Journal of Neural Transmission

, Volume 116, Issue 11, pp 1403–1409 | Cite as

Kynurenines in chronic neurodegenerative disorders: future therapeutic strategies

  • D. Zádori
  • P. Klivényi
  • E. Vámos
  • F. Fülöp
  • J. Toldi
  • L. Vécsei
Basic Neurosciences, Genetics and Immunology - Review Article

Abstract

Parkinson’s, Alzheimer’s and Huntington’s diseases are chronic neurodegenerative disorders of a progressive nature which lead to a considerable deterioration of the quality of life. Their pathomechanisms display some common features, including an imbalance of the tryptophan metabolism. Alterations in the concentrations of neuroactive kynurenines can be accompanied by devastating excitotoxic injuries and metabolic disturbances. From therapeutic considerations, possibilities that come into account include increasing the neuroprotective effect of kynurenic acid, or decreasing the levels of neurotoxic 3-hydroxy-l-kynurenine and quinolinic acid. The experimental data indicate that neuroprotection can be achieved by both alternatives, suggesting opportunities for further drug development in this field.

Keywords

Kynurenines Kynurenic acid Kynurenine aminotransferase Parkinson’s disease Alzheimer’s disease Huntington’s disease 

Notes

Acknowledgment

This work was supported by grants RET-NORT 08/2004 and ETT 215/2006.

