Skip to main content
SpringerLink
Log in

Endogenous Kynurenic Acid and Neurotoxicity

  • Living reference work entry
  • First Online:
Handbook of Neurotoxicity

Abstract

Tryptophan metabolism along with kynurenine pathway yields a number of neuroactive compounds. Among kynurenine derivatives, neuroprotective kynurenic acid (KYNA) and neurotoxic quinolinic acid and 3-hydroxykynurenine have stimulated the greatest scientific interest. KYNA, initially considered merely a side-product of tryptophan degradation, was discovered in 1982 to act as an endogenous antagonist of excitatory amino acid receptors. Since then, a number of novel KYNA targets emerged. KYNA is a ligand of G protein-coupled GPR35 and human aryl hydrocarbon receptors and was suggested to play a role as antagonist of α7 nicotinic receptors. In here, we review research data supporting the idea that produced by astrocytes KYNA serves as an endogenous neuroprotectant. Mechanisms controlling brain levels of KYNA are discussed in the context of neurodegenerative disorders, brain ischemia, and seizures. Available data concerning changes of brain KYNA in respective animal models and in human diseases, together with an overview of effects following the application of KYNA, KYNA analogs, or compounds influencing the activity of enzymes along kynurenine pathway, are presented. Emerging therapies designed to increase the level of neuroprotective KYNA may become an important avenue in the treatment of brain disorders accompanied by neuronal loss.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

Abbreviations

AADAT:

Aminoadipate aminotransferase

AD:

Alzheimer’s disease

AHR:

Aryl hydrocarbon receptor

AMPA:

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

AOAA:

Aminooxyacetic acid

CCBL:

Cysteine conjugate beta-lyase

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

GOT:

Glutamic-oxaloacetic transaminase

GPR35:

G protein-coupled receptor 35

HD:

Huntington’s disease

ICAM-1:

Intercellular adhesion molecule 1

IDO:

Indoleamine 2,3-dioxygenase

KAT:

Kynurenine aminotransferase

KMO:

Kynurenine 3-monooxygenase

KYNA:

Kynurenic acid

MPP+:

1-Methyl-4-phenylpyridinium

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

NAD:

Nicotinamide adenine dinucleotide

NMDA:

N-methyl-D-aspartate

NO:

Nitric oxide

3-NPA:

3-nitropropionic acid

PD:

Parkinson’s disease

PKA:

Protein kinase A

SIN-1:

3-Morpholinosydnonimine

SNAP:

S-nitroso-N-acetylpenicillamine

TDO:

Tryptophan 2,3-dioxygenase

References

  • Andiné, P., Lehmann, A., Ellren, K., Wennberg, E., Kjellmer, I., Nielsen, T., & Hagberg, H. (1988). The excitatory amino acid antagonist kynurenic acid administered after hypoxic-ischemia in neonatal rats offers neuroprotection. Neuroscience Letters, 90, 208–212.

    Article  PubMed  Google Scholar 

  • Arnaiz-Cot, J. J., González, J. C., Sobrado, M., Baldelli, P., Carbone, E., Gandía, L., García, A. G., & Hernández-Guijo, J. M. (2008). Allosteric modulation of alpha 7 nicotinic receptors selectively depolarizes hippocampal interneurons, enhancing spontaneous GABAergic transmission. The European Journal of Neuroscience, 27, 1097–1110.

    Article  CAS  PubMed  Google Scholar 

  • Baran, H., Cairns, N., Lubec, B., & Lubec, G. (1996). Increased kynurenic acid levels and decreased brain kynurenine aminotransferase I in patients with Down syndrome. Life Sciences, 58, 1891–1899.

    Article  CAS  PubMed  Google Scholar 

  • Baran, H., Gramer, M., Hönack, D., & Löscher, W. (1995). Systemic administration of kainate induces marked increases of endogenous kynurenic acid in various brain regions and plasma of rats. European Journal of Pharmacology, 286, 167–175.

    Article  CAS  PubMed  Google Scholar 

  • Baran, H., Jellinger, K., & Deecke, L. (1999). Kynurenine metabolism in Alzheimer’s disease. Journal of Neural Transmission, 106, 165–181.

    Article  CAS  PubMed  Google Scholar 

  • Barth, M. C., Ahluwalia, N., Anderson, T. J., Hardy, G. J., Sinha, S., Alvarez-Cardona, J. A., Pruitt, I. E., Rhee, E. P., Colvin, R. A., & Gerszten, R. E. (2009). Kynurenic acid triggers firm arrest of leukocytes to vascular endothelium under flow conditions. The Journal of Biological Chemistry, 17(284), 19189–19195.

    Article  CAS  Google Scholar 

  • Beal, M. F., Matson, W. R., Storey, E., Milbury, P., Ryan, E. A., Ogawa, T., & Bird, E. D. (1992). Kynurenic acid concentrations are reduced in Huntington’s disease cerebral cortex. Journal of the Neurological Sciences, 108, 80–87.

    Article  CAS  PubMed  Google Scholar 

  • Beal, M. F., Matson, W. R., Swartz, K. J., Gamache, P. H., & Bird, E. D. (1990). Kynurenine pathway measurements in Huntington’s disease striatum: Evidence for reduced formation of kynurenic acid. Journal of Neurochemistry, 55, 1327–1339.

    Article  CAS  PubMed  Google Scholar 

  • Beal, M. F., Swartz, K. J., Hyman, B. T., Storey, E., Finn, S. F., & Koroshetz, W. (1991). Aminooxyacetic acid results in excitotoxin lesions by a novel indirect mechanism. Journal of Neurochemistry, 57, 1068–1073.

    Article  CAS  PubMed  Google Scholar 

  • Beaumont, V., Mrzljak, L., Dijkman, U., Freije, R., Heins, M., Rassoulpour, A., Tombaugh, G., Gelman, S., Bradaia, A., Steidl, E., Gleyzes M., Heikkinen, T., Lehtimäki, K., Puoliväli, J., Kontkanen, O., Javier, R.M., Neagoe, I., Deisemann, H., Winkler, D., & … , Munoz-Sanjuan, I. (2016). The novel KMO inhibitor CHDI-340246 leads to a restoration of electrophysiological alterations in mouse models of Huntington's disease. Experimental Neurology 282, 99–118.

    Google Scholar 

  • Braidy, N., Guillemin, G. J., Mansour, H., Chan-Ling, T., & Grant, R. (2011). Changes in kynurenine pathway metabolism in the brain, liver and kidney of aged female Wistar rats. The FEBS Journal, 278, 4425–4434.

    Article  CAS  PubMed  Google Scholar 

  • Breda, C., Sathyasaikumar, K. V., Sograte Idrissi, S., Notarangelo, F. M., Estranero, J. G., Moore, G. G., Green, E. W., Kyriacou, C. P., Schwarcz, R., & Giorgini, F. (2016). Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites. Proceedings of the National Academy of Sciences of the United States of America, 113(19), 5435–5440. https://doi.org/10.1073/pnas.1604453113. Epub 2016 Apr 25. PMID: 27114543.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brotchie, J. M., Mitchell, I. J., Sambrook, M. A., & Crossman, A. R. (1991). Alleviation of parkinsonism by antagonism of excitatory amino acid transmission in the medial segment of the globus pallidus in rat and primate. Movement Disorders, 6, 133–138.

    Article  CAS  PubMed  Google Scholar 

  • Brouillet, E., Jenkins, B. G., Hyman, B. T., Ferrante, R. J., Kowall, N. W., Srivastava, R., Roy, D. S., Rosen, B. R., & Beal, M. F. (1993). Age-dependent vulnerability of the striatum to the mitochondrial toxin 3-nitropropionic acid. Journal of Neurochemistry, 1993(60), 356–359.

