have been made of whether the EAA receptor antagonist KYNA can exert a therapeutic effect in these neurological disorders. It has been established that KYNA has only a very limited ability to cross the BBB. Other KYNA derivatives have been synthesised (e.g. glucosamine-KYNA, 4-chloro-KYNA and 7-chloro-KYNA), which are well transported across the BBB and act on the glutamate receptors. Moreover, it has been demonstrated that probenecid, a known inhibitor of the transport of organic acids (e.g. KYNA), increases the cerebral concentration of KYNA. There is another new perspective to the maintenance of a high level of KYNA in the brain: the use of enzyme inhibitors, which can block the synthesis of the neurotoxic QUIN. These are some of the most promising possibilities as novel therapeutic strategies for the treatment of neurodegenerative diseases, in which the hyperactivation of amino acid receptors could be involved. The presence and importance of KYN derivatives in the periphery are also discussed in the light of recent publications.

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BackgroundSelf-citation
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“Kynurenic acid is subsequently generated from kynurenine by kynurenine aminotransferase (Nemeth et al., 2005; Turski et al., 2011).”
Background
Metabolomic and proteomic characterization of sng and pain phenotypes in fibromyalgia
Hsu, W., Han, D., Ku, W., Chao, Y., Chen, C., & Lin, Y. (2021) · European Journal of Pain · doi:10.1002/ejp.1871 · Cited by 38
“reported an increased level of kynurenine, an intermediate in the major pathway for tryptophan degradation (Hackshaw et al., 2013; Nemeth et al., 2005), and decreased levels of serotonin (5- hydroxytryptamine, 5HT) and tryptophan, in serum of FM patients (Heils et al.”
Background
Synthesis and biological effects of some kynurenic acid analogs
Nagy, K., Plangár, I., Tuka, B., et al. (2011) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2011.10.029 · Cited by 37
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Kynurenine Metabolites and Migraine: Experimental Studies and Therapeutic Perspectives
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“KYNA could potentially have therapeutic effects in neurological disorders [75, 111, 112] via the above-described receptor inhibitory effects, but its use as a neuroprotective agent is rather restricted because it has only a very limited ability to cross the blood–brain barrier [69].”
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Pneumococcal meningitis causes accumulation of neurotoxic kynurenine metabolites in brain regions prone to injury
Bellac, C. L., Coimbra, R. S., Christen, S., & Leib, S. L. (2006) · Neurobiology of Disease · doi:10.1016/j.nbd.2006.07.014 · Cited by 38
“The kynurenine (KYN) pathway is induced in other diseases associated with inflammation leading to brain injury, such as multiple sclerosis, AIDS-dementia complex and cerebral malaria (Nemeth et al., 2005; Stone, 2001, 2003).”
Background
Determination of kynurenic acid in human serum and its correlation with the concentration of certain amino acids
Fukushima, T., Mitsuhashi, S., Tomiya, M., et al. (2006) · Clinica Chimica Acta · doi:10.1016/j.cca.2006.09.019 · Cited by 37
Alteration of kynurenic acid concentration in rat plasma following optically pure kynurenine administration: A comparative study between enantiomers
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The inimitable kynurenic acid: The roles of different ionotropic receptors in the action of kynurenic acid at a spinal level
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Saliva metabolomic profile of COVID-19 patients associates with disease severity
Sharif‐Askari, N. S., Soares, N. C., Mohamed, H. A., Sharif‐Askari, F. S., Alsayed, H. A. H., Al-Hroub, H. M., Salameh, L. I. J., Osman, R., Mahboub, B. H., Hamid, Q. A., et al. (2022) · Metabolomics · doi:10.1007/s11306-022-01936-1 · Cited by 34
The l ‐kynurenine–probenecid combination reduces neuropathic pain in rats
Pineda-Farías, J. B., Pérez‐Severiano, F., González‐Esquivel, D. F., et al. (2013) · European Journal of Pain · doi:10.1002/j.1532-2149.2013.00305.x · Cited by 32
“Once produced, kynurenic acid is actively extruded from the central nervous system by organic anion transporters (Németh et al., 2005; Uwai et al., 2012).”
