Endogenous Kynurenic Acid and Neurotoxicity

Reference work entry


Tryptophan metabolism along kynurenine pathway yields a number of compounds affecting brain function. 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 excitatory amino acid receptor antagonist. Since then, a number of novel KYNA targets emerged. KYNA was suggested to play a role as antagonist of α7 nicotinic receptors and ligand of G protein-coupled GPR35 and human aryl hydrocarbon (AHR) receptors. In here, research data is reviewed 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 analogues 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.


Ketogenic Diet Quinolinic Acid Kynurenine Pathway Cortical Slice Organotypic Hippocampal Slice Culture 
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  1. Ali, S. F., Binienda, Z. K., & Imam, S. Z. (2011). Molecular aspects of dopaminergic neurodegeneration: Gene-environment interaction in parkin dysfunction. International Journal of Environmental Research and Public Health, 8, 4702–4713.PubMedCentralPubMedGoogle Scholar
  2. 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.PubMedGoogle Scholar
  3. 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. European Journal of Neuroscience, 27, 1097–1110.PubMedGoogle Scholar
  4. Bano, D., Zanetti, F., Mende, Y., & Nicotera, P. (2011). Neurodegenerative processes in Huntington’s disease. Cell Death and Disease, 2, e228. 10.PubMedCentralPubMedGoogle Scholar
  5. 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.PubMedGoogle Scholar
  6. 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.PubMedGoogle Scholar
  7. Baran, H., Jellinger, K., & Deecke, L. (1999). Kynurenine metabolism in Alzheimer’s disease. Journal of Neural Transmission, 106, 165–181.PubMedGoogle Scholar
  8. Baran, H., Kepplinger, B., & Draxler, M. (2010). Endogenous kynurenine aminotransferases inhibitor is proposed to act as “Glia depressing factor” (GDF). International Journal of Tryptophan Research, 3, 13–22.PubMedCentralPubMedGoogle Scholar
  9. 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. Journal of Biological Chemistry, 17(284), 19189–19195.Google Scholar
  10. 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.PubMedGoogle Scholar
  11. 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.PubMedGoogle Scholar
  12. 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 Neurological Sciences, 108, 80–87.Google Scholar
  13. Bellocchi, D., Macchiarulo, A., Carotti, A., & Pellicciari, R. (2009). Quantum mechanics/molecular mechanics (QM/MM) modeling of the irreversible transamination of L-kynurenine to kynurenic acid: The round dance of kynurenine aminotransferase II. Biochimica et Biophysica Acta, 1794, 1802–1812.PubMedGoogle Scholar
  14. Bender, D. A., & McCreanor, G. M. (1985). Kynurenine hydroxylase: A potential rate-limiting enzyme in tryptophan metabolism. Biochemical Society Transactions, 13, 441–443.PubMedGoogle Scholar
  15. Bock, K. W., & Köhle, C. (2009). The mammalian aryl hydrocarbon (Ah) receptor: From mediator of dioxin toxicity toward physiological functions in skin and liver. Biological Chemistry, 390, 1225–1235.PubMedGoogle Scholar
  16. Bradshaw, T. D., & Bell, D. R. (2009). Relevance of the aryl hydrocarbon receptor (AhR) for clinical toxicology. Clinical Toxicology (Philadelphia, Pa.), 47, 632–642.Google Scholar
  17. Brady, R. J., & Swann, J. W. (1988). Suppression of ictal-like activity by kynurenic acid does not correlate with its efficacy as an NMDA receptor antagonist. Epilepsy Research, 2, 232–238.PubMedGoogle Scholar
  18. 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. FEBS Journal, 278, 4425–4434.PubMedGoogle Scholar
  19. Brotchie, J., & Jenner, P. (2011). New approaches to therapy. International Review of Neurobiology, 98, 123–150.PubMedGoogle Scholar
  20. 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.PubMedGoogle Scholar
  21. 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, 60, 356–359.PubMedGoogle Scholar
  22. 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.PubMedGoogle Scholar
  23. 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.PubMedGoogle Scholar
  24. 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.PubMedCentralPubMedGoogle Scholar
  25. 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.PubMedGoogle Scholar
  26. 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.PubMedGoogle Scholar
  27. Carpenedo, R., Pittaluga, A., Cozzi, A., Attucci, S., Galli, A., Raiteri, M., & Moroni, F. (2001). Presynaptic kynurenate-sensitive receptors inhibit glutamate release. European Journal of Neuroscience, 13, 2141–2147.PubMedGoogle Scholar
  28. 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.PubMedGoogle Scholar
  29. 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.PubMedGoogle Scholar
  30. Chintamaneni, M., & Bhaskar, M. (2012). Biomarkers in Alzheimer’s disease: A review. ISRN Pharmacology, 2012, 984786.Google Scholar
  31. 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.PubMedGoogle Scholar
  32. 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.PubMedGoogle Scholar
  33. Connick, J. H., Stone, T. W., Carla, V., & Moroni, F. (1988). Increased kynurenic acid levels in Huntington’s disease. Lancet, 2, 1373.PubMedGoogle Scholar
  34. Connick, J. H., Carlà, V., Moroni, F., & Stone, T. W. (1989). Increase in kynurenic acid in Huntington’s disease motor cortex. Journal of Neurochemistry, 52, 985–987.PubMedGoogle Scholar
  35. 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.PubMedGoogle Scholar
  36. Coyle, J. T., & Schwarcz, R. (1976). Lesion of striatal neurones with kainic acid provides a model for Huntington’s chorea. Nature, 263, 244–246.PubMedGoogle Scholar
  37. 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.PubMedGoogle Scholar
  38. 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.PubMedGoogle Scholar
  39. Dajas-Bailador, F. A., Lima, P. A., & Wonnacott, S. (2000). The alpha7 nicotinic acetylcholine receptor subtype mediates nicotine protection against NMDA excitotoxicity in primary hippocampal cultures through a Ca(2+) dependent mechanism. Neuropharmacology, 39, 2799–2807.PubMedGoogle Scholar
  40. Dale, W. E., Dang, Y., Amiridze, N., & Brown, O. R. (2000). Evidence that kynurenine pathway metabolites mediate hyperbaric oxygen-induced convulsions. Toxicology Letters, 117, 37–43.PubMedGoogle Scholar
  41. 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.PubMedGoogle Scholar
  42. 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. European Journal of Neuroscience, 26, 2211–2221.PubMedGoogle Scholar
  43. 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.PubMedCentralPubMedGoogle Scholar
  44. 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.PubMedCentralPubMedGoogle Scholar
  45. 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.PubMedGoogle Scholar
  46. 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.PubMedGoogle Scholar
  47. Eid, T., Du, F., & Schwarcz, R. (1995). Differential neuronal vulnerability to amino-oxyacetate and quinolinate in the rat parahippocampal region. Neuroscience, 68, 645–656.PubMedGoogle Scholar
  48. Ellinger, A. (1904). Die Entstehung der Kynurensaure. Zeitschrift für Physiologische Chemie, 43, 325–337.Google Scholar
  49. Erhardt, S., Blennow, K., Nordin, C., Skogh, E., Lindström, L. H., & Engberg, G. (2001). Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia. Neuroscience Letters, 313, 96–98.PubMedGoogle Scholar
  50. Esser, C. (2012). Biology and function of the aryl hydrocarbon receptor: Report of an international and interdisciplinary conference. Archives of Toxicology, 86, 1323–1329.PubMedGoogle Scholar
  51. 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.PubMedGoogle Scholar
  52. 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.PubMedGoogle Scholar
  53. Fukushima, T., Sone, Y., Mitsuhashi, S., Tomiya, M., & Toyo’oka, T. (2009). Alteration of kynurenic acid concentration in rat plasma following optically pure kynurenine administration: A comparative study between enantiomers. Chirality, 21, 468–472.PubMedGoogle Scholar
  54. 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.PubMedGoogle Scholar
  55. 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.PubMedGoogle Scholar
  56. 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.PubMedGoogle Scholar
  57. Ginsberg, M. D. (2008). Neuroprotection for ischemic stroke: Past, present and future. Neuropharmacology, 55, 363–389.PubMedCentralPubMedGoogle Scholar
  58. 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.PubMedGoogle Scholar
  59. Graham, W. C., Robertson, R. G., Sambrook, M. A., & Crossman, A. R. (1990). Injection of excitatory amino acid antagonists into the medial pallidal segment of a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated primate reverses motor symptoms of parkinsonism. Life Sciences, 47, PL91–PL97.PubMedGoogle Scholar
  60. Gramsbergen, J. B., Turski, W. A., & Schwarcz, R. (1991). Brain-specific control of kynurenic acid production by depolarizing agents. Advances in Experimental Medicine and Biology, 294, 587–590.PubMedGoogle Scholar
  61. 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.PubMedGoogle Scholar
  62. 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.PubMedGoogle Scholar
  63. Guidetti, P., Okuno, E., & Schwarcz, R. (1997). Characterization of rat brain kynurenine aminotransferases I and II. Journal of Neuroscience Research, 50, 457–465.PubMedGoogle Scholar
  64. 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.PubMedGoogle Scholar
  65. 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.PubMedGoogle Scholar
  66. Guidetti, P., Amori, L., Sapko, M. T., Okuno, E., & Schwarcz, R. (2007). Mitochondrial aspartate aminotransferase: A third kynurenate-producing enzyme in the mammalian brain. Journal of Neurochemistry, 102, 103–111.PubMedGoogle Scholar
  67. 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.PubMedGoogle Scholar
  68. 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.PubMedGoogle Scholar
  69. 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. Journal of Pharmacology and Experimental Therapeutics, 324, 342–251.PubMedGoogle Scholar
  70. Hamilton, B. F., & Gould, D. H. (1987). Nature and distribution of brain lesions in rats intoxicated with 3-nitropropionic acid: A type of hypoxic (energy deficient) brain damage. Acta Neuropathologica, 72, 286–297.PubMedGoogle Scholar
  71. 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.PubMedCentralPubMedGoogle Scholar
  72. 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.PubMedCentralPubMedGoogle Scholar
  73. 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 Neurological Sciences, 239, 31–35.Google Scholar
  74. 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.PubMedGoogle Scholar
  75. 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.PubMedGoogle Scholar
  76. 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.PubMedGoogle Scholar
  77. 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. Journal of Neuroscience, 21, 7463–7473.PubMedGoogle Scholar
  78. 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. The Journal of Physiology, 27, 418–428.PubMedCentralPubMedGoogle Scholar
  79. Hotta, S. S. (1968). Oxidative metabolism of isolated brain mitochondria: Changes caused by aminooxyacetate. Archives of Biochemistry and Biophysics, 127, 132–139.PubMedGoogle Scholar
  80. 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 heatstroke. Acta Pharmacologica Sinica, 32, 167–174.PubMedGoogle Scholar
  81. Iłżecka, J., Kocki, T., Stelmasiak, Z., & Turski, W. A. (2003). Endogenous protectant kynurenic acid in amyotrophic lateral sclerosis. Acta Neurologica Scandinavica, 107, 412–418.PubMedGoogle Scholar
  82. 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 Neurological Sciences, 130, 39–47.Google Scholar
  83. 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.PubMedCentralPubMedGoogle Scholar
  84. 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.PubMedGoogle Scholar
  85. 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.PubMedGoogle Scholar
  86. 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.PubMedGoogle Scholar
  87. 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.PubMedGoogle Scholar
  88. 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.PubMedGoogle Scholar
  89. 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.PubMedGoogle Scholar
  90. Klockgether, T., & Turski, L. (1990). NMDA antagonists potentiate antiparkinsonian actions of L-dopa in monoamine-depleted rats. Annals of Neurology, 28, 539–546.PubMedGoogle Scholar
  91. Klockgether, T., Turski, L., Honoré, T., Zhang, Z. M., Gash, D. M., Kurlan, R., & Greenamyre, J. T. (1991). The AMPA receptor antagonist NBQX has antiparkinsonian effects in monoamine-depleted rats and MPTP-treated monkeys. Annals of Neurology, 30, 717–723.PubMedGoogle Scholar
  92. 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.PubMedGoogle Scholar
  93. 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.PubMedGoogle Scholar
  94. 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.PubMedGoogle Scholar
  95. 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.PubMedGoogle Scholar
  96. 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.PubMedGoogle Scholar
  97. 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.PubMedGoogle Scholar
  98. 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.PubMedGoogle Scholar
  99. Lapin, I. P. (1978). Stimulant and convulsive effects of kynurenines injected into brain ventricles in mice. Journal of Neural Transmission, 42, 37–43.PubMedGoogle Scholar
  100. Lapin, I. P. (1983). Antagonism of kynurenine-induced seizures by picolinic, kynurenic and xanthurenic acids. Journal of Neural Transmission, 56, 177–185.PubMedGoogle Scholar
  101. 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.PubMedGoogle Scholar
  102. 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.PubMedGoogle Scholar
  103. Lees, A. J., Hardy, J., & Revesz, T. (2009). Parkinson’s disease. Lancet, 373, 2055–2066.PubMedGoogle Scholar
  104. Liebig, J. (1853). Uber Kynurensäure. Justus Liebigs Annalen der Chemie, 86, 125–126.Google Scholar
  105. Lin, H., Vicini, S., Hsu, F. C., Doshi, S., Takano, H., Coulter, D. A., & Lynch, D. R. (2010). Axonal α7 nicotinic ACh receptors modulate presynaptic NMDA receptor expression and structural plasticity of glutamatergic presynaptic boutons. Proceedings of the National Academy of Sciences of the United States of America, 107, 16661–16666.PubMedCentralPubMedGoogle Scholar
  106. 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.PubMedGoogle Scholar
  107. Luchowska, E., Luchowski, P., Sarnowska, A., Wielosz, M., Turski, W. A., & Urbańska, E. M. (2003). 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.PubMedGoogle Scholar
  108. 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.PubMedGoogle Scholar
  109. 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.PubMedGoogle Scholar
  110. 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.Google Scholar
  111. Luchowski, P., & Urbanska, E. M. (2007). SNAP and SIN-1 increase brain production of kynurenic acid. European Journal of Pharmacology, 563, 130–133.PubMedGoogle Scholar
  112. 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.PubMedGoogle Scholar
  113. 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.PubMedGoogle Scholar
  114. Mattson, M. P. (2008). Glutamate and neurotrophic factors in neuronal plasticity and disease. Annals of the New York Academy of Sciences, 1144, 97–112.PubMedCentralPubMedGoogle Scholar
  115. 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.PubMedGoogle Scholar
  116. 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.PubMedGoogle Scholar
  117. Min, K. D., Asakura, M., Liao, Y., Nakamaru, K., Okazaki, H., Takahashi, T., Fujimoto, K., Ito, S., Takahashi, A., Asanuma, H., Yamazaki, S., Minamino, T., Sanada, S., Seguchi, O., Nakano, A., Ando, Y., Otsuka, T., Furukawa, H., Isomura, T., Takashima, S., Mochizuki, N., & Kitakaze, M. (2010). Identification of genes related to heart failure using global gene expression profiling of human failing myocardium. Biochemical and Biophysical Research Communications, 393, 55–60.PubMedGoogle Scholar
  118. 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.PubMedGoogle Scholar
  119. Miranda, A. F., Sutton, M. A., Beninger, R. J., Jhamandas, K., & Boegman, R. J. (1999). Quinolinic acid lesion of the nigrostriatal pathway: Effect on turning behaviour and protection by elevation of endogenous kynurenic acid in Rattus norvegicus. Neuroscience Letters, 262, 81–84.PubMedGoogle Scholar
  120. 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.PubMedGoogle Scholar
  121. Moroni, F. (1999). Tryptophan metabolism and brain function: Focus on kynurenine and other indole metabolites. European Journal of Pharmacology, 375, 87–100.PubMedGoogle Scholar
  122. Moroni, F., Russi, P., Carla, V., & Lombardi, G. (1988a). Kynurenic acid is present in the rat brain and its content increases during development and aging processes. Neuroscience Letters, 94, 145–150.PubMedGoogle Scholar
  123. Moroni, F., Russi, P., Lombardi, G., Beni, M., & Carlà, V. (1988b). Presence of kynurenic acid in the mammalian brain. Journal of Neurochemistry, 51, 177–180.PubMedGoogle Scholar
  124. Muir, K. W., & Lees, K. R. (2003). Excitatory amino acid antagonists for acute stroke. Cochrane Database of Systematic Reviews, 3, CD001244.PubMedGoogle Scholar
  125. 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 (Oxf), 47, 667–677.Google Scholar
  126. Németh, H., Robotka, H., Kis, Z., Rózsa, E., Janáky, T., Somlai, C., Marosi, M., Farkas, T., Toldi, J., & Vécsei, L. (2004). Kynurenine administered together with probenecid markedly inhibits pentylenetetrazol-induced seizures. An electrophysiological and behavioural study. Neuropharmacology, 47, 916–925.PubMedGoogle Scholar
  127. Németh, H., Toldi, J., & Vecsei, L. (2005). Role of kynurenines in the central and peripheral nervous systems. Current Neurovascular Research, 2, 249–260.PubMedGoogle Scholar
  128. Németh, H., Toldi, J., & Vécsei, L. (2006). Kynurenines, Parkinson’s disease and other neurodegenerative disorders: Preclinical and clinical studies. Journal of Neural Transmission. Supplementum, 70, 285–304.PubMedGoogle Scholar
  129. 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.PubMedGoogle Scholar
  130. 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.PubMedGoogle Scholar
  131. Ohshiro, H., Tonai-Kachi, H., & Ichikawa, K. (2008). GPR35 is a functional receptor in rat dorsal root ganglion neurons. Biochemical and Biophysical Research Communications, 365, 344–348.PubMedGoogle Scholar
  132. Okumura, S., Baba, H., Kumada, T., Nanmoku, K., Nakajima, H., Nakane, Y., Hioki, K., & Ikenaka, K. (2004). Cloning of a G-protein-coupled receptor that shows an activity to transform NIH3T3 cells and is expressed in gastric cancer cells. Cancer Science, 95, 131–135.PubMedGoogle Scholar
  133. Okuno, E., Nakamura, M., & Schwarcz, R. (1991a). Two kynurenine aminotransferases in human brain. Brain Research, 542, 307–312.PubMedGoogle Scholar
  134. Okuno, E., Schmidt, W., Parks, D. A., Nakamura, M., & Schwarcz, R. (1991b). Measurement of rat brain kynurenine aminotransferase at physiological kynurenine concentrations. Journal of Neurochemistry, 57, 533–540.PubMedGoogle Scholar
  135. Opitz, C. A., Litzenburger, U. M., Sahm, F., Ott, M., Tritschler, I., Trump, S., Schumacher, T., Jestaedt, L., Schrenk, D., Weller, M., Jugold, M., Guillemin, G. J., Miller, C. L., Lutz, C., Radlwimmer, B., Lehmann, I., von Deimling, A., Wick, W., & Platten, M. (2011). An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature, 478, 197–203.PubMedGoogle Scholar
  136. Pearson, S. J., & Reynolds, G. P. (1992). Increased brain concentrations of a neurotoxin, 3-hydroxykynurenine, in Huntington’s disease. Neuroscience Letters, 144, 199–201.PubMedGoogle Scholar
  137. Peeters, B. W., Ramakers, G. M., Ellenbroek, B. A., Vossen, J. M., & Coenen, A. M. (1994a). Interactions between NMDA and nonNMDA receptors in nonconvulsive epilepsy in the WAG/Rij inbred strain. Brain Research Bulletin, 33, 715–718.PubMedGoogle Scholar
  138. Peeters, B. W., Ramakers, G. M., Vossen, J. M., & Coenen, A. M. (1994b). The WAG/Rij rat model for nonconvulsive absence epilepsy: Involvement of nonNMDA receptors. Brain Research Bulletin, 33, 709–713.PubMedGoogle Scholar
  139. 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.PubMedGoogle Scholar
  140. Perkins, M. N., & Stone, T. W. (1983). In vivo release of [3H]-purines by quinolinic acid and related compounds. British Journal of Pharmacology, 80, 263–267.PubMedCentralPubMedGoogle Scholar
  141. 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.PubMedGoogle Scholar
  142. 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.Google Scholar
  143. 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.PubMedCentralPubMedGoogle Scholar
  144. 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.PubMedGoogle Scholar
  145. 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.PubMedGoogle Scholar
  146. 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.PubMedGoogle Scholar
  147. Reynolds, G. P., & Pearson, S. J. (1989). Increased brain 3-hydroxykynurenine in Huntington’s disease. Lancet, 2, 979–980.PubMedGoogle Scholar
  148. Roberts, R. C., Du, F., McCarthy, K. E., Okuno, E., & Schwarcz, R. (1992). Immunocytochemical localization of kynurenine aminotransferase in the rat striatum: A light and electron microscopic study. The Journal of Comparative Neurology, 326, 82–90.PubMedGoogle Scholar
  149. 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.PubMedGoogle Scholar
  150. 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.PubMedGoogle Scholar
  151. 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.PubMedGoogle Scholar
  152. 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.Google Scholar
  153. Samadi, P., Grégoire, L., Rassoulpour, A., Guidetti, P., Izzo, E., Schwarcz, R., & Bédard, P. J. (2005). Effect of kynurenine 3-hydroxylase inhibition on the dyskinetic and antiparkinsonian responses to levodopa in Parkinsonian monkeys. Movement Disorders, 20, 792–802.PubMedGoogle Scholar
  154. Sanberg, P. R. (1980). Haloperidol-induced catalepsy is mediated by postsynaptic dopamine receptors. Nature, 284, 472–473.PubMedGoogle Scholar
  155. Sanberg, P. R., Pisa, M., & Fibiger, H. C. (1981). Kainic acid injections in the striatum alter the cataleptic and locomotor effects of drugs influencing dopaminergic and cholinergic systems. European Journal of Pharmacology, 74, 347–357.PubMedGoogle Scholar
  156. 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.PubMedGoogle Scholar
  157. Scharfman, H. E., & Goodman, J. H. (1998). Effects of central and peripheral administration of kynurenic acid on hippocampal evoked responses in vivo and in vitro. Neuroscience, 86, 751–764.PubMedGoogle Scholar
  158. 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.PubMedGoogle Scholar
  159. 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.PubMedGoogle Scholar
  160. Schwarcz, R., & Pellicciari, R. (2002). Manipulation of brain kynurenines: Glial targets, neuronal effects, and clinical opportunities. Journal of Pharmacology and Experimental Therapeutics, 303, 1–10.PubMedGoogle Scholar
  161. 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.PubMedGoogle Scholar
  162. Schwarcz, R., Guidetti, P., Sathyasaikumar, K. V., & Muchowski, P. J. (2010). Of mice, rats and men: Revisiting the quinolinic acid hypothesis of Huntington’s disease. Progress in Neurobiology, 90, 230–245.PubMedCentralPubMedGoogle Scholar
  163. 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.PubMedGoogle Scholar
  164. 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.PubMedGoogle Scholar
  165. 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.PubMedGoogle Scholar
  166. 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.PubMedGoogle Scholar
  167. 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, 517, 217–223.PubMedGoogle Scholar
  168. Stevens, E. A., Mezrich, J. D., & Bradfield, C. A. (2009). The aryl hydrocarbon receptor: A perspective on potential roles in the immune system. Immunology, 127, 299–311.PubMedCentralPubMedGoogle Scholar
  169. Stone, T. W. (1988). Comparison of kynurenic acid and 2-APV suppression of epileptiform activity in rat hippocampal slices. Neuroscience Letters, 84, 234–238.PubMedGoogle Scholar
  170. Stone, T. W. (1993). Neuropharmacology of quinolinic and kynurenic acids. Pharmacological Reviews, 45, 309–379.PubMedGoogle Scholar
  171. Stone, T. W. (2001). Endogenous neurotoxins from tryptophan. Toxicon, 39, 61–73.PubMedGoogle Scholar
  172. Stone, T. W. (2007). Kynurenic acid blocks nicotinic synaptic transmission to hippocampal interneurons in young rats. European Journal of Neuroscience, 25, 2656–2665.PubMedGoogle Scholar
  173. Stone, T. W., & Darlington, L. G. (2002). Endogenous kynurenines as targets for drug discovery and development. Nature Reviews. Drug Discovery, 1, 609–620.PubMedGoogle Scholar
  174. Swan, J. S., Kragten, E. Y., & Veening, H. (1983). Liquid-chromatographic study of fluorescent materials in uremic fluids. Clinical Chemistry, 29, 1082–1084.PubMedGoogle Scholar
  175. 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.PubMedGoogle Scholar
  176. Szabó, N., Kincses, Z. T., Toldi, J., & Vécsei, L. (2011). Altered tryptophan metabolism in Parkinson’s disease: A possible novel therapeutic approach. Journal of Neurological Sciences, 310, 256–260.Google Scholar
  177. 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.PubMedGoogle Scholar
  178. 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.PubMedGoogle Scholar
  179. 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.PubMedGoogle Scholar
  180. 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.PubMedGoogle Scholar
  181. 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.PubMedGoogle Scholar
  182. 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.PubMedGoogle Scholar
  183. 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.PubMedGoogle Scholar
  184. Turski, W., Dziki, M., Parada, J., Kleinrok, Z., & Cavalheiro, E. A. (1992). Age dependency of the susceptibility of rats to aminooxyacetic acid seizures. Brain Research. Developmental Brain Research, 67, 137–144.PubMedGoogle Scholar
  185. 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.PubMedGoogle Scholar
  186. Urbańska, E. M. (2005). Mitochondrial toxins with potent neurodegenerative and convulsive properties – effects on kynurenine metabolism in the brain. In L. Vecsei (Ed.), Kynurenines in the brain: From experiments to clinics (pp. 115–131). New York: Nova Science.Google Scholar
  187. Urbańska, E., Ikonomidou, C., Sieklucka, M., & Turski, W. A. (1989). Aminooxyacetic acid produces excitotoxic lesions in the rat striatum. Society for Neuroscience Abstract, 15, 764.Google Scholar
  188. Urbańska, E., Ikonomidou, C., Sieklucka, M., & Turski, W. A. (1991). Aminooxyacetic acid produces excitotoxic lesions in the rat striatum. Synapse, 9, 129–135.PubMedGoogle Scholar
  189. Urbańska, 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.PubMedGoogle Scholar
  190. Urbańska, E. M., Dekundy, A., Kleinrok, Z., Turski, W. A., & Czuczwar, S. J. (1998). Glutamatergic receptor agonists and brain pathology. In R. M. Kostrzewa (Ed.), Highly selective neurotoxins: Basic and clinical applications (pp. 329–354). Totowa: Humana Press.Google Scholar
  191. Urbańska, 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.PubMedGoogle Scholar
  192. Urbańska, 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.PubMedGoogle Scholar
  193. 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.PubMedGoogle Scholar
  194. Vécsei, L., & Beal, M. F. (1991). Comparative behavioral and pharmacological studies with centrally administered kynurenine and kynurenic acid in rats. European Journal of Pharmacology, 196, 239–246.PubMedGoogle Scholar
  195. 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.PubMedGoogle Scholar
  196. Vizi, E. S., & Lendvai, B. (1999). Modulatory role of presynaptic nicotinic receptors in synaptic and non-synaptic chemical communication in the central nervous system. Brain Research. Brain Research Reviews, 30, 219–235.PubMedGoogle Scholar
  197. Walker, B. R., Easton, A., & Gale, K. (1999). Regulation of limbic motor seizures by GABA and glutamate transmission in nucleus tractus solitarius. Epilepsia, 40, 1051–1057.PubMedGoogle Scholar
  198. 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. Journal of Biological Chemistry, 281, 22021–22028.PubMedGoogle Scholar
  199. 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.PubMedGoogle Scholar
  200. Wonodi, I., & Schwarcz, R. (2010). Cortical kynurenine pathway metabolism: A novel target for cognitive enhancement in Schizophrenia. Schizophrenia Bulletin, 36, 211–218.PubMedCentralPubMedGoogle Scholar
  201. Wood, J. D., & Peesker, S. J. (1973). The role of GABA metabolism in the convulsant and anticonvulsant actions of aminooxyacetic acid. Journal of Neurochemistry, 20, 379–387.PubMedGoogle Scholar
  202. 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.PubMedGoogle Scholar
  203. 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.PubMedGoogle Scholar
  204. 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.PubMedGoogle Scholar
  205. 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.PubMedGoogle Scholar
  206. Yamamoto, H., Shindo, I., Egawa, B., & Horiguchi, K. (1994). Kynurenic acid is decreased in cerebrospinal fluid of patients with infantile spasms. Pediatric Neurology, 10, 9–12.PubMedGoogle Scholar
  207. Yamamoto, H., Murakami, H., Horiguchi, K., & Egawa, B. (1995). Studies on cerebrospinal fluid kynurenic acid concentrations in epileptic children. Brain & Development, 17, 327–329.Google Scholar
  208. 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.PubMedGoogle Scholar
  209. 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.PubMedCentralPubMedGoogle Scholar
  210. Zhao, P., Sharir, H., Kapur, A., Cowan, A., Geller, E. B., Adler, M. W., Seltzman, H. H., Reggio, P. H., Heynen-Genel, S., Sauer, M., Chung, T. D., Bai, Y., Chen, W., Caron, M. G., Barak, L. S., & Abood, M. E. (2010). Targeting of the orphan receptor GPR35 by pamoic acid: A potent activator of extracellular signal-regulated kinase and β-arrestin2 with antinociceptive activity. Molecular Pharmacology, 78, 560–568.PubMedCentralPubMedGoogle Scholar
  211. 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.PubMedGoogle Scholar
  212. 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.PubMedGoogle Scholar
  213. Zuccato, C., Valenza, M., & Cattaneo, E. (2010). Molecular mechanisms and potential therapeutical targets in Huntington’s disease. Physiological Reviews, 90, 905–981.PubMedGoogle Scholar
  214. 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., Flik, G., Huang, Y., Muchowski, J. M., Masliah, E., Schwarcz, R., & Muchowski, P. J. (2011). Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration. Cell, 145, 863–874.PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Laboratory of Cellular and Molecular Pharmacology, Department of Experimental and Clinical PharmacologyMedical University of LublinLublinPoland
  2. 2.Department of ToxicologyInstitute of Agricultural MedicineLublinPoland
  3. 3.Department of PsychiatryMedical University of LublinLublinPoland
  4. 4.Department of EndocrinologyMedical University of LublinLublinPoland
  5. 5.Department of Clinical NeuroscienceKarolinska Institutet, Section of Psychiatry at Karolinska University Hospital HuddingeStockholmSweden

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