    Article  Google Scholar 

  • Brouns, R., Verkerk, R., Aerts, T., De Surgeloose, D., Wauters, A., Scharpé, S., & De Deyn, P. P. (2010). The role of tryptophan catabolism along the kynurenine pathway in acute ischemic stroke. Neurochemical Research, 35, 1315–1322.

    Article  CAS  PubMed  Google Scholar 

  • Butler, E. G., Bourke, D. W., Finkelstein, D. I., & Horne, M. K. (1997). The effects of reversible inactivation of the subthalamo-pallidal pathway on the behaviour of naive and hemiparkinsonian monkeys. Journal of Clinical Neuroscience, 4, 218–227.

    Article  CAS  PubMed  Google Scholar 

  • Campesan, S., Green, E. W., Breda, C., Sathyasaikumar, K. V., Muchowski, P. J., Schwarcz, R., Kyriacou, C. P., & Giorgini, F. (2011). The kynurenine pathway modulates neurodegeneration in a Drosophila model of Huntington’s disease. Current Biology, 21, 961–966.

    Article  CAS  PubMed  Google Scholar 

  • Carlá, V., Lombardi, G., Beni, M., Russi, P., Moneti, G., & Moroni, F. (1988). Identification and measurement of kynurenic acid in the rat brain and other organs. Analytical Biochemistry, 169, 89–94.

    Article  PubMed  Google Scholar 

  • Carpenedo, R., Chiarugi, A., Russi, P., Lombardi, G., Carlà, V., Pellicciari, R., Mattoli, L., & Moroni, F. (1994). Inhibitors of kynurenine hydroxylase and kynureninase increase cerebral formation of kynurenate and have sedative and anticonvulsant activities. Neuroscience, 61, 237–243.

    Article  CAS  PubMed  Google Scholar 

  • Carpenedo, R., Meli, E., Peruginelli, F., Pellegrini-Giampietro, D. E., & Moroni, F. (2002). Kynurenine 3-mono-oxygenase inhibitors attenuate post-ischemic neuronal death in organotypic hippocampal slice cultures. Journal of Neurochemistry, 82, 1465–1471.

    Article  CAS  PubMed  Google Scholar 

  • Carpenedo, R., Pittaluga, A., Cozzi, A., Attucci, S., Galli, A., Raiteri, M., & Moroni, F. (2001). Presynaptic kynurenate-sensitive receptors inhibit glutamate release. The European Journal of Neuroscience, 13, 2141–2147.

    Article  CAS  PubMed  Google Scholar 

  • Ceresoli-Borroni, G., Rassoulpour, A., Wu, H. Q., Guidetti, P., & Schwarcz, R. (2006). Chronic neuroleptic treatment reduces endogenous kynurenic acid levels in rat brain. Journal of Neural Transmission, 113(10), 1355–1365.

    Article  CAS  PubMed  Google Scholar 

  • Chang, K. H., Cheng, M. L., Tang, H. Y., Huang, C. Y., Wu, Y. R., & Chen, C. M. (2018). Alternations of metabolic profile and kynurenine metabolism in the plasma of Parkinson’s disease. Molecular Neurobiology, 55, 6319–6328.

    Article  CAS  PubMed  Google Scholar 

  • Chiamulera, C., Costa, S., & Reggiani, A. (1990). Effect of NMDA- and strychnine-insensitive glycine site antagonists on NMDA-mediated convulsions and learning. Psychopharmacology, 102, 551–552.

    Article  CAS  PubMed  Google Scholar 

  • Chmiel-Perzyńska, I., Kloc, R., Perzyński, A., Rudzki, S., & Urbańska, E. M. (2011). Novel aspect of ketone action: β-hydroxybutyrate increases brain synthesis of kynurenic acid in vitro. Neurotoxicity Research, 20, 40–50.

    Article  PubMed  CAS  Google Scholar 

  • Chmiel-Perzyńska, I., Perzyński, A., Olajossy, B., Gil-Kulik, P., Kocki, J., & Urbańska, E. M. (2019). Losartan reverses hippocampal increase of kynurenic acid in type 1 diabetic rats: A novel procognitive aspect of Sartan action. Journal Diabetes Research, 2019, 4957879. https://doi.org/10.1155/2019/4957879. eCollection 2019.

    Article  CAS  Google Scholar 

  • Chmiel-Perzyńska, I., Perzyński, A., Wielosz, M., & Urbańska, E. M. (2007). Hyperglycemia enhances the inhibitory effect of mitochondrial toxins and D,L-homocysteine on the brain production of kynurenic acid. Pharmacological Reports, 59, 268–273.

    PubMed  Google Scholar 

  • Connick, J. H., Stone, T. W., Carla, V., & Moroni, F. (1988). Increased kynurenic acid levels in Huntington’s disease. Lancet, 2, 1373.

    Article  CAS  PubMed  Google Scholar 

  • Cosi, C., Mannaioni, G., Cozzi, A., Carlà, V., Sili, M., Cavone, L., Maratea, D., & Moroni, F. (2011). G-protein coupled receptor 35 (GPR35) activation and inflammatory pain: Studies on the antinociceptive effects of kynurenic acid and zaprinast. Neuropharmacology, 60, 1227–1231.

    Article  CAS  PubMed  Google Scholar 

  • Coyle, J. T., & Schwarcz, R. (1976). Lesion of striatal neurones with kainic acid provides a model for Huntington’s chorea. Nature, 263, 244–246.

    Article  CAS  PubMed  Google Scholar 

  • Cozzi, A., Carpenedo, R., & Moroni, F. (1999). Kynurenine hydroxylase inhibitors reduce ischemic brain damage: Studies with (m-nitrobenzoyl)-alanine (mNBA) and 3,4-dimethoxy-[-N-4-(nitrophenyl)thiazol-2yl]-benzenesulfonamide (Ro 61-8048) in models of focal or global brain ischemia. Journal of Cerebral Blood Flow and Metabolism, 19, 771–777.

    Article  CAS  PubMed  Google Scholar 

  • Csillik, A., Knyihár, E., Okuno, E., Krisztin-Péva, B., Csillik, B., & Vécsei, L. (2002). Effect of 3-nitropropionic acid on kynurenine aminotransferase in the rat brain. Experimental Neurology, 177, 233–241.

    Article  CAS  PubMed  Google Scholar 

  • Danysz, W., & Parsons, C. G. (2003). The NMDA receptor antagonist memantine as a symptomatological and neuroprotective treatment for Alzheimer’s disease: Preclinical evidence. International Journal of Geriatric Psychiatry, 18, S23–S32.

    Article  PubMed  Google Scholar 

  • Darlington, L. G., Mackay, G. M., Forrest, C. M., Stoy, N., George, C., & Stone, T. W. (2007). Altered kynurenine metabolism correlates with infarct volume in stroke. The European Journal of Neuroscience, 26, 2211–2221.

