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Kynurenines in Parkinson’s disease: therapeutic perspectives

  • Basic Neurosciences, Genetics and Immunology - Review article
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Abstract

Parkinson’s disease (PD) is a chronic progressive neurodegenerative disorder the pathomechanism of which is not yet fully known. With regard to the molecular mechanism of development of the disease, oxidative stress/mitochondrial impairment, glutamate excitotoxicity and neuroinflammation are certainly involved. Alterations in the kynurenine pathway, the main pathway of the tryptophan metabolism, can contribute to the complex pathomechanism. There are several possibilities for therapeutic intervention involving targeting of this altered metabolic route. The development of synthetic molecules that would shift the altered balance towards the achievement of neuroprotective effects would be of great promise for future clinical studies on PD.

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References

  • Acuna-Castroviejo D, Tapias V, Lopez LC, Doerrier C, Camacho E, Carrion MD, Mora F, Espinosa A, Escames G (2011) Protective effects of synthetic kynurenines on 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-induced parkinsonism in mice. Brain Res Bull 85:133–140

    Article  PubMed  CAS  Google Scholar 

  • Andres-Mateos E, Perier C, Zhang L, Blanchard-Fillion B, Greco TM, Thomas B, Ko HS, Sasaki M, Ischiropoulos H, Przedborski S, Dawson TM, Dawson VL (2007) DJ-1 gene deletion reveals that DJ-1 is an atypical peroxiredoxin-like peroxidase. Proc Natl Acad Sci USA 104:14807–14812

    Article  PubMed  CAS  Google Scholar 

  • Bahn A, Ljubojevic M, Lorenz H, Schultz C, Ghebremedhin E, Ugele B, Sabolic I, Burckhardt G, Hagos Y (2005) Murine renal organic anion transporters mOAT1 and mOAT3 facilitate the transport of neuroactive tryptophan metabolites. Am J Physiol Cell Physiol 289:C1075–C1084

    Article  PubMed  CAS  Google Scholar 

  • Banerjee R, Starkov AA, Beal MF, Thomas B (2009) Mitochondrial dysfunction in the limelight of Parkinson’s disease pathogenesis. Biochim Biophys Acta 1792:651–663

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Beal MF (2001) Experimental models of Parkinson’s disease. Nat Rev Neurosci 2:325–334

    Article  PubMed  CAS  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  PubMed  CAS  Google Scholar 

  • Bekris LM, Mata IF, Zabetian CP (2010) The genetics of Parkinson disease. J Geriatr Psychiatry Neurol 23:228–242

    Article  PubMed  Google Scholar 

  • Bereczki D (2010) The description of all four cardinal signs of Parkinson’s disease in a Hungarian medical text published in 1690. Parkinsonism Relat Disord 16:290–293

    Article  PubMed  Google Scholar 

  • Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT (2000) Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci 3:1301–1306

    Article  PubMed  CAS  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  PubMed  CAS  Google Scholar 

  • Blandini F (2010) An update on the potential role of excitotoxicity in the pathogenesis of Parkinson’s disease. Funct Neurol 25:65–71

    PubMed  Google Scholar 

  • Borza I, Kolok S, Galgoczy K, Gere A, Horvath C, Farkas S, Greiner I, Domany G (2007) Kynurenic acid amides as novel NR2B selective NMDA receptor antagonists. Bioorg Med Chem Lett 17:406–409

    Article  PubMed  CAS  Google Scholar 

  • Bove J, Prou D, Perier C, Przedborski S (2005) Toxin-induced models of Parkinson’s disease. NeuroRx 2:484–494

    Article  PubMed  Google Scholar 

  • Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211

    Article  PubMed  Google Scholar 

  • Bredt DS (1999) Endogenous nitric oxide synthesis: biological functions and pathophysiology. Free Radic Res 31:577–596

    Article  PubMed  CAS  Google Scholar 

  • Brochard V, Combadiere B, Prigent A, Laouar Y, Perrin A, Beray-Berthat V, Bonduelle O, Alvarez-Fischer D, Callebert J, Launay JM, Duyckaerts C, Flavell RA, Hirsch EC, Hunot S (2009) Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Invest 119:182–192