Background
Human kynurenine aminotransferase II – reactivity with substrates and inhibitors
Passera, E., Campanini, B., Rossi, F., et al. (2011) · FEBS Journal · doi:10.1111/j.1742-4658.2011.08106.x · Cited by 31
β-adrenergic enhancement of brain kynurenic acid production mediated via cAMP-related protein kinase A signaling
Luchowska, E., Kloc, R., Olajossy, B., et al. (2009) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2009.02.002 · Cited by 30
“KYNA blocks the glycine co-agonist site of N-methyl-D-aspartate (NMDA) receptor (Németh et al., 2005) and affects α-amino-3-hydroxy-5methyl-4-isoxazole propionic acid (AMPA) receptors — either facil-”
A bloodspot-based diagnostic test for fibromyalgia syndrome and related disorders
Hackshaw, K. V., RODRIGUEZ‐SAONA, L. E., Plans, M., Bell, L. N., & Buffington, C. A. T. (2013) · The Analyst · doi:10.1039/c3an36615d · Cited by 30
Chronic sleep restriction in the rotenone Parkinson’s disease model in rats reveals peripheral early-phase biomarkers
Fagotti, J., Targa, A., Rodrigues, L. S., Noseda, A. C. D., Dorieux, F. W. C., Scarante, F. F., Ilkiw, J. L., Louzada, F. M., Chowdhury, N. R., van der Veen, D. R., et al. (2019) · Scientific Reports · doi:10.1038/s41598-018-37657-6 · Cited by 29
Disturbance of neurotransmitter metabolism in drug-naïve, first-episode major depressive disorder: a comparative study on adult and adolescent cohorts
Wang, L., Yang, P., Yang, C., Yang, D. H., Wu, X., Cao, T., Zeng, C., Chen, Q., Zhang, S., Zhu, Z., et al. (2022) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-022-01406-8 · Cited by 33
“KYN could be catabolized into two active metabolites: the neuroprotective KYNA and neurotoxicity QA [11].”
BackgroundInfluential
Somatic Drugs for Psychiatric Diseases: Aspirin or Simvastatin for Depression?
Rahola, J. G. (2012) · Current Neuropharmacology · doi:10.2174/157015912800604533 · Cited by 28
“Quinolinic acid causes a dose-dependent decrease in cholinergic circuits and may empty dopamine, choline, GABA and encephalin deposits [129-133].”
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Determination of kynurenine levels in rat plasma by high-performance liquid chromatography with pre-column fluorescence derivatization
Mitsuhashi, S., Fukushima, T., Tomiya, M., Santa, T., Imai, K., & Toyo’oka, T. (2006) · Analytica Chimica Acta · doi:10.1016/j.aca.2006.11.040 · Cited by 28
Chromatographic Fingerprint Analysis, Acetylcholinesterase Inhibitory Properties and Antioxidant Activities of Redflower Ragleaf (C rassocephalum Crepidioides) Extract
Adefegha, S. A., Oboh, G., Molehin, O. R., Saliu, J. A., Athayde, M. L., & Boligon, A. A. (2015) · Journal of Food Biochemistry · doi:10.1111/jfbc.12200 · Cited by 26
Modifications on the carboxylic function of kynurenic acid
Fülöp, F., Szatmári, I., Toldi, J., et al. (2011) · Journal of Neural Transmission · doi:10.1007/s00702-011-0721-7 · Cited by 26
“, together with probenecid (200 mg/kg), which is effective in blocking NMDA receptors (Nemeth et al. 2005), 2 was similarly or even more effective in reducing the amplitude of the population spikes (Nagy et al.”