    Article  CAS  PubMed  Google Scholar 

  • DiNatale, B. C., Murray, I. A., Schroeder, J. C., Flaveny, C. A., Lahoti, T. S., Laurenzana, E. M., Omiecinski, C. J., & Perdew, G. H. (2010). Kynurenic acid is a potent endogenous aryl hydrocarbon receptor ligand that synergistically induces interleukin-6 in the presence of inflammatory signaling. Toxicological Sciences, 115, 89–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dobelis, P., Staley, K. J., & Cooper, D. C. (2012). Lack of modulation of nicotinic acetylcholine alpha-7 receptor currents by kynurenic acid in adult hippocampal interneurons. PLoS One, 7(7), e41108. Epub 2012 Jul 25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Du, F., Schmidt, W., Okuno, E., Kido, R., Köhler, C., & Schwarcz, R. (1992). Localization of kynurenine aminotransferase immunoreactivity in the rat hippocampus. The Journal of Comparative Neurology, 321, 477–487.

    Article  CAS  PubMed  Google Scholar 

  • Du, F., & Schwarcz, R. (1992). Aminooxyacetic acid causes selective neuronal loss in layer III of the rat medial entorhinal cortex. Neuroscience Letters, 147, 185–188.

    Article  CAS  PubMed  Google Scholar 

  • Eid, T., Du, F., & Schwarcz, R. (1995). Differential neuronal vulnerability to amino-oxyacetate and quinolinate in the rat parahippocampal region. Neuroscience, 68, 645–656.

    Article  CAS  PubMed  Google Scholar 

  • Ellinger, A. (1904). Die Entstehung der Kynurensaure. Zeitschrift für Physiologische Chemie, 43, 325–337.

    Article  Google Scholar 

  • Foster, A. C., Vezzani, A., French, E. D., & Schwarcz, R. (1984). Kynurenic acid blocks neurotoxicity and seizures induced in rats by the related brain metabolite quinolinic acid. Neuroscience Letters, 48, 273–278.

    Article  CAS  PubMed  Google Scholar 

  • Fukui, S., Schwarcz, R., Rapoport, S. I., Takada, Y., & Smith, Q. R. (1991). Blood-brain barrier transport of kynurenines: Implications for brain synthesis and metabolism. Journal of Neurochemistry, 56, 2007–2017.

    Article  CAS  PubMed  Google Scholar 

  • Germano, I. M., Pitts, L. H., Meldrum, B. S., Bartnikowski, H. M., & Simon, R. P. (1987). Kynurenate inhibition of cell excitation decreases stroke size and deficits. Annals of Neurology, 22, 730–734.

    Article  CAS  PubMed  Google Scholar 

  • Ghribi, O., Callebert, J., Plotkine, M., & Boulu, R. G. (1994). Effect of kynurenic acid on the ischaemia-induced accumulation of glutamate in rat striatum. Neuroreport, 5, 435–437.

    Article  CAS  PubMed  Google Scholar 

  • Gigler, G., Szénási, G., Simó, A., Lévay, G., Hársing, L. G., Jr., Sas, K., Vécsei, L., & Toldi, J. (2007). Neuroprotective effect of L-kynurenine sulfate administered before focal cerebral ischemia in mice and global cerebral ischemia in gerbils. European Journal of Pharmacology, 564, 116–122.

    Article  CAS  PubMed  Google Scholar 

  • Giil, L. M., Midttun, Ø., Refsum, H., Ulvik, A., Advani, R., Smith, A. D., & Ueland, P. M. (2017). Kynurenine pathway metabolites in Alzheimer’s disease. Journal of Alzheimer’s Disease, 60(2), 495–504.

    Article  CAS  PubMed  Google Scholar 

  • González-Sánchez, M., Jiménez, J., Narváez, A., Antequera, D., Llamas-Velasco, S., Martín, A. H., Arjona, J. A. M., Munain, A. L., Bisa, A. L., Marco, M. P., Rodríguez-Núñez, M., Pérez-Martínez, D. A., Villarejo-Galende, A., Bartolome, F., Domínguez, E., & Carro, E. (2020). Kynurenic acid levels are increased in the CSF of Alzheimer’s disease patients. Biomolecules, 10(4), 571.

    Article  PubMed Central  CAS  Google Scholar 

  • Gould, D. H., & Gustine, D. L. (1982). Basal ganglia degeneration, myelin alterations, and enzyme inhibition induced in mice by the plant toxin 3-nitropropanoic acid. Neuropathology and Applied Neurobiology, 8, 377–393.

    Article  CAS  PubMed  Google Scholar 

  • Gramsbergen, J. B., Hodgkins, P. S., Rassoulpour, A., Turski, W. A., Guidetti, P., & Schwarcz, R. (1997). Brain-specific modulation of kynurenic acid synthesis in the rat. Journal of Neurochemistry, 69, 290–298.

    Article  CAS  PubMed  Google Scholar 

  • Gramsbergen, J. B., Schmidt, W., Turski, W. A., & Schwarcz, R. (1992). Age-related changes in kynurenic acid production in rat brain. Brain Research, 588, 1–5.

    Article  CAS  PubMed  Google Scholar 

  • Guidetti, P., Amori, L., Sapko, M. T., Okuno, E., & Schwarcz, R. (2007). Mitochondrial aspartate aminotransferase: A third kynurenate-producing enzyme in the mammalian brain. J FNeurochem, 102, 103–111.

    Article  CAS  Google Scholar 

  • Guidetti, P., Luthi-Carter, R. E., Augood, S. J., & Schwarcz, R. (2004). Neostriatal and cortical quinolinate levels are increased in early grade Huntington’s disease. Neurobiology of Disease, 17, 455–461.

    Article  CAS  PubMed  Google Scholar 

  • Guidetti, P., Okuno, E., & Schwarcz, R. (1997). Characterization of rat brain kynurenine aminotransferases I and II. Journal of Neuroscience Research, 50, 457–465.

    Article  CAS  PubMed  Google Scholar 

  • Guidetti, P., Reddy, P. H., Tagle, D. A., & Schwarcz, R. (2000). Early kynurenergic impairment in Huntington’s disease and in a transgenic animal model. Neuroscience Letters, 283, 233–235.

    Article  CAS  PubMed  Google Scholar 

  • Guillemin, G. J., Williams, K. R., Smith, D. G., Smythe, G. A., Croitoru-Lamoury, J., & Brew, B. J. (2003). Quinolinic acid in the pathogenesis of Alzheimer’s disease. Advances in Experimental Medicine and Biology, 527, 167–176.

    Article  CAS  PubMed  Google Scholar 

  • Gulaj, E., Pawlak, K., Bien, B., & Pawlak, D. (2010). Kynurenine and its metabolites in Alzheimer’s disease patients. Advances in Medical Sciences, 55, 204–211.

    Article  CAS  PubMed  Google Scholar 

  • Guo, J., Williams, D. J., Puhl, H. L., 3rd, & Ikeda, S. R. (2008). Inhibition of N-type calcium channels by activation of GPR35, an orphan receptor, heterologously expressed in rat sympathetic neurons. The Journal of Pharmacology and Experimental Therapeutics, 324, 342–251.

    Article  CAS  PubMed  Google Scholar 

  • Han, Q., Cai, T., Tagle, D. A., & Li, J. (2010). Structure, expression, and function of kynurenine aminotransferases in human and rodent brains. Cellular and Molecular Life Sciences, 67, 353–368.

    Article  CAS  PubMed  Google Scholar 

  • Harris, C. A., Miranda, A. F., Tanguay, J. J., Boegman, R. J., Beninger, R. J., & Jhamandas, K. (1998). Modulation of striatal quinolinate neurotoxicity by elevation of endogenous brain kynurenic acid. British Journal of Pharmacology, 124, 391–399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hartai, Z., Juhász, A., Rimanóczy, A., Janáky, T., Donkó, T., Dux, L., Penke, B., Tóth, G. K., Janka, Z., & Kálmán, J. (2007). Decreased serum and red blood cell kynurenic acid levels in Alzheimer’s disease. Neurochemistry International, 50, 308–313.