References

  1. Amori L, Guidetti P, Pellicciari R, Kajii Y, Schwarcz R (2009) On the relationship between the two branches of the kynurenine pathway in the rat brain in vivo. J Neurochem 109:316–325CrossRefPubMedGoogle Scholar
  2. Baran H, Jellinger K, Deecke L (1999) Kynurenine metabolism in Alzheimer’s disease. J Neural Transm 106:165–181CrossRefPubMedGoogle Scholar
  3. Battie C, Verity MA (1981) Presence of kynurenine hydrolase in developing rat brain. J Neurochem 36:1308–1310CrossRefPubMedGoogle Scholar
  4. Beal MF (1998) Excitotoxicity and nitric oxide in Parkinson’s disease pathogenesis. Ann Neurol 44:S110–S114CrossRefPubMedGoogle Scholar
  5. Beal MF, Kowall NW, Ellison DW, Mazurek MF, Swartz KJ, Martin JB (1986) Replication of the neurochemical characteristics of Huntington’s disease by quinolinic acid. Nature 321:168–171CrossRefPubMedGoogle Scholar
  6. 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 55:1327–1339CrossRefPubMedGoogle Scholar
  7. Behan WM, McDonald M, Darlington LG, Stone TW (1999) Oxidative stress as a mechanism for quinolinic acid-induced hippocampal damage: protection by melatonin and deprenyl. Br J Pharmacol 128:1754–1760CrossRefPubMedGoogle Scholar
  8. Birch PJ, Grossman CJ, Hayes AG (1988) Kynurenate and FG9041 have both competitive and non-competitive antagonist actions at excitatory amino acid receptors. Eur J Pharmacol 151:313–315CrossRefPubMedGoogle Scholar
  9. Connick JH, Stone TW (1988) Quinolinic acid effects on amino acid release from the rat cerebral cortex in vitro and in vivo. Br J Pharmacol 93:868–876PubMedGoogle Scholar
  10. Coyle JT, Schwarcz R (1976) Lesion of striatal neurons with kainic acid provides a model for Huntington’s chorea. Nature 263:244–246CrossRefPubMedGoogle Scholar
  11. Csillik A, Knyihár E, Okuno E, Krisztin-Péva B, Csillik B, Vécsei L (2002a) Effect of 3-nitropropionic acid on kynurenine aminotransferase in the rat brain. Exp Neurol 177:233–241CrossRefPubMedGoogle Scholar
  12. Csillik AE, Okuno E, Csillik B, Knyihár E, Vécsei L (2002b) Expression of kynurenine aminotransferase in the subplate of the rat and its possible role in the regulation of programmed cell death. Cereb Cortex 12:1193–1201CrossRefPubMedGoogle Scholar
  13. de Carvalho LP, Bochet P, Rossier J (1996) The endogenous agonist quinolinic acid and the non endogenous homoquinolinic acid discriminate between NMDAR2 receptor subunits. Neurochem Int 28:445–452CrossRefPubMedGoogle Scholar
  14. DiFiglia M (1990) Excitotoxic injury of the neostriatum: a model for Huntington’s disease. Trends Neurosci 13:286–289CrossRefPubMedGoogle Scholar
  15. Dykens JA, Sullivan SG, Stern A (1987) Oxidative reactivity of the tryptophan metabolites 3-hydroxyanthranilate, cinnabarinate, quinolinate and picolinate. Biochem Pharmacol 36:211–217CrossRefPubMedGoogle Scholar
  16. Eastman CL, Guilarte TR (1990) The role of hydrogen peroxide in the in vitro cytotoxicity of 3-hydroxykynurenine. Neurochem Res 15:1101–1107CrossRefPubMedGoogle Scholar
  17. Fonnum F, Storm-Mathisen J, Divac I (1981) Biochemical evidence for glutamate as neurotransmitter in corticostriatal and corticothalamic fibres in rat brain. Neuroscience 6:863–873CrossRefPubMedGoogle Scholar
  18. Fornstedt-Wallin B, Lundström J, Fredriksson G, Schwarcz R, Luthman J (1999) 3-Hydroxyanthranilic acid accumulation following administration of the 3-hydroxyanthranilic acid 3,4-dioxygenase inhibitor NCR-631. Eur J Pharmacol 386:15–24CrossRefPubMedGoogle Scholar
  19. Foster AC, White RJ, Schwarcz R (1986) Synthesis of quinolinic acid by 3-hydroxyanthranilic acid oxygenase in rat brain tissue in vitro. J Neurochem 47:23–30PubMedGoogle Scholar
  20. Francis PT, Sims NR, Procter AW, Bowen DM (1993) Cortical pyramidal neurone loss may cause glutamatergic hypoactivity and cognitive impairment in Alzheimer’s disease: investigative and therapeutic perspectives. J Neurochem 60:1589–1604CrossRefPubMedGoogle Scholar
  21. Fukui S, Schwarcz R, Rapoport SI, Takada Y, Smith OR (1991) Blood-brain barrier transport of kynurenines: implications for brain synthesis and metabolism. J Neurochem 56:2007–2017CrossRefPubMedGoogle Scholar
