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Kynurenines in chronic neurodegenerative disorders: future therapeutic strategies

  • Basic Neurosciences, Genetics and Immunology - Review Article
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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.

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References

  • 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 109:316–325

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Battie C, Verity MA (1981) Presence of kynurenine hydrolase in developing rat brain. J Neurochem 36:1308–1310

    Article  CAS  PubMed  Google Scholar 

  • Beal MF (1998) Excitotoxicity and nitric oxide in Parkinson’s disease pathogenesis. Ann Neurol 44:S110–S114

    Article  CAS  PubMed  Google Scholar 

  • 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 321:168–171

    Article  CAS  PubMed  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 55:1327–1339

    Article  CAS  PubMed  Google Scholar 

  • 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 128:1754–1760

    Article  CAS  PubMed  Google Scholar 

  • 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 151:313–315

    Article  CAS  PubMed  Google Scholar 

  • 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 93:868–876

    CAS  PubMed  Google Scholar 

  • Coyle JT, Schwarcz R (1976) Lesion of striatal neurons with kainic acid provides a model for Huntington’s chorea. Nature 263:244–246

    Article  CAS  PubMed  Google Scholar 

  • 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 177:233–241

    Article  CAS  PubMed  Google Scholar 

  • 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 12:1193–1201

    Article  PubMed  Google Scholar 

  • 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 28:445–452

    Article  PubMed  Google Scholar 

  • DiFiglia M (1990) Excitotoxic injury of the neostriatum: a model for Huntington’s disease. Trends Neurosci 13:286–289

    Article  CAS  PubMed  Google Scholar 

  • Dykens JA, Sullivan SG, Stern A (1987) Oxidative reactivity of the tryptophan metabolites 3-hydroxyanthranilate, cinnabarinate, quinolinate and picolinate. Biochem Pharmacol 36:211–217

    Article  CAS  PubMed  Google Scholar 

  • Eastman CL, Guilarte TR (1990) The role of hydrogen peroxide in the in vitro cytotoxicity of 3-hydroxykynurenine. Neurochem Res 15:1101–1107

    Article  CAS  PubMed  Google Scholar 

  • Fonnum F, Storm-Mathisen J, Divac I (1981) Biochemical evidence for glutamate as neurotransmitter in corticostriatal and corticothalamic fibres in rat brain. Neuroscience 6:863–873

    Article  CAS  PubMed  Google Scholar 

  • 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 386:15–24

    Article  CAS  PubMed  Google Scholar 

  • Foster AC, White RJ, Schwarcz R (1986) Synthesis of quinolinic acid by 3-hydroxyanthranilic acid oxygenase in rat brain tissue in vitro. J Neurochem 47:23–30

    CAS  PubMed  Google Scholar 

  • 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 60:1589–1604

    Article  CAS  PubMed  Google Scholar 

  • 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 56:2007–2017

    Article  CAS  PubMed  Google Scholar 

  • 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 37:526–531

    Article  CAS  PubMed  Google Scholar 

  • Greenamyre JT, Young AB (1989) Excitatory amino acids and Alzheimer’s disease. Neurobiol Aging 10:593–602

    Article  CAS  PubMed  Google Scholar 

  • Guidetti P, Schwarcz R (1999) 3-Hydroxykynurenine potentiates quinolinate, but not NMDA toxicity in the rat striatum. Eur J Neurosci 11:3857–3863

    Article  CAS  PubMed  Google Scholar 

  • 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 65:2621–2632

    CAS  PubMed  Google Scholar 

  • 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 163:123–130

    Article  CAS  PubMed  Google Scholar 

  • 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 17:455–461

    Article  CAS  PubMed  Google Scholar 

  • 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 102:103–111

    Article  CAS  PubMed  Google Scholar 

  • Guillemin GJ, Brew BJ (2002) Implications of the kynurenine pathway and quinolinic acid in Alzheimer’s disease. Redox Rep 7:199–206

    Article  CAS  PubMed  Google Scholar 

  • 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 31:395–404

    Article  CAS  PubMed  Google Scholar 

  • 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 124:391–399

    Article  CAS  PubMed  Google Scholar 

  • 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 111–143

    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 21:7463–7473

    CAS  PubMed  Google Scholar 

  • 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 130:39–47

    Article  CAS  PubMed  Google Scholar 

  • Jhamandas K, Boegman RJ, Beninger RJ, Bialik M (1990) Quinolinate-induced cortical cholinergic damage: modulation by tryptophan metabolites. Brain Res 529:185–191

    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. J Neurochem 52:1319–1328

    Article  CAS  PubMed  Google Scholar 

  • 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 59:776–779

    Article  CAS  PubMed  Google Scholar 

  • 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 94:269–277

    Article  PubMed  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 

  • 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 112:127–137

    Article  PubMed  CAS  Google Scholar 

  • 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 15:5297–5307

    CAS  PubMed  Google Scholar 

  • 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 34:1243–1252

    Article  CAS  PubMed  Google Scholar 

  • 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 566:261–269

    Article  CAS  PubMed  Google Scholar 

  • 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 330:49–52

    Article  CAS  PubMed  Google Scholar 

  • 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 80:1071–1078

    Article  CAS  PubMed  Google Scholar 

  • McGeer EG, McGeer PL (1976) Duplication of biochemical changes of Huntington’s chorea by intrastriatal injections of glutamic and kainic acids. Nature 263:517–519