    Article  CAS  PubMed  Google Scholar 

  • Hartai, Z., Klivenyi, P., Janaky, T., Penke, B., Dux, L., & Vecsei, L. (2005). Kynurenine metabolism in plasma and in red blood cells in Parkinson’s disease. Journal of the Neurological Sciences, 239, 31–35.

    Article  CAS  PubMed  Google Scholar 

  • Havelund, J. F., Andersen, A. D., Binzer, M., Blaabjerg, M., Heegaard, N. H. H., Stenager, E., Faergeman, N. J., & Gramsbergen, J. B. (2017). Changes in kynurenine pathway metabolism in Parkinson patients with L-DOPA-induced dyskinesia. Journal of Neurochemistry, 142(5), 756–766. https://doi.org/10.1111/jnc.14104. Epub 2017 Jul 11. PMID: 28628213.

    Article  CAS  PubMed  Google Scholar 

  • Heyes, M. P., Saito, K., Crowley, J. S., Davis, L. E., Demitrack, M. A., Der, M., Dilling, L. A., Elia, J., Kruesi, M. J., Lackner, A., et al. (1992). Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurological disease. Brain, 115, 1249–1273.

    Article  PubMed  Google Scholar 

  • Heyes, M. P., Saito, K., Devinsky, O., & Nadi, N. S. (1994). Kynurenine pathway metabolites in cerebrospinal fluid and serum in complex partial seizures. Epilepsia, 35, 251–257.

    Article  CAS  PubMed  Google Scholar 

  • Hilmas, C., Pereira, E. F., Alkondon, M., Rassoulpour, A., Schwarcz, R., & Albuquerque, E. X. (2001). The brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: Physiopathological implications. The Journal of Neuroscience, 21, 7463–7473.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hopkins, F. G., & Cole, S. W. (1901). A contribution to the chemistry of proteids: Part I. A preliminary study of a hitherto undescribed product of tryptic digestion. J Physiol, 27, 418–428.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hotta, S. S. (1968). Oxidative metabolism of isolated brain mitochondria: Changes caused by aminooxyacetate. Archives of Biochemistry and Biophysics, 127, 132–139.

    Article  CAS  PubMed  Google Scholar 

  • Hsieh, Y. C., Chen, R. F., Yeh, Y. S., Lin, M. T., Hsieh, J. H., & Chen, S. H. (2011). Kynurenic acid attenuates multiorgan dysfunction in rats after heat stroke. Acta Pharmacologica Sinica, 32, 167–174.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jacobs, K. R., Lim, C. K., Blennow, K., Zetterberg, H., Chatterjee, P., Martins, R. N., Brew, B. J., Guillemin, G. J., & Lovejoy D. B. (2019). Correlation between plasma and CSF concentrations of kynurenine pathway metabolites in Alzheimer's disease and relationship to amyloid-β and tau. Neurobiology of Aging, 80, 11–20. https://doi.org/10.1016/j.neurobiolaging.2019.03.015.

  • Jauch, D., Urbanska, E. M., Guidetti, P., Bird, E. D., Vonsattel, J. P., Whetsell, W. O., Jr., & Schwarcz, R. (1995). Dysfunction of brain kynurenic acid metabolism in Huntington’s disease: Focus on kynurenine aminotransferases. Journal of the Neurological Sciences, 130, 39–47.

    Article  CAS  PubMed  Google Scholar 

  • Jenkins, L., Alvarez-Curto, E., Campbell, K., de Munnik, S., Canals, M., Schlyer, S., & Milligan, G. (2011). Agonist activation of the G protein-coupled receptor GPR35 involves transmembrane domain III and is transduced via Gα13 and β-arrestin-2. British Journal of Pharmacology, 162, 733–748.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kamiński, R. M., Zielińska, E., Dekundy, A., van Luijtelaar, G., & Turski, W. (2003). Deficit of endogenous kynurenic acid in the frontal cortex of rats with a genetic form of absence epilepsy. Polish Journal of Pharmacology, 55, 741–746.

    PubMed  Google Scholar 

  • Katayama, Y., Kawamata, T., Kano, T., & Tsubokawa, T. (1992). Excitatory amino acid antagonist administered via microdialysis attenuates lactate accumulation during cerebral ischemia and subsequent hippocampal damage. Brain Research, 584, 329–333.

    Article  CAS  PubMed  Google Scholar 

  • Kepplinger, B., Baran, H., Kainz, A., Ferraz-Leite, H., Newcombe, J., & Kalina, P. (2005). Age-related increase of kynurenic acid in human cerebrospinal fluid – IgG and beta2-microglobulin changes. Neurosignals, 14, 126–135.

    Article  CAS  PubMed  Google Scholar 

  • Kessler, M., Terramani, T., Lynch, G., & Baudry, M. (1989). A glycine site associated with N-methyl-D-aspartic acid receptors: Characterization and identification of a new class of antagonists. Journal of Neurochemistry, 52, 1319–1328.

    Article  CAS  PubMed  Google Scholar 

  • Kimura, H., Suda, H., Kassai, M., Endo, M., Deai, Y., Yahata, M., Miyajima, M., & Isobe, Y. (2021). N-(6-phenylpyridazin-3-yl)benzenesulfonamides as highly potent, brain-permeable, and orally active kynurenine monooxygenase inhibitors. Bioorganic & Medicinal Chemistry Letters, 33, 127753.

    Article  CAS  Google Scholar 

  • Kiś, J., Czuczwar, M., Zielińska, E., Bojar, I., Czuczwar, S. J., & Turski, W. A. (2000). Kynurenic acid does not protect against nicotine-induced seizures in mice. Polish Journal of Pharmacology, 52, 477–480.

    PubMed  Google Scholar 

  • Kloc, R., Luchowska, E., Wielosz, M., Owe-Larsson, B., & Urbanska, E. M. (2008). Memantine increases brain production of kynurenic acid via protein kinase A-dependent mechanism. Neuroscience Letters, 435, 169–173.

    Article  CAS  PubMed  Google Scholar 

  • Knyihár-Csillik, E., Chadaide, Z., Mihály, A., Krisztin-Péva, B., Fenyo, R., & Vécsei, L. (2006). Effect of 6-hydroxydopamine treatment on kynurenine aminotransferase-I (KAT-I) immunoreactivity of neurons and glial cells in the rat substantia nigra. Acta Neuropathologica, 112, 127–137.

    Article  PubMed  CAS  Google Scholar 

  • Knyihár-Csillik, E., Csillik, B., Pákáski, M., Krisztin-Péva, B., Dobó, E., Okuno, E., & Vécsei, L. (2004). Decreased expression of kynurenine aminotransferase-I (KAT-I) in the substantia nigra of mice after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. Neuroscience, 126, 899–914.

    Article  PubMed  CAS  Google Scholar 

  • Kocki, T., Kocki, J., Wielosz, M., Turski, W. A., & Urbanska, E. M. (2004). Carbamazepine enhances brain production of kynurenic acid in vitro. European Journal of Pharmacology, 498, 325–326.

    Article  CAS  PubMed  Google Scholar 

  • Kocki, T., Luchowski, P., Luchowska, E., Wielosz, M., Turski, W. A., & Urbanska, E. M. (2003). L-cysteine sulphinate, endogenous Sulphur-containing amino acid, inhibits rat brain kynurenic acid production via selective interference with kynurenine aminotransferase II. Neuroscience Letters, 346, 97–100.