  22. Giorgini F, Guidetti P, Nguyen Q, Bennett SC, Muchowski PJ (2005) A genomic screen in yeast implicates kynurenine 3-monooxygenase as a therapeutic target for Huntington disease. Nat Genet 37:526–531CrossRefPubMedGoogle Scholar
  23. Greenamyre JT, Young AB (1989) Excitatory amino acids and Alzheimer’s disease. Neurobiol Aging 10:593–602CrossRefPubMedGoogle Scholar
  24. Guidetti P, Schwarcz R (1999) 3-Hydroxykynurenine potentiates quinolinate, but not NMDA toxicity in the rat striatum. Eur J Neurosci 11:3857–3863CrossRefPubMedGoogle Scholar
  25. Guidetti P, Eastman CL, Schwarcz R (1995) Metabolism of [5–3H]kynurenine in the rat brain in vivo: evidence for the existence of a functional kynurenine pathway. J Neurochem 65:2621–2632PubMedGoogle Scholar
  26. Guidetti P, Wu HQ, Schwarcz R (2000) In situ produced 7-chlorokynurenate provides protection against quinolinate- and malonate-induced neurotoxicity in the rat striatum. Exp Neurol 163:123–130CrossRefPubMedGoogle Scholar
  27. Guidetti P, Luthi-Carter RE, Augood SJ, Schwarcz R (2004) Neostriatal and cortical quinolinate levels are increased in early grade Huntington’s disease. Neurobiol Dis 17:455–461CrossRefPubMedGoogle Scholar
  28. Guidetti P, Amori L, Sapko MT, Okuno E, Schwarcz R (2007) Mitochondrial aspartate aminotransferase: a third kynurenate-producing enzyme in the mammalian brain. J Neurochem 102:103–111CrossRefPubMedGoogle Scholar
  29. Guillemin GJ, Brew BJ (2002) Implications of the kynurenine pathway and quinolinic acid in Alzheimer’s disease. Redox Rep 7:199–206CrossRefPubMedGoogle Scholar
  30. Guillemin GJ, Brew BJ, Noonan CE, Takikawa O, Cullen KM (2005) Indolamine 2,3 dioxygenase and quinolinic acid immunoreactivity in Alzheimer’s disease hippocampus. Neuropathol Appl Neurobiol 31:395–404CrossRefPubMedGoogle Scholar
  31. Harris CA, Miranda AF, Tanguay JJ, Boegman RJ, Beninger RJ, Jhamandas K (1998) Modulation of striatal quinolinate neurotoxicity by elevation of endogenous brain kynurenic acid. Br J Pharmacol 124:391–399CrossRefPubMedGoogle Scholar
  32. Henneberry RC (1997) Excitotoxicity as a consequence of impairment of energy metabolism: the energy-linked excitotoxic hypothesis. In: Beal MF, Howell N, Bodis-Wollner I (eds) Mitochondria & free radicals in neurodegenerative diseases. Wiley, New York, pp 111–143Google Scholar
  33. 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 21:7463–7473PubMedGoogle Scholar
  34. Jauch D, Urbańska EM, Guidetti P, Bird ED, Vonsattel JP, Whetsell WO Jr, Schwarcz R (1995) Dysfunction of brain kynurenic acid metabolism in Huntington’s disease: focus on kynurenine aminotransferases. J Neurol Sci 130:39–47CrossRefPubMedGoogle Scholar
  35. Jhamandas K, Boegman RJ, Beninger RJ, Bialik M (1990) Quinolinate-induced cortical cholinergic damage: modulation by tryptophan metabolites. Brain Res 529:185–191CrossRefPubMedGoogle Scholar
  36. 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 52:1319–1328CrossRefPubMedGoogle Scholar
  37. Kish SJ, Bergeron C, Rajput A, Dozic S, Mastrogiacomo F, Chang LJ, Wilson JM, DiStefano LM, Nobrega JN (1992) Brain cytochrome oxidase in Alzheimer’s disease. J Neurochem 59:776–779CrossRefPubMedGoogle Scholar
  38. Knyihár-Csillik E, Okuno E, Vécsei L (1999) Effects of in vivo sodium azide administration on the immunohistochemical localization of kynurenine aminotransferase in the rat brain. Neuroscience 94:269–277CrossRefPubMedGoogle Scholar
  39. 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 126:899–914CrossRefPubMedGoogle Scholar
  40. Knyihár-Csillik E, Chadaide Z, Mihály A, Krisztin-Péva B, Fenyő 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 Neuropathol 112:127–137CrossRefPubMedGoogle Scholar
  41. Landwehrmeyer GB, Standaert DG, Testa CM, Penney JB Jr, Young AB (1995) NMDA receptor subunit mRNA expression by projection neurons and interneurons in rat striatum. J Neurosci 15:5297–5307PubMedGoogle Scholar