    Article  CAS  PubMed  Google Scholar 

  • 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 73:750–757

    Article  CAS  PubMed  Google Scholar 

  • Miranda AF, Boegman RJ, Beninger RJ, Jhamandas K (1997) Protection against quinolinic acid-mediated excitotoxicity in nigrostriatal dopaminergic neurons by endogenous kynurenic acid. Neuroscience 78:967–975

    Article  CAS  PubMed  Google Scholar 

  • Misgeld U (2004) Innervation of the substantia nigra. Cell Tissue Res 318:107–114

    Article  PubMed  Google Scholar 

  • 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 57:1630–1635

    Article  CAS  PubMed  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 42:1702–1706

    CAS  PubMed  Google Scholar 

  • 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 70:299–307

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Olney JW (1969) Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science 164:719–721

    Article  CAS  PubMed  Google Scholar 

  • 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 203:161–166

    Article  CAS  PubMed  Google Scholar 

  • Pearson SJ, Reynolds GP (1992) Increased brain concentrations of a neurotoxin, 3-hydroxykynurenine, in Huntington’s disease. Neurosci Lett 144:199–201

    Article  CAS  PubMed  Google Scholar 

  • 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 247:184–187

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • 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)

  • Rios C, Santamaria A (1991) Quinolinic acid is a potent lipid peroxidant in rat brain homogenates. Neurochem Res 16:1139–1143

    Article  CAS  PubMed  Google Scholar 

  • Robotka H, Toldi J, Vécsei L (2008) l-kynurenine: metabolism and mechanism of neuroprotection. Future Neurol 3:169–188

    Article  CAS  Google Scholar 

  • Rózsa É, Robotka H, Vécsei L, Toldi J (2008) The Janus-face kynurenic acid. J Neural Transm 115:1087–1091

    Article  PubMed  CAS  Google Scholar 

  • 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 197:31–40

    Article  CAS  PubMed  Google Scholar 

  • 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 257:221–239

    Article  CAS  PubMed  Google Scholar 

  • Schapira AH, Cooper JM, Dexter D, Jenner P, Clark JB, Marsden CD (1989) Mitochondrial complex I deficiency in Parkinson’s disease. Lancet 1:1269

    Article  CAS  PubMed  Google Scholar 

  • Schwarcz R (2004) The kynurenine pathway of tryptophan degradation as a drug target. Curr Opin Pharmacol 4:12–17

    Article  CAS  PubMed  Google Scholar 

  • Schwarcz R, Köhler C (1983) Differential vulnerability of central neurons of the rat to quinolinic acid. Neurosci Lett 38:85–90

    Article  CAS  PubMed  Google Scholar 

  • 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 85:4079–4081

    Article  CAS  PubMed  Google Scholar 

  • Smith Y, Raju DV, Pare JF, Sidibe M (2004) The thalamostriatal system: a highly specific network of the basal ganglia circuitry. Trends Neurosci 27:520–527

    Article  CAS  PubMed  Google Scholar 

  • Stahl WL, Swanson PD (1974) Biochemical abnormalities in Huntington’s chorea brains. Neurology 24:813–819

    CAS  PubMed  Google Scholar 

  • Stone TW (2000) Development and therapeutic potential of kynurenic acid and kynurenine derivatives for neuroprotection. Trends Pharmacol Sci 21:149–154

    Article  CAS  PubMed  Google Scholar 

  • Stone TW, Perkins MN (1981) Quinolinic acid: a potent endogenous excitant at amino acid receptors in CNS. Eur J Pharmacol 72:411–412

    Article  CAS  PubMed  Google Scholar 

  • 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 40:621–627

    Article  CAS  PubMed  Google Scholar 

  • 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 14:6317–6324

    PubMed  Google Scholar 

  • Vécsei L (ed) (2005) Kynurenines in the brain. From experiments to clinics. Nova, New York

  • Vécsei L, Beal MF (1991) Comparative behavioural and neurochemical studies with striatal kainic acid- or quinolinic acid-lesioned rats. Pharmacol Biochem Behav 39:473–478

    Article  PubMed  Google Scholar 

  • 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):1–186

    Google Scholar 

  • Wu HQ, Lee SC, Schwarcz R (2000) Systemic administration of 4-chlorokynurenine prevents quinolinate neurotoxicity in the rat hippocampus. Eur J Pharmacol 390:267–274

    Article  CAS  PubMed  Google Scholar 

  • 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 365:111–118

    Article  CAS  PubMed  Google Scholar 

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Acknowledgment

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

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Authors and Affiliations

  1. Department of Neurology, Albert Szent-Györgyi Clinical Centre, University of Szeged, Semmelweis u. 6, 6725, Szeged, Hungary

    D. Zádori, P. Klivényi, E. Vámos & L. Vécsei

  2. Department of Pharmaceutical Chemistry, University of Szeged, Eötvös u. 6, 6720, Szeged, Hungary

    F. Fülöp

  3. Department of Physiology, Anatomy and Neuroscience, University of Szeged, Közép fasor 52, 6726, Szeged, Hungary

    J. Toldi

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  1. D. Zádori
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  2. P. Klivényi
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Correspondence to L. Vécsei.

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Zádori, D., Klivényi, P., Vámos, E. et al. Kynurenines in chronic neurodegenerative disorders: future therapeutic strategies. J Neural Transm 116, 1403–1409 (2009). https://doi.org/10.1007/s00702-009-0263-4

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