    Article  CAS  PubMed  Google Scholar 

  • Kocki, T., Wielosz, M., Turski, W. A., & Urbanska, E. M. (2006). Enhancement of brain kynurenic acid production by anticonvulsants – novel mechanism of antiepileptic activity? European Journal of Pharmacology, 541, 147–151.

    Article  CAS  PubMed  Google Scholar 

  • Kocki, T., Wnuk, S., Kloc, R., Kocki, J., Owe-Larsson, B., & Urbanska, E. M. (2012). New insight into the antidepressants action: Modulation of kynurenine pathway by increasing the kynurenic acid/3-hydroxykynurenine ratio. Journal of Neural Transmission, 119, 235–243.

    Article  CAS  PubMed  Google Scholar 

  • Kuc, D., Zgrajka, W., Parada-Turska, J., Urbanik-Sypniewska, T., & Turski, W. A. (2008). Micromolar concentration of kynurenic acid in rat small intestine. Amino Acids, 35, 503–505.

    Article  CAS  PubMed  Google Scholar 

  • Lapin, I. P. (1978). Stimulant and convulsive effects of kynurenines injected into brain ventricles in mice. Journal of Neural Transmission, 42, 37–43.

    Article  CAS  PubMed  Google Scholar 

  • Lapin, I. P. (1983). Antagonism of kynurenine-induced seizures by picolinic, kynurenic and xanthurenic acids. Journal of Neural Transmission, 56, 177–185.

    Article  CAS  PubMed  Google Scholar 

  • Lapin, I. P., Prakhie, I. B., & Kiseleva, I. P. (1986). Antagonism of seizures induced by the administration of the endogenous convulsant quinolinic acid into rat brain ventricles. Journal of Neural Transmission, 65, 177–185.

    Article  CAS  PubMed  Google Scholar 

  • Lee do, Y., Lee, K. S., Lee, H. J., Noh, Y. H., Kim do, H., Lee, J. Y., Cho, S. H., Yoon, O. J., Lee, W. B., Kim, K. Y., Chung, Y. H., & Kim, S. S. (2008). Kynurenic acid attenuates MPP(+)-induced dopaminergic neuronal cell death via a Bax-mediated mitochondrial pathway. European Journal of Cell Biology, 87, 389–397.

    Article  PubMed  CAS  Google Scholar 

  • Liebig, J. (1853). Uber Kynurensäure. Justus Liebigs Annalen der Chemie, 86, 125–126.

    Article  Google Scholar 

  • Löscher, W., Ebert, U., & Lehmann, H. (1996). Kindling induces a lasting, regionally selective increase of kynurenic acid in the nucleus accumbens. Brain Research, 725, 252–256.

    Article  PubMed  Google Scholar 

  • Luchowska, E., Kloc, R., Olajossy, B., Wnuk, S., Wielosz, M., Owe-Larsson, B., & Urbanska, E. M. (2009). β-adrenergic enhancement of brain kynurenic acid production mediated via cAMP-related protein kinase A signaling. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 33, 519–529.

    Article  CAS  Google Scholar 

  • Luchowska, E., Kloc, R., Wnuk, S., Olajossy, B., Wielosz, M., & Urbańska, E. M. (2008). Clenbuterol enhances the production of kynurenic acid in brain cortical slices and glial cultures. Pharmacological Reports, 60, 574–577.

    CAS  PubMed  Google Scholar 

  • Luchowska, E., Luchowski, P., Paczek, R., Ziembowicz, A., Kocki, T., Turski, W. A., Wielosz, M., Lazarewicz, J., & Urbanska, E. M. (2005). Dual effect of DL-homocysteine and S-adenosylhomocysteine on brain synthesis of the glutamate receptor antagonist, kynurenic acid. Journal of Neuroscience Research, 79, 375–382.

    Article  CAS  PubMed  Google Scholar 

  • Luchowska, E., Luchowski, P., Sarnowska, A., Wielosz, M., Turski, W. A., & Urbańska, E. M. (2003a). Endogenous level of kynurenic acid and activities of kynurenine aminotransferases following transient global ischemia in the gerbil hippocampus. Polish Journal of Pharmacology, 55, 443–447.

    CAS  PubMed  Google Scholar 

  • Luchowska, E., Luchowski, P., Wielosz, M., Turski, W. A., & Urbanska, E. M. (2003b). FK506 attenuates 1-methyl-4-phenylpyridinium- and 3-nitropropionic acid-evoked inhibition of kynurenic acid synthesis in rat cortical slices. Acta Neurobiologiae Experimentalis (Wars), 63(2), 101–108.

    Google Scholar 

  • Luchowski, P., Luchowska, E., Turski, W. A., & Urbanska, E. M. (2002). 1-Methyl-4-phenylpyridinium and 3-nitropropionic acid diminish cortical synthesis of kynurenic acid via interference with kynurenine aminotransferases in rats. Neuroscience Letters, 330, 49–52.

    Article  CAS  PubMed  Google Scholar 

  • Luchowski, P., & Urbanska, E. M. (2007). SNAP and SIN-1 increase brain production of kynurenic acid. European Journal of Pharmacology, 563, 130–133.

    Article  CAS  PubMed  Google Scholar 

  • Maciejak, P., Szyndler, J., Turzyńska, D., Sobolewska, A., Taracha, E., Skórzewska, A., Lehner, M., Bidziński, A., & Płaźnik, A. (2009). Time course of changes in the concentration of kynurenic acid in the brain of pentylenetetrazol-kindled rats. Brain Research Bulletin, 78, 299–305.

    Article  CAS  PubMed  Google Scholar 

  • McIntosh, T. K., Vink, R., Soares, H., Hayes, R., & Simon, R. (1990). Effect of noncompetitive blockade of N-methyl-D-aspartate receptors on the neurochemical sequelae of experimental brain injury. Journal of Neurochemistry, 55, 1170–1179.

    Article  CAS  PubMed  Google Scholar 

  • McMaster, O. G., Du, F., French, E. D., & Schwarcz, R. (1991). Focal injection of aminooxyacetic acid produces seizures and lesions in rat hippocampus: Evidence for mediation by NMDA receptors. Experimental Neurology, 113, 378–385.

    Article  CAS  PubMed  Google Scholar 

  • Miranda, A. F., Boegman, R. J., Beninger, R. J., & Jhamandas, K. (1997). Protection against quinolinic acid-mediated excitotoxicity in nigrostriatal dopaminergic neurons by endogenous kynurenic acid. Neuroscience, 78, 967–975.

    Article  CAS  PubMed  Google Scholar 

  • Mo, X., Pi, L., Yang, J., Xiang, Z., & Tang, A. (2014). Serum indoleamine 2,3-dioxygenase and kynurenine aminotransferase enzyme activity in patients with ischemic stroke. Journal of Clinical Neuroscience, 21, 482–486.

    Article  CAS  PubMed  Google Scholar 

  • Mok, M. H., Fricker, A. C., Weil, A., & Kew, J. N. (2009). Electrophysiological characterisation of the actions of kynurenic acid at ligand-gated ion channels. Neuropharmacology, 57, 242–249.

    Article  CAS  PubMed  Google Scholar 

  • Moroni, F., Russi, P., Carla, V., & Lombardi, G. (1988). Kynurenic acid is present in the rat brain and its content increases during development and aging processes. Neuroscience Letters, 94, 145–150.

    Article  CAS  PubMed  Google Scholar 

  • Muñóz-Hoyos, A., Molina-Carballo, A., Rodríguez-Cabezas, T., Uberos-Fernández, J., Ruiz-Cosano, C., & Acuña-Castroviejo, D. (1997). Relationships between methoxyindole and kynurenine pathway metabolites in plasma and urine in children suffering from febrile and epileptic seizures. Clinical Endocrinology, 47, 667–677.

    Article  PubMed  Google Scholar 

  • Newell, D. W., Barth, A., & Malouf, A. T. (1995). Glycine site NMDA receptor antagonists provide protection against ischemia-induced neuronal damage in hippocampal slice cultures. Brain Research, 675, 38–44.

    Article  CAS  PubMed  Google Scholar 

  • Ogawa, T., Matson, W. R., Beal, M. F., Myers, R. H., Bird, E. D., Milbury, P., & Saso, S. (1992). Kynurenine pathway abnormalities in Parkinson’s disease. Neurology, 42, 1702–1706.

    Article  CAS  PubMed  Google Scholar 

  • Okuno, E., Nakamura, M., & Schwarcz, R. (1991). Two kynurenine aminotransferases in human brain. Brain Research, 542, 307–312.

    Article  CAS  PubMed  Google Scholar 

  • Ouattara, B., Belkhir, S., Morissette, M., Dridi, M., Samadi, P., Grégoire, L., Meltzer, L. T., & Di Paolo, T. (2009). Implication of NMDA receptors in the antidyskinetic activity of cabergoline, CI-1041, and Ro 61-8048 in MPTP monkeys with levodopa-induced dyskinesias. Journal of Molecular Neuroscience, 38, 128–142. https://doi.org/10.1007/s12031-008-9137-8.

  • Oxenkrug, G., van der Hart, M., Roeser, J., & Summergrad P. (2017). Peripheral tryptophan-kynurenine metabolism associated with metabolic syndrome is different in Parkinson’s and Alzheimer’s diseases. Endocrinol Diabetes Metab. 1 http://researchopenworld.com/wp-content/uploads/2017/11/EDMJ-2017

  • Peeters, B. W., Ramakers, G. M., Ellenbroek, B. A., Vossen, J. M., & Coenen, A. M. (1994). Interactions between NMDA and nonNMDA receptors in nonconvulsive epilepsy in the WAG/Rij inbred strain. Brain Research Bulletin, 33, 715–718.

    Article  CAS  PubMed  Google Scholar 

  • Perkins, M. N., & Stone, T. W. (1982). An iontophoretic investigation of the actions of convulsant kynurenines and their interaction with the endogenous excitant quinolinic acid. Brain Research, 247, 184–187.

    Article  CAS  PubMed  Google Scholar 

  • Phillis, J. W., Song, D., Guyot, L. L., & O'Regan, M. H. (1999). Failure of kynurenic acid to inhibit amino acid release from the ischemic rat cerebral cortex. Neuroscience Letters, 273, 21–24.

    Article  CAS  PubMed  Google Scholar 

  • Pinsky, C., Glavin, G. B., & Bose, R. (1989). Kynurenic acid protects against neurotoxicity and lethality of toxic extracts from contaminated Atlantic coast mussels. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 13, 595–598.

    Article  CAS  Google Scholar 

  • Pocivavsek, A., Wu, H. Q., Potter, M. C., Elmer, G. I., Pellicciari, R., & Schwarcz, R. (2011). Fluctuations in endogenous kynurenic acid control hippocampal glutamate and memory. Neuropsychopharmacology, 36, 2357–2367.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rassoulpour, A., Wu, H. Q., Albuquerque, E. X., & Schwarcz, R. (2005). Prolonged nicotine administration results in biphasic, brain-specific changes in kynurenate levels in the rat. Neuropsychopharmacology, 30, 697–704.

    Article  CAS  PubMed  Google Scholar 

  • Rassoulpour, A., Wu, H. Q., Poeggeler, B., & Schwarcz, R. (1998). Systemic d-amphetamine administration causes a reduction of kynurenic acid levels in rat brain. Brain Research, 802, 111–118.

    Article  CAS  PubMed  Google Scholar 

  • Rejdak, K., Bartosik-Psujek, H., Dobosz, B., Kocki, T., Grieb, P., Giovannoni, G., Turski, W. A., & Stelmasiak, Z. (2002). Decreased level of kynurenic acid in cerebrospinal fluid of relapsing-onset multiple sclerosis patients. Neuroscience Letters, 331, 63–65.

    Article  CAS  PubMed  Google Scholar 

  • Reynolds, G. P., & Pearson, S. J. (1989). Increased brain 3-hydroxykynurenine in Huntington's disease. Lancet, 2, 979–980.

    Article  CAS  PubMed  Google Scholar 

  • Robotka, H., Sas, K., Agoston, M., Rózsa, E., Szénási, G., Gigler, G., Vécsei, L., & Toldi, J. (2008). Neuroprotection achieved in the ischaemic rat cortex with L-kynurenine sulphate. Life Sciences, 82, 915–919.

    Article  CAS  PubMed  Google Scholar 

  • Russi, P., Alesiani, M., Lombardi, G., Davolio, P., Pellicciari, R., & Moroni, F. (1992). Nicotinylalanine increases the formation of kynurenic acid in the brain and antagonizes convulsions. Journal of Neurochemistry, 59, 2076–2080.

    Article  CAS  PubMed  Google Scholar 

  • Rzeski, W., Kocki, T., Dybel, A., Wejksza, K., Zdzisińska, B., Kandefer-Szerszeń, M., Turski, W. A., Okuno, E., & Albrecht, J. (2005). Demonstration of kynurenine aminotransferases I and II and characterization of kynurenic acid synthesis in cultured cerebral cortical neurons. Journal of Neuroscience Research, 80, 677–682.

    Article  CAS  PubMed  Google Scholar 

  • Salvati, P., Ukmar, G., Dho, L., Rosa, B., Cini, M., Marconi, M., Molinari, A., & Post, C. (1999). Brain concentrations of kynurenic acid after a systemic neuroprotective dose in the gerbil model of global ischemia. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 23, 741–752.

    Article  CAS  Google Scholar 

  • Sapko, M. T., Guidetti, P., Yu, P., Tagle, D. A., Pellicciari, R., & Schwarcz, R. (2006). Endogenous kynurenate controls the vulnerability of striatal neurons to quinolinate: Implications for Huntington's disease. Experimental Neurology, 197, 31–40.

    Article  CAS  PubMed  Google Scholar 

  • Scharfman, H. E., & Ofer, A. (1997). Pretreatment with L-kynurenine, the precursor to the excitatory amino acid antagonist kynurenic acid, suppresses epileptiform activity in combined entorhinal/hippocampal slices. Neuroscience Letters, 224, 115–118.

    Article  CAS  PubMed  Google Scholar 

  • Schneiderman, J. H., & MacDonald, J. F. (1989). Excitatory amino acid blockers differentially affect bursting of in vitro hippocampal neurons in two pharmacological models of epilepsy. Neuroscience, 31, 593–603.

    Article  CAS  PubMed  Google Scholar 

  • Schwarcz, R., Whetsell, W. O., Jr., & Mangano, R. M. (1983). Quinolinic acid: An endogenous metabolite that produces axon-sparing lesions in rat brain. Science, 219, 316–318.

    Article  CAS  PubMed  Google Scholar 

  • Silva-Adaya, D., Pérez-De La Cruz, V., Villeda-Hernández, J., Carrillo-Mora, P., González-Herrera, I. G., García, E., Colín-Barenque, L., Pedraza-Chaverrí, J., & Santamaría, A. (2011). Protective effect of L-kynurenine and probenecid on 6-hydroxydopamine-induced striatal toxicity in rats: Implications of modulating kynurenate as a protective strategy. Neurotoxicology and Teratology, 33, 303–312.

    Article  CAS  PubMed  Google Scholar 

  • Simon, R. P., Young, R. S., Stout, S., & Cheng, J. (1986). Inhibition of excitatory neurotransmission with kynurenate reduces brain edema in neonatal anoxia. Neuroscience Letters, 71, 361–364.

    Article  CAS  PubMed  Google Scholar 

  • Speciale, C., Wu, H. Q., Gramsbergen, J. B., Turski, W. A., Ungerstedt, U., & Schwarcz, R. (1990). Determination of extracellular kynurenic acid in the striatum of unanesthetized rats: Effect of aminooxyacetic acid. Neuroscience Letters, 116, 198–203.

    Article  CAS  PubMed  Google Scholar 

  • Stazka, J., Luchowski, P., & Urbanska, E. M. (2005). Homocysteine, a risk factor for atherosclerosis, biphasically changes the endothelial production of kynurenic acid. European Journal of Pharmacology, 2005(517), 217–223.

    Article  CAS  Google Scholar 

  • Stazka, J., Luchowski, P., Wielosz, M., Kleinrok, Z., & Urbanska, E. M. (2002). Endothelium-dependent production and liberation of kynurenic acid by rat aortic rings exposed to L-kynurenine. European Journal of Pharmacology, 448, 133–137.

    Article  CAS  PubMed  Google Scholar 

  • Stone, T. W. (1988). Comparison of kynurenic acid and 2-APV suppression of epileptiform activity in rat hippocampal slices. Neuroscience Letters, 84, 234–238.

    Article  CAS  PubMed  Google Scholar 

  • Stone, T. W. (2007). Kynurenic acid blocks nicotinic synaptic transmission to hippocampal interneurons in young rats. The European Journal of Neuroscience, 25, 2656–2665.

    Article  PubMed  Google Scholar 

  • Swartz, K. J., Matson, W. R., MacGarvey, U., Ryan, E. A., & Beal, M. F. (1990). Measurement of kynurenic acid in mammalian brain extracts and cerebrospinal fluid by high-performance liquid chromatography with fluorometric and coulometric electrode array detection. Analytical Biochemistry, 185, 363–376.

    Article  CAS  PubMed  Google Scholar 

  • Thompson, J. L., Holmes, G. L., Taylor, G. W., & Feldman, D. R. (1988). Effects of kynurenic acid on amygdaloid kindling in the rat. Epilepsy Research, 2, 302–308.

    Article  CAS  PubMed  Google Scholar 

  • Tohgi, H., Abe, T., Takahashi, S., Kimura, M., Takahashi, J., & Kikuchi, T. (1992). Concentrations of serotonin and its related substances in the cerebrospinal fluid in patients with Alzheimer type dementia. Neuroscience Letters, 141, 9–12.

    Article  CAS  PubMed  Google Scholar 

  • Tomczyk, T., & Urbańska, E. M. (2020). Experimental hypothyroidism raises brain kynurenic acid – Novel aspect of thyroid dysfunction. Eur J Pharmacol, 883, 173363. https://doi.org/10.1016/j.ejphar.2020.173363. Epub 2020 Jul 11.

    Article  CAS  PubMed  Google Scholar 

  • Turski, L., Bressler, K., Rettig, K. J., Löschmann, P. A., & Wachtel, H. (1991a). Protection of substantia nigra from MPP+ neurotoxicity by N-methyl-D-aspartate antagonists. Nature, 349, 414–418.

    Article  CAS  PubMed  Google Scholar 

  • Turski, M. P., Turska, M., Zgrajka, W., Kuc, D., & Turski, W. A. (2009). Presence of kynurenic acid in food and honeybee products. Amino Acids, 36, 75–80.

    Article  CAS  PubMed  Google Scholar 

  • Turski, W. A., Dziki, M., Parada, J., Kleinrok, Z., & Cavalheiro, E. A. (1992). Age dependency of the susceptibility of rats to aminooxyacetic acid seizures. Developmental Brain Research, 67, 137–144.

    Google Scholar 

  • Turski, W. A., Dziki, M., Urbanska, E., Calderazzo-Filho, L. S., & Cavalheiro, E. A. (1991b). Seizures induced by aminooxyacetic acid in mice: Pharmacological characteristics. Synapse, 7, 173–180.

    Google Scholar 

  • Turski, W. A., Gramsbergen, J. B., Traitler, H., & Schwarcz, R. (1989). Rat brain slices produce and liberate kynurenic acid upon exposure to L-kynurenine. Journal of Neurochemistry, 52, 1629–1636.

    Article  CAS  PubMed  Google Scholar 

  • Turski, W. A., Nakamura, M., Todd, W. P., Carpenter, B. K., Whetsell, W. O., Jr., & Schwarcz, R. (1988). Identification and quantification of kynurenic acid in human brain tissue. Brain Research, 454, 164–169.

    Article  CAS  PubMed  Google Scholar 

  • Turski, W. A., Urbanska, E., Dziki, M., Parada-Turska, J., & Ikonomidou, C. (1990). Excitatory amino acid antagonists protect mice against seizures induced by bicuculline. Brain Research, 514, 131–134.

    Article  CAS  PubMed  Google Scholar 

  • Urbanska, E., Ikonomidou, C., Sieklucka, M., & Turski, W. A. (1991). Aminooxyacetic acid produces excitotoxic lesions in the rat striatum. Synapse, 9, 129–135.

    Article  CAS  PubMed  Google Scholar 

  • Urbanska, E. M., Chmielewski, M., Kocki, T., & Turski, W. A. (2000). Formation of endogenous glutamatergic receptors antagonist kynurenic acid - differences between cortical and spinal cord slices. Brain Research, 878, 210–212.

    Article  CAS  PubMed  Google Scholar 

  • Urbanska, E. M., Kocki, T., Saran, T., Kleinrok, Z., & Turski, W. A. (1997). Impairment of brain kynurenic acid production by glutamate metabotropic receptor agonists. Neuroreport, 8, 3501–3505.

    Article  CAS  PubMed  Google Scholar 

  • Urbanska, E. M., Luchowski, P., Luchowska, E., Pniewski, J., Woźniak, R., Chodakowska-Zebrowska, M., & Lazarewicz, J. (2006). Serum kynurenic acid positively correlates with cardiovascular disease risk factor, homocysteine: A study in stroke patients. Pharmacological Reports, 58, 507–511.

    CAS  PubMed  Google Scholar 

  • Uwai, Y., Honjo, H., & Iwamoto, K. (2012). Interaction and transport of kynurenic acid via human organic anion transporters hOAT1 and hOAT3. Pharmacological Research, 65, 254–260.

    Article  CAS  PubMed  Google Scholar 

  • van der Velpen, V., Teav, T., Gallart-Ayala, H., Mehl, F., Konz, I., Clark, C., Oikonomidi, A., Peyratout, G., Henry, H., Delorenzi, M., Ivanisevic, J., & Popp, J. (2019). Systemic and central nervous system metabolic alterations in Alzheimer’s disease. Alzheimer's Research & Therapy, 11(1), 93.

    Article  CAS  Google Scholar 

  • Vécsei, L., Miller, J., MacGarvey, U., & Beal, M. F. (1992). Kynurenine and probenecid inhibit pentylenetetrazol- and NMDLA-induced seizures and increase kynurenic acid concentrations in the brain. Brain Research Bulletin, 28, 233–238.

    Article  PubMed  Google Scholar 

  • Wang, J., Simonavicius, N., Wu, X., Swaminath, G., Reagan, J., Tian, H., & Ling, L. (2006). Kynurenic acid as a ligand for orphan G protein-coupled receptor GPR35. The Journal of Biological Chemistry, 281, 22021–22028.

    Article  CAS  PubMed  Google Scholar 

  • Whiley, L., Chappell, K. E., D'Hondt, E., Lewis, M. R., Jiménez, B., Snowden, S. G., Soininen, H., Kłoszewska, I., Mecocci, P., Tsolaki, M., Vellas, B., Swann, J. R., Hye, A., Lovestone, S., Legido-Quigley, C., Holmes, E., & AddNeuroMed consortium. (2021). Metabolic phenotyping reveals a reduction in the bioavailability of serotonin and kynurenine pathway metabolites in both the urine and serum of individuals living with Alzheimer’s disease. Alzheimer’s Research & Therapy, 13(1), 20.

    Article  CAS  Google Scholar 

  • Widner, B., Leblhuber, F., Walli, J., Tilz, G. P., Demel, U., & Fuchs, D. (2000). Tryptophan degradation and immune activation in Alzheimer’s disease. Journal of Neural Transmission, 107, 343–353.

    Article  CAS  PubMed  Google Scholar 

  • Wu, H. Q., Rassoulpour, A., Goodman, J. H., Scharfman, H. E., Bertram, E. H., & Schwarcz, R. (2005). Kynurenate and 7-chlorokynurenate formation in chronically epileptic rats. Epilepsia, 46, 1010–1016.

    Article  CAS  PubMed  Google Scholar 

  • Wu, H. Q., Rassoulpour, A., & Schwarcz, R. (2002). Effect of systemic L-DOPA administration on extracellular kynurenate levels in the rat striatum. Journal of Neural Transmission, 109, 239–249.

    Article  CAS  PubMed  Google Scholar 

  • Wu, H. Q., & Schwarcz, R. (1996). Seizure activity causes elevation of endogenous extracellular kynurenic acid in the rat brain. Brain Research Bulletin, 39, 155–162.

    Article  CAS  PubMed  Google Scholar 

  • Wu, H. Q., Turski, W. A., Ungerstedt, U., & Schwarcz, R. (1991). Systemic kainic acid administration in rats: Effects on kynurenic acid production in vitro and in vivo. Experimental Neurology, 113, 47–52.

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto, H., Murakami, H., Horiguchi, K., & Egawa, B. (1995). Studies on cerebrospinal fluid kynurenic acid concentrations in epileptic children. Brain Dev, 17, 327–329.

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto, H., Shindo, I., Egawa, B., & Horiguchi, K. (1994). Kynurenic acid is decreased in cerebrospinal fluid of patients with infantile spasms. Pediatric Neurology, 1994(10), 9–12.

    Article  Google Scholar 

  • Zádori, D., Nyiri, G., Szonyi, A., Szatmári, I., Fülöp, F., Toldi, J., Freund, T. F., Vécsei, L., & Klivényi, P. (2011). Neuroprotective effects of a novel kynurenic acid analogue in a transgenic mouse model of Huntington’s disease. Journal of Neural Transmission, 118, 865–875.

    Article  PubMed  CAS  Google Scholar 

  • Zakrocka, I., Targowska-Duda, K. M., Wnorowski, A., Kocki, T., Jóźwiak, K., & Turski, W. A. (2017). Angiotensin II type 1 receptor blockers inhibit KAT II activity in the brain-its possible clinical applications. Neurotoxicity Research, 32(4), 639–648. https://doi.org/10.1007/s12640-017-9781-2. Epub 2017 Jul 21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Żarnowska, I., Wróbel-Dudzińska, D., Tulidowicz-Bielak, M., Kocki, T., Mitosek-Szewczyk, K., Gasior, M., & Turski, W. A. (2019). Changes in tryptophan and kynurenine pathway metabolites in the blood of children treated with ketogenic diet for refractory epilepsy. Seizure, 69, 265–272.

    Article  PubMed  Google Scholar 

  • Zarnowski, T., Chorągiewicz, T., Tulidowicz-Bielak, M., Thaler, S., Rejdak, R., Żarnowski, I., Turski, W. A., & Gasior, M. (2012). Ketogenic diet increases concentrations of kynurenic acid in discrete brain structures of young and adult rats. Journal of Neural Transmission, 119, 679–684.

    Article  CAS  PubMed  Google Scholar 

  • Zielińska, E., Kocki, T., Saran, T., Borbely, S., Kuc, D., Vilagi, I., Urbańska, E. M., & Turski, W. A. (2005). Effect of pesticides on kynurenic acid production in rat brain slices. Annals of Agricultural and Environmental Medicine, 12, 177–179.

    PubMed  Google Scholar 

  • Zielińska, E., Kuc, D., Zgrajka, W., Turski, W. A., & Dekundy, A. (2009). Long-term exposure to nicotine markedly reduces kynurenic acid in rat brain - in vitro and ex vivo evidence. Toxicology and Applied Pharmacology, 240, 174–179.

    Article  PubMed  CAS  Google Scholar 

  • Zwilling, D., Huang, S. Y., Sathyasaikumar, K. V., Notarangelo, F. M., Guidetti, P., Wu, H. Q., Lee, J., Truong, J., Andrews-Zwilling, Y., Hsieh, E. W., Louie, J. Y., Wu, T., Scearce-Levie, K., Patrick, C., Adame, A., Giorgini, F., Moussaoui, S., Laue, G., Rassoulpour, A., & … Muchowski, P. J. (2011). Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration. Cell, 145, 863–874.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Cellular and Molecular Pharmacology, Department of Experimental and Clinical Pharmacology, Medical University of Lublin, Lublin, Poland

    Ewa M. Urbańska

  2. District Health Center in Opole Lubelskie, Hospital in Poniatowa, Poniatowa, Poland

    Iwona Chmiel-Perzyńska

  3. Department of Psychiatry, Medical University of Lublin, Lublin, Poland

    Adam Perzyński

  4. Department of Endocrinology, Independent Public Clinical Hospital No. 4 in Lublin, Lublin, Poland

    Marek Derkacz

  5. Department of Clinical Neuroscience, Karolinska Institutet, Section of Psychiatry at Karolinska University Hospital Huddinge, Stockholm, Sweden

    Björn Owe-Larsson

Authors
  1. Ewa M. Urbańska
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Iwona Chmiel-Perzyńska
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Adam Perzyński
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marek Derkacz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Björn Owe-Larsson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ewa M. Urbańska .

Editor information

Editors and Affiliations

  1. Department of Biomedical Sciences, East Tennessee State University, Johnson City, TN, USA

    Richard M. Kostrzewa

Rights and permissions

Reprints and permissions

Copyright information

© 2021 Springer Nature Switzerland AG

About this entry

Check for updates. Verify currency and authenticity via CrossMark

Cite this entry

Urbańska, E.M., Chmiel-Perzyńska, I., Perzyński, A., Derkacz, M., Owe-Larsson, B. (2021). Endogenous Kynurenic Acid and Neurotoxicity. In: Kostrzewa, R.M. (eds) Handbook of Neurotoxicity. Springer, Cham. https://doi.org/10.1007/978-3-030-71519-9_92-1

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-71519-9_92-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-71519-9

  • Online ISBN: 978-3-030-71519-9

  • eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences

Publish with us

Policies and ethics

Search

Navigation