    PubMed  CAS  Google Scholar 

  • Brooks AI, Chadwick CA, Gelbard HA, Cory-Slechta DA, Federoff HJ (1999) Paraquat elicited neurobehavioral syndrome caused by dopaminergic neuron loss. Brain Res 823:1–10

    Article  PubMed  CAS  Google Scholar 

  • Brown GC (2010) Nitric oxide and neuronal death. Nitric Oxide 23:153–165

    Article  PubMed  CAS  Google Scholar 

  • Butler EG, Bourke DW, Finkelstein DI, Horne MK (1997) The effects of reversible inactivation of the subthalamo-pallidal pathway on the behaviour of naive and hemiparkinsonian monkeys. J Clin Neurosci 4:218–227

    Article  PubMed  CAS  Google Scholar 

  • Camacho E, Leon J, Carrion A, Entrena A, Escames G, Khaldy H, Acuna-Castroviejo D, Gallo MA, Espinosa A (2002) Inhibition of nNOS activity in rat brain by synthetic kynurenines: structure-activity dependence. J Med Chem 45:263–274

    Article  PubMed  CAS  Google Scholar 

  • Caudle WM, Zhang J (2009) Glutamate, excitotoxicity, and programmed cell death in Parkinson disease. Exp Neurol 220:230–233

    Article  PubMed  CAS  Google Scholar 

  • Chiba K, Trevor A, Castagnoli N Jr (1984) Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase. Biochem Biophys Res Commun 120:574–578

    Article  PubMed  CAS  Google Scholar 

  • Chung YC, Ko HW, Bok E, Park ES, Huh SH, Nam JH, Jin BK (2010) The role of neuroinflammation on the pathogenesis of Parkinson’s disease. BMB Rep 43:225–232

    Article  PubMed  CAS  Google Scholar 

  • Cohen G (1984) Oxy-radical toxicity in catecholamine neurons. Neurotoxicology 5:77–82

    PubMed  CAS  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

    PubMed  CAS  Google Scholar 

  • Csillik AE, Okuno E, Csillik B, Knyihar E, Vecsei L (2002) 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 Lau LM, Breteler MM (2006) Epidemiology of Parkinson’s disease. Lancet Neurol 5:525–535

    Article  PubMed  Google Scholar 

  • de Rijk MC, Launer LJ, Berger K, Breteler MM, Dartigues JF, Baldereschi M, Fratiglioni L, Lobo A, Martinez-Lage J, Trenkwalder C, Hofman A (2000) Prevalence of Parkinson’s disease in Europe: a collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology 54:S21–S23

    PubMed  Google Scholar 

  • Devi L, Raghavendran V, Prabhu BM, Avadhani NG, Anandatheerthavarada HK (2008) Mitochondrial import and accumulation of alpha-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain. J Biol Chem 283:9089–9100

    Article  PubMed  CAS  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  PubMed  CAS  Google Scholar 

  • Escames G, Leon J, Macias M, Khaldy H, Acuna-Castroviejo D (2003) Melatonin counteracts lipopolysaccharide-induced expression and activity of mitochondrial nitric oxide synthase in rats. FASEB J 17:932–934

    PubMed  CAS  Google Scholar 

  • Espey MG, Chernyshev ON, Reinhard JF Jr, Namboodiri MA, Colton CA (1997) Activated human microglia produce the excitotoxin quinolinic acid. Neuroreport 8:431–434

    Article  PubMed  CAS  Google Scholar 

  • Farrer M, Gwinn-Hardy K, Muenter M, DeVrieze FW, Crook R, Perez-Tur J, Lincoln S, Maraganore D, Adler C, Newman S, MacElwee K, McCarthy P, Miller C, Waters C, Hardy J (1999) A chromosome 4p haplotype segregating with Parkinson’s disease and postural tremor. Hum Mol Genet 8:81–85

    Article  PubMed  CAS  Google Scholar 

  • Fornstedt-Wallin B, Lundstrom 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  PubMed  CAS  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

    Article  PubMed  CAS  Google Scholar 

  • Fukui S, Schwarcz R, Rapoport SI, Takada Y, Smith QR (1991) Blood-brain barrier transport of kynurenines: implications for brain synthesis and metabolism. J Neurochem 56:2007–2017