  42. Leeson PD, Baker R, Carling RW, Curtis NR, Moore KW, Williams BJ, Foster AC, Donald AE, Kemp JA, Marshall GR (1991) Kynurenic acid derivatives–structure-activity relationships for excitatory amino acid antagonism and identification of potent and selective antagonists at the glycine site on the NMDA receptor. J Med Chem 34:1243–1252CrossRefPubMedGoogle Scholar
  43. Li L, Sengupta A, Haque N, Grundke-Iqbal I, Iqbal K (2004) Memantine inhibits and reverses the Alzheimer type abnormal hyperphosphorylation of tau and associated neurodegeneration. FEBS Lett 566:261–269CrossRefPubMedGoogle Scholar
  44. Luchowski P, Luchowska E, Turski WA, Urbanska EM (2002) 1-Methyl-4-phenylpyridinium and 3-nitropropionic acid diminish cortical synthesis of kynurenic acid via interference with kynurenine aminotransferases in rats. Neurosci Lett 330:49–52CrossRefPubMedGoogle Scholar
  45. Marchi M, Risso F, Viola C, Cavazzani P, Raiteri M (2002) Direct evidence that release-stimulating alpha7* nicotinic cholinergic receptors are localized on human and rat brain glutamatergic axon terminals. J Neurochem 80:1071–1078CrossRefPubMedGoogle Scholar
  46. McGeer EG, McGeer PL (1976) Duplication of biochemical changes of Huntington’s chorea by intrastriatal injections of glutamic and kainic acids. Nature 263:517–519CrossRefPubMedGoogle Scholar
  47. Merino M, Vizuete ML, Cano J, Machado A (1999) The non-NMDA glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione and 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline, but not NMDA antagonists, block the intrastriatal neurotoxic effect of MPP+. J Neurochem 73:750–757CrossRefPubMedGoogle Scholar
  48. Miranda AF, Boegman RJ, Beninger RJ, Jhamandas K (1997) Protection against quinolinic acid-mediated excitotoxicity in nigrostriatal dopaminergic neurons by endogenous kynurenic acid. Neuroscience 78:967–975CrossRefPubMedGoogle Scholar
  49. Misgeld U (2004) Innervation of the substantia nigra. Cell Tissue Res 318:107–114CrossRefPubMedGoogle Scholar
  50. Moroni F, Russi P, Gallo-Mezo MA, Moneti G, Pellicciari R (1991) Modulation of quinolinic and kynurenic acid content in the rat brain: effects of endotoxin and nicotinylalanine. J Neurochem 57:1630–1635CrossRefPubMedGoogle Scholar
  51. Ogawa T, Matson WR, Beal MF, Myers RH, Bird ED, Milbury P, Saso S (1992) Kynurenine pathway abnormalities in Parkinson’s disease. Neurology 42:1702–1706PubMedGoogle Scholar
  52. Okuda S, Nishiyama N, Saito H, Katsuki H (1998) 3-Hydroxykynurenine, an endogenous oxidative stress generator, causes neuronal cell death with apoptotic features and region selectivity. J Neurochem 70:299–307PubMedCrossRefGoogle Scholar
  53. Okuno E, Nakamura M, Schwarcz R (1991) Two kynurenine aminotransferases in human brain. Brain Res 542:307–312CrossRefPubMedGoogle Scholar
  54. Olney JW (1969) Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science 164:719–721CrossRefPubMedGoogle Scholar
  55. Parli CJ, Krieter P, Schmidt B (1980) Metabolism of 6-chlorotryptophan to 4-chloro-3-hydroxyanthranilic acid: a potent inhibitor of 3-hydroxyanthranilic acid oxidase. Arch Biochem Biophys 203:161–166CrossRefPubMedGoogle Scholar
  56. Pearson SJ, Reynolds GP (1992) Increased brain concentrations of a neurotoxin, 3-hydroxykynurenine, in Huntington’s disease. Neurosci Lett 144:199–201CrossRefPubMedGoogle Scholar
  57. Perkins MN, Stone TW (1982) An iontophoretic investigation of the actions of convulsant kynurenines and their interaction with the endogenous excitant quinolinic acid. Brain Res 247:184–187CrossRefPubMedGoogle Scholar
  58. Prescott C, Weeks AM, Staley KJ, Partin KM (2006) Kynurenic acid has a dual action on AMPA receptor responses. Neurosci Lett 402:108–112CrossRefPubMedGoogle Scholar
  59. Reichmann H, Riederer P (1989) Biochemical analyses of respiratory chain enzymes in different brain regions of patients with Parkinson’s disease. BMFT Symposium “Morbus Parkinson und andere Basalganglienerkrankungen”, Bad Kissingen, p 44 (abstract)Google Scholar
  60. Rios C, Santamaria A (1991) Quinolinic acid is a potent lipid peroxidant in rat brain homogenates. Neurochem Res 16:1139–1143CrossRefPubMedGoogle Scholar