BackgroundSelf-citation
Association of kynurenine aminotransferase II gene C401T polymorphism with immune response in patients with meningitis
de Souza, F. R. S., Fontes-Dantas, F. L., da Silva, T. A., et al. (2011) · BMC Medical Genetics · doi:10.1186/1471-2350-12-51 · Cited by 26
“The KYN pathway is also induced in other diseases associated with inflammation-induced brain injury, such as Huntington’s disease [21], schizophrenia [22], multiple sclerosis AIDS-dementia complex and cerebral malaria [23,24].”
Changes in Extracellular Kynurenic Acid Concentrations in Rat Prefrontal Cortex After d-Kynurenine Infusion: An In vivo Microdialysis Study
Ogaya, T., Song, Z., Ishii, K., & Fukushima, T. (2009) · Neurochemical Research · doi:10.1007/s11064-009-0099-1 · Cited by 25
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“Given that 60% of brain kynurenine is derived from the periphery [112], systemic processes that drive large kynurenine increases, such as from white adipocyte (WAT) in obesity [113], can drive significant changes in the CNS relevant to dementia pathophysiology, including depriving tryptophan for…”
Background
Kynurenines and Neurofilament Light Chain in Multiple Sclerosis
Pukoli, D., Polyák, H., Rajda, C., & Vécsei, L. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.658202 · Cited by 24
“…IDO, indoleamine 2,3-dioxygenase; KAT, kynurenine aminotransferase; KMO, kynurenine 3-monooxygenase; MAO, monoamine oxidase; NAD+, nicotinamide adenine dinucleotide; QPRT, quinolinate phosphoribosyltransferase; TDO, tryptophan 2,3-dioxygenase. stress (Németh et al., 2005).”
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Kynurenine pathway and its role in neurologic, psychiatric, and inflammatory bowel diseases
Sheibani, M., Shayan, M., Khalilzadeh, M., Soltani, Z. E., Jafari‐Sabet, M., Ghasemi, M., & Dehpour, A. R. (2023) · Molecular Biology Reports · doi:10.1007/s11033-023-08859-7 · Cited by 24
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“Metabolites of kynurenine may cause neurotoxicity which can lead to fatigue complaints in long COVID patients [21].”
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The potential role of kynurenines in Alzheimer’s disease: pathomechanism and therapeutic possibilities by influencing the glutamate receptors
Majláth, Z., Toldi, J., & Vécsei, L. (2013) · Journal of Neural Transmission · doi:10.1007/s00702-013-1135-5 · Cited by 23
“The metabolites produced in this metabolic cascade, collectively termed kynurenines, are involved in a number of physiological processes, including neurotransmission and immune responses (Nemeth et al. 2005; Vecsei et al. 2013).”
BackgroundSelf-citation
Synthesis of New C-3 Substituted Kynurenic Acid Derivatives
Lőrinczi, B., Csámpai, A., Fülöp, F., et al. (2020) · Molecules · doi:10.3390/molecules25040937 · Cited by 21
“KYNA (kynurenic acid) is an endogenous product of the tryptophan (TRP) metabolism, a pathway known to be responsible for the production of nicotinamide adenine dinucleotide (NAD+) and NAD phosphate (NADP+) [1,2].”
Background
The IDO genetic polymorphisms and postpartum depressive symptoms: an association study in Chinese parturients who underwent cesarean section
Duan, K., Wang, S., Yin, J., Li, X., Ma, J., Huang, Z., Zhou, Y., Yu, H., Yang, M., Zhou, H., et al. (2018) · Archives of Women s Mental Health · doi:10.1007/s00737-018-0898-y · Cited by 21
Kynurenic acid selectively reduces heart rate in spontaneously hypertensive rats
Bądzyńska, B., Zakrocka, I. N., Turski, W. A., Olszyński, K. H., Sadowski, J., & Kompanowska‐Jezierska, E. (2019) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-019-01771-7 · Cited by 18
“Kynurenic acid (KYNA), a tryptophan metabolite, is formed from L-kynurenine (KYN) by kynurenine aminotransferases (KATs) (Németh et al. 2005).”
Background
Time-course of kynurenic acid concentration in mouse serum following the administration of a novel kynurenic acid analog
Zádori, D., Ilisz, I., Klivènyi, P., et al. (2011) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2011.02.014 · Cited by 19
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The pentylenetetrazole-induced activity in the hippocampus can be inhibited by the conversion of l-kynurenine to kynurenic acid: An in vitro study
Rózsa, É., Robotka, H., Nagy, D., Farkas, T., Sas, K., Vécsei, L., & Toldi, J. (2008) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2007.12.001 · Cited by 19
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The L-kynurenine signalling pathway in trigeminal pain processing: A potential therapeutic target in migraine?
Guo, S., Vécsei, L., & Ashina, M. (2011) · Cephalalgia · doi:10.1177/0333102411404717 · Cited by 19
“A growing body of evidence indicates that KYNA has a mediatory and modulatory role for glutamate and its receptors in peripheral and central pain processing (25,37,47,48).”
BackgroundSelf-citation
Determination of rat brain kynurenic acid by column‐switching HPLC with fluorescence detection
Fukushima, T., Mitsuhashi, S., Tomiya, M., Kawai, J., Hashimoto, K., & Toyo’oka, T. (2007) · Biomedical Chromatography · doi:10.1002/bmc.786 · Cited by 19
The Omics Landscape of Long COVID —A Comprehensive Systematic Review to Advance Biomarker, Target and Drug Discovery
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“The expression of IDO2 is moreover linked to decreased levels of tryptophan and increased kynurenine quantities, which have been proposed to cause fatigue symptoms [48].”
The Usefulness of the Low-FODMAP Diet with Limited Tryptophan Intake in the Treatment of Diarrhea-Predominant Irritable Bowel Syndrome
Chojnacki, C. J., Popławski, T., Błońska, A., Konrad, P., Chojnacki, J., & Błasiak, J. (2023) · Nutrients · doi:10.3390/nu15081837 · Cited by 18
The Interactions Between Kynurenine, Folate, Methionine and Pteridine Pathways in Obesity.
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Prolonged therapy with antidepressants increases hippocampal level of kynurenic acid and expression of Kat1 and Kat2 genes
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Experimental diabetes mellitus type 1 increases hippocampal content of kynurenic acid in rats
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Memantine increases brain production of kynurenic acid via protein kinase A-dependent mechanism
Kloc, R., Luchowska, E., Wielosz, M., Owe‐Larsson, B., & Urbańska, E. M. (2008) · Neuroscience Letters · doi:10.1016/j.neulet.2008.02.027 · Cited by 17

Authors: Nemeth, H., Toldi, J., & Vecsei, L.
Venue: Current Neurovascular Research
Publisher: Bentham Science Publishers Ltd.
Published: 2005-07-01
Volume: 2
Issue: 3
Pages: 249-260
ISSN: 1567-2026 (ISSN-L)
DOI: 10.2174/1567202054368326
OpenAlex: W2111737222
Cited by: 169
References: 0
Citations by year: 2026: 2 · 2025: 6 · 2024: 9 · 2023: 7 · 2022: 10 · 2021: 10 · 2020: 6 · 2019: 5 · 2018: 7 · 2017: 4 · 2016: 6 · 2015: 9 · 2014: 7 · 2013: 9 · 2012: 7
FWCI: 3.32
Type: journal article
Language: en
Open access: closed
Locations: Current Neurovascular Research (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: kynurenine, tryptophan metabolism, kynurenic acid, quinolinic acid, NMDA receptor, alpha7 nicotinic acetylcholine receptor, blood-brain barrier, excitotoxicity, neurodegenerative diseases, probenecid, kynurenine derivatives, glutamate receptors, neuroprotection, epilepsy, Parkinson's disease
MeSH terms: Animals, Central Nervous System, Humans, Kynurenine, Nervous System Diseases, Peripheral Nervous System

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Role of Kynurenines in the Central and Peripherial Nervous Systems

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