    Article  PubMed  CAS  Google Scholar 

  • Fulop F, Szatmari I, Vamos E, Zadori D, Toldi J, Vecsei L (2009) Syntheses, transformations and pharmaceutical applications of kynurenic acid derivatives. Curr Med Chem 16:4828–4842

    Article  PubMed  CAS  Google Scholar 

  • Funayama M, Hasegawa K, Kowa H, Saito M, Tsuji S, Obata F (2002) A new locus for Parkinson’s disease (PARK8) maps to chromosome 12p11.2–q13.1. Ann Neurol 51:296–301

    Article  PubMed  CAS  Google Scholar 

  • Gal EM, Sherman AD (1978) Synthesis and metabolism of l-kynurenine in rat brain. J Neurochem 30:607–613

    Article  PubMed  CAS  Google Scholar 

  • Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH (2010) Mechanisms underlying inflammation in neurodegeneration. Cell 140:918–934

    Article  PubMed  CAS  Google Scholar 

  • Graham WC, Robertson RG, Sambrook MA, Crossman AR (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 Sci 47:PL91–PL97

    Article  PubMed  CAS  Google Scholar 

  • Gregoire L, Rassoulpour A, Guidetti P, Samadi P, Bedard PJ, Izzo E, Schwarcz R, Di Paolo T (2008) Prolonged kynurenine 3-hydroxylase inhibition reduces development of levodopa-induced dyskinesias in parkinsonian monkeys. Behav Brain Res 186:161–167

    Article  PubMed  CAS  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  PubMed  CAS  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  PubMed  CAS  Google Scholar 

  • Guillemin GJ, Kerr SJ, Smythe GA, Smith DG, Kapoor V, Armati PJ, Croitoru J, Brew BJ (2001) Kynurenine pathway metabolism in human astrocytes: a paradox for neuronal protection. J Neurochem 78:842–853

    Article  PubMed  CAS  Google Scholar 

  • Hallman H, Olson L, Jonsson G (1984) Neurotoxicity of the meperidine analogue N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine on brain catecholamine neurons in the mouse. Eur J Pharmacol 97:133–136

    Article  PubMed  CAS  Google Scholar 

  • Hamza TH, Zabetian CP, Tenesa A, Laederach A, Montimurro J, Yearout D, Kay DM, Doheny KF, Paschall J, Pugh E, Kusel VI, Collura R, Roberts J, Griffith A, Samii A, Scott WK, Nutt J, Factor SA, Payami H (2010) Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease. Nat Genet 42:781–785

    Article  PubMed  CAS  Google Scholar 

  • Han Q, Cai T, Tagle DA, Li J (2010) Structure, expression, and function of kynurenine aminotransferases in human and rodent brains. Cell Mol Life Sci 67:353–368

    Article  PubMed  CAS  Google Scholar 

  • Hartai Z, Klivenyi P, Janaky T, Penke B, Dux L, Vecsei L (2005) Kynurenine metabolism in plasma and in red blood cells in Parkinson’s disease. J Neurol Sci 239:31–35

    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 21:7463–7473

    PubMed  CAS  Google Scholar 

  • Javoy F, Sotelo C, Herbet A, Agid Y (1976) Specificity of dopaminergic neuronal degeneration induced by intracerebral injection of 6-hydroxydopamine in the nigrostriatal dopamine system. Brain Res 102:201–215

    Article  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 52:1319–1328

    Article  PubMed  CAS  Google Scholar 

  • Kim Y, Park J, Kim S, Song S, Kwon SK, Lee SH, Kitada T, Kim JM, Chung J (2008) PINK1 controls mitochondrial localization of Parkin through direct phosphorylation. Biochem Biophys Res Commun 377:975–980

    Article  PubMed  CAS  Google Scholar 

  • Kincses ZT, Vecsei L (2010) Pharmacological Therapy in Parkinson’s Disease: Focus on Neuroprotection. CNS Neurosci Ther. doi:10.1111/j.1755-5949.2010.00150.x (in press)

  • Kiss C, Vecsei L (2009) Kynurenines in the brain: preclinical and clinical studies, therapeutic considerations. In: Lajtha A (ed) Handbook of neurochemistry and molecular neurobiology, 3rd edn., Brain and Spinal Cord Trauma. Springer-Verlag