  61. Robotka H, Toldi J, Vécsei L (2008) l-kynurenine: metabolism and mechanism of neuroprotection. Future Neurol 3:169–188CrossRefGoogle Scholar
  62. Rózsa É, Robotka H, Vécsei L, Toldi J (2008) The Janus-face kynurenic acid. J Neural Transm 115:1087–1091CrossRefPubMedGoogle Scholar
  63. Sapko MT, Guidetti P, Yu P, Tagle DA, Pellicciari R, Schwarcz R (2006) Endogenous kynurenate controls the vulnerability of striatal neurons to quinolinate: implications for Huntington’s disease. Exp Neurol 197:31–40CrossRefPubMedGoogle Scholar
  64. Sas K, Robotka H, Toldi J, Vécsei L (2007) Mitochondria, metabolic disturbances, oxidative stress and the kynurenine system, with focus on neurodegenerative disorders. J Neurol Sci 257:221–239CrossRefPubMedGoogle Scholar
  65. Schapira AH, Cooper JM, Dexter D, Jenner P, Clark JB, Marsden CD (1989) Mitochondrial complex I deficiency in Parkinson’s disease. Lancet 1:1269CrossRefPubMedGoogle Scholar
  66. Schwarcz R (2004) The kynurenine pathway of tryptophan degradation as a drug target. Curr Opin Pharmacol 4:12–17CrossRefPubMedGoogle Scholar
  67. Schwarcz R, Köhler C (1983) Differential vulnerability of central neurons of the rat to quinolinic acid. Neurosci Lett 38:85–90CrossRefPubMedGoogle Scholar
  68. Schwarcz R, Okuno E, White RJ, Bird ED, Whetsell WO Jr (1988) 3-Hydroxyanthranilate oxygenase activity is increased in the brains of Huntington disease victims. Proc Natl Acad Sci USA 85:4079–4081CrossRefPubMedGoogle Scholar
  69. Smith Y, Raju DV, Pare JF, Sidibe M (2004) The thalamostriatal system: a highly specific network of the basal ganglia circuitry. Trends Neurosci 27:520–527CrossRefPubMedGoogle Scholar
  70. Stahl WL, Swanson PD (1974) Biochemical abnormalities in Huntington’s chorea brains. Neurology 24:813–819PubMedGoogle Scholar
  71. Stone TW (2000) Development and therapeutic potential of kynurenic acid and kynurenine derivatives for neuroprotection. Trends Pharmacol Sci 21:149–154CrossRefPubMedGoogle Scholar
  72. Stone TW, Perkins MN (1981) Quinolinic acid: a potent endogenous excitant at amino acid receptors in CNS. Eur J Pharmacol 72:411–412CrossRefPubMedGoogle Scholar
  73. Tavares RG, Tasca CI, Santos CE, Alves LB, Porciúncula LO, Emanuelli T, Souza DO (2002) Quinolinic acid stimulates synaptosomal glutamate release and inhibits glutamate uptake into astrocytes. Neurochem Int 40:621–627CrossRefPubMedGoogle Scholar
  74. Ułas J, Weihmuller FB, Brunner LC, Marshall JF, Cotman CW (1994) Selective increase of NMDA-sensitive glutamate binding in the striatum of Parkinson’s disease, Alzheimer’s disease, and mixed Parkinson’s disease/Alzheimer’s disease patients: an autoradiographic study. J Neurosci 14:6317–6324PubMedGoogle Scholar
  75. Vécsei L (ed) (2005) Kynurenines in the brain. From experiments to clinics. Nova, New YorkGoogle Scholar
  76. Vécsei L, Beal MF (1991) Comparative behavioural and neurochemical studies with striatal kainic acid- or quinolinic acid-lesioned rats. Pharmacol Biochem Behav 39:473–478CrossRefPubMedGoogle Scholar
  77. Wolf H (1974) Studies on tryptophan metabolism in man: The effect of hormones and vitamin B6 on urinary excretion of metabolites of the kynurenine pathway. Scand J Clin Lab Invest 136(Suppl):1–186Google Scholar
  78. Wu HQ, Lee SC, Schwarcz R (2000) Systemic administration of 4-chlorokynurenine prevents quinolinate neurotoxicity in the rat hippocampus. Eur J Pharmacol 390:267–274CrossRefPubMedGoogle Scholar
  79. Yu P, Li Z, Zhang L, Tagle DA, Cai T (2006) Characterization of kynurenine aminotransferase III, a novel member of a phylogenetically conserved KAT family. Gene 365:111–118CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • D. Zádori
    • 1
  • P. Klivényi
    • 1
  • E. Vámos
    • 1
  • F. Fülöp
    • 2
  • J. Toldi
    • 3
  • L. Vécsei
    • 1
  1. 1.Department of Neurology, Albert Szent-Györgyi Clinical CentreUniversity of SzegedSzegedHungary
  2. 2.Department of Pharmaceutical ChemistryUniversity of SzegedSzegedHungary
  3. 3.Department of Physiology, Anatomy and NeuroscienceUniversity of SzegedSzegedHungary

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