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The Janus-face kynurenic acid

  • Basic Neurosciences, Genetics and Immunology - Original Article
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Abstract

Kynurenic acid is an endogenous product of the tryptophan metabolism. Studies on the mechanism of its action have revealed that kynurenic acid at high concentrations is a competitive antagonist of the N-methyl-d-aspartate receptor and acts as a neuroprotectant in different neurological disorders. This in vitro investigation was designed to show that kynurenic acid acts differently at low concentrations. In vitro electrophysiological examinations on the young rat hippocampus confirmed the well-known finding that kynurenic acid in micromolar concentrations exerts an inhibitory effect. However, in nanomolar concentrations, kynurenic acid does not give rise to inhibition, but in fact facilitates the field excitatory postsynaptic potentials. The results available so far are compatible with the idea that kynurenic acid in the concentration range between a few hundred nanomolar and micromolar displays different effects. Its probable action on different receptors, inducing the different mechanisms, is discussed. The findings strongly suggest the neuromodulatory role of kynurenic acid under both physiological and pathological circumstances.

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References

  • Alkondon M, Pereira EF, Yu P, Arruda EZ, Almeida LE, Guidetti P et al (2004) Targeted deletion of the kynurenine aminotransferase ii gene reveals a critical role of endogenous kynurenic acid in the regulation of synaptic transmission via alpha7 nicotinic receptors in the hippocampus. J. Neurosci 24:4635–4648

    Article  PubMed  CAS  Google Scholar 

  • Baran H, Jellinger K, Deecke L (1999) Kynurenine metabolism in Alzheimer’s disease. J Neural Transm 106(2):165–181

    Article  PubMed  CAS  Google Scholar 

  • Beal MF, Matson WR, Swartz KJ, Gamache PH, Bird ED (1990) Kynurenine pathway measurements in Huntington’s disease striatum: evidence for reduced formation of kynurenic acid. J Neurochem 55(4):1327–1339

    Article  PubMed  CAS  Google Scholar 

  • Carpenedo R, Meli E, Peruginelli F, Pellegrini-Giampietro DE, Moroni F (2002) Kynurenine 3-mono-oxygenase inhibitors attenuate post-ischemic neuronal death in organotypic hippocampal slice cultures. J Neurochem 82(6):1465–1471

    Article  PubMed  CAS  Google Scholar 

  • Erhardt S, Schwieler L, Engberg G (2003) Kynurenic acid and schizophrenia. Adv Exp Med Biol 527:155–165

    PubMed  CAS  Google Scholar 

  • Fuvesi J, Somlai C, Nemeth H, Varga H, Kis Z, Farkas T, Karoly N, Dobszay M, Penke Z, Penke B et al (2004) Comparative study on the effects of kynurenic acid and glucosamine-kynurenic acid. Pharmacol Biochem Behav 77(1):95–102

    Article  PubMed  CAS  Google Scholar 

  • Gigler G, Szenasi G, Simo A, Levay G, Harsing LG Jr, Sas K, Vecsei L, Toldi J (2007) Neuroprotective effect of l-kynurenine sulfate administered before focal cerebral ischemia in mice and global cerebral ischemia in gerbils. Eur J Pharmacol 564(1–3):116–122

    Article  PubMed  CAS  Google Scholar 

  • Giles GI, Collins CA, Stone TW, Jacob C (2003) Electrochemical and in vitro evaluation of the redox-properties of kynurenine species. Biochem Biophys Res Commun 300(3):719–724

    Article  PubMed  CAS  Google Scholar 

  • Hilmas C, Pereira EF, Alkondon M, Rassoulpour A, Schwarcz R, Albuquerque EX (2001) The brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: physiopathological implications. J Neurosci 21(19):7463–7473

    PubMed  CAS  Google Scholar 

  • Kaminski RM, Zielinska 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. Pol J Pharmacol 55(5):741–746

    PubMed  CAS  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. J Neurochem 52(4):1319–1328

    Article  PubMed  CAS  Google Scholar 

  • Kiss C, Shepard PD, Bari F, Schwarcz R (2004) Cortical spreading depression augments kynurenate levels and reduces malonate toxicity in the rat cortex. Brain Res 1002(1–2):129–135

    Article  PubMed  CAS  Google Scholar 

  • Klivenyi P, Toldi J, Vecsei L (2004) Kynurenines in neurodegenerative disorders: therapeutic consideration. Adv Exp Med Biol 541:169–183

    PubMed  CAS  Google Scholar 

  • Knyihar-Csillik E, Csillik B, Pakaski M, Krisztin-Peva B, Dobo E, Okuno E, Vecsei 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(4):899–914

    Article  PubMed  CAS  Google Scholar 

  • Luccini E, Musante V, Neri E, Raiteri M, Pittaluga A (2007) N-methyl-d-aspartate autoreceptors respond to low and high agonist concentrations by facilitating, respectively, exocytosis and carrier-mediated release of glutamate in rat hippocampus. J Neurosci Res 85(16):3657–3665

    Article  PubMed  CAS  Google Scholar 

  • Luchowska E, Luchowski P, Sarnowska A, Wielosz M, Turski WA, Urbanska EM (2003) Endogenous level of kynurenic acid and activities of kynurenine aminotransferases following transient global ischemia in the gerbil hippocampus. Pol J Pharmacol 55(3):443–447

    PubMed  CAS  Google Scholar 

  • Minatogawa Y, Noguchi T, Kido R (1974) Kynurenine pyruvate transaminase in rat brain. J Neurochem 23(1):271–272

    Article  PubMed  CAS  Google Scholar 

  • Moroni F (1999) Tryptophan metabolism and brain function: focus on kynurenine and other indole metabolites. Eur J Pharmacol 375(1–3):87–100

    Article  PubMed  CAS  Google Scholar 

  • Moroni F, Russi P, Lombardi G, Beni M, Carla V (1988) Presence of kynurenic acid in the mammalian brain. J Neurochem 51(1):177–180

    Article  PubMed  CAS  Google Scholar 

  • Moroni F, Carpenedo R, Cozzi A, Meli E, Chiarugi A, Pellegrini-Giampietro DE (2003) Studies on the neuroprotective action of kynurenine mono-oxygenase inhibitors in post-ischemic brain damage. Adv Exp Med Biol 527:127–136

    PubMed  CAS  Google Scholar 

  • Nemeth H, Toldi J, Vecsei L (2005) Role of kynurenines in the central and peripheral nervous systems. Curr Neurovasc Res 2(3):249–260

    Article  PubMed  Google Scholar 

  • Nemeth H, Robotka H, Toldi J, Vecsei L (2007) Kynurenines in the central nervous system: recent developments. Cent Nerv Syst Agent Med Chem 7:45–56

    CAS  Google Scholar 

  • Nilsson LK, Linderholm KR, Engberg G, Paulson L, Blennow K, Lindstrom LH, Nordin C, Karanti A, Persson P, Erhardt S (2005) Elevated levels of kynurenic acid in the cerebrospinal fluid of male patients with schizophrenia. Schizophr Res 80(2–3):315–322

    Article  PubMed  CAS  Google Scholar 

  • Ogawa T, Matson WR, Beal MF, Myers RH, Bird ED, Milbury P, Saso S (1992) Kynurenine pathway abnormalities in Parkinson’s disease. Neurology 42(9):1702–1706

    PubMed  CAS  Google Scholar 

  • Pellicciari R, Natalini B, Costantino G, Mahmoud MR, Mattoli L, Sadeghpour BM, Moroni F, Chiarugi A, Carpenedo R (1994) Modulation of the kynurenine pathway in search for new neuroprotective agents. Synthesis and preliminary evaluation of (m-nitrobenzoyl)alanine, a potent inhibitor of kynurenine-3-hydroxylase. J Med Chem 37(5):647–655

    Article  PubMed  CAS  Google Scholar 

  • Prescott C, Weeks AM, Staley KJ, Partin KM (2006) Kynurenic acid has a dual action on AMPA receptor responses. Neurosci Lett 402(1–2):108–112

    Article  PubMed  CAS  Google Scholar 

  • Robotka H, Nemeth H, Somlai C, Vecsei L, Toldi J (2005) Systemically administered glucosamine-kynurenic acid, but not pure kynurenic acid, is effective in decreasing the evoked activity in area CA1 of the rat hippocampus. Eur J Pharmacol 513(1–2):75–80

    Article  PubMed  CAS  Google Scholar 

  • Schwarcz R, Pellicciari R (2002) Manipulation of brain kynurenines: glial targets, neuronal effects, and clinical opportunities. J Pharmacol Exp Ther 303(1):1–10

    Article  PubMed  CAS  Google Scholar 

  • Schwarcz R, Ceresoli-Borroni G, Wu HQ, Rassoulpour A, Poeggeler B, Hodgkins PS, Guidetti P (1999) Modulation and function of kynurenic acid in the immature rat brain. Adv Exp Med Biol 467:113–123

    PubMed  CAS  Google Scholar 

  • Schwarcz R, Rassoulpour A, Wu HQ, Medoff D, Tamminga CA, Roberts RC (2001) Increased cortical kynurenate content in schizophrenia. Biol Psychiatry 50(7):521–530

    Article  PubMed  CAS  Google Scholar 

  • Smith DH, Okiyama K, Thomas MJ, McIntosh TK (1993) Effects of the excitatory amino acid receptor antagonists kynurenate and indole-2-carboxylic acid on behavioral and neurochemical outcome following experimental brain injury. J Neurosci 13(12):5383–5392

    PubMed  CAS  Google Scholar 

  • Stone TW (1993) Neuropharmacology of quinolinic and kynurenic acids. Pharmacol Rev 45(3):309–379

    PubMed  CAS  Google Scholar 

  • Stone TW (2001) Kynurenic acid antagonists and kynurenine pathway inhibitors. Expert Opin Investig Drugs 10(4):633–645

    Article  PubMed  CAS  Google Scholar 

  • Swartz KJ, During MJ, Freese A, Beal MF (1990) Cerebral synthesis and release of kynurenic acid: an endogenous antagonist of excitatory amino acid receptors. J Neurosci 10(9):2965–2973

    PubMed  CAS  Google Scholar 

  • Vecsei L, Beal MF (1996) Huntington’s disease, behavioral disturbances, and kynurenines: preclinical findings and therapeutic perspectives. Biol Psychiatry 39(12):1061–1063

    Article  PubMed  CAS  Google Scholar 

  • Widner B, Leblhuber F, Walli J, Tilz GP, Demel U, Fuchs D (2000) Tryptophan degradation and immune activation in Alzheimer’s disease. J Neural Transm 107(3):343–353

    Article  PubMed  CAS  Google Scholar 

  • Wolf H (1974) Studies on tryptophan metabolism in man. Scan J Clin Lab Invest 136S:1–186

    Google Scholar 

  • Wu HQ, Rassoulpour A, Goodman JH, Scharfman HE, Bertram EH, Schwarcz R (2005) Kynurenate and 7-chlorokynurenate formation in chronically epileptic rats. Epilepsia 46(7):1010–1016

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto H, Murakami H, Horiguchi K, Egawa B (1995) Studies on cerebrospinal fluid kynurenic acid concentrations in epileptic children. Brain Dev 17(5):327–329

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by grants OTKA T046687 and RET-08/2004.

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Correspondence to József Toldi.

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Rózsa, É., Robotka, H., Vécsei, L. et al. The Janus-face kynurenic acid. J Neural Transm 115, 1087–1091 (2008). https://doi.org/10.1007/s00702-008-0052-5

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  • DOI: https://doi.org/10.1007/s00702-008-0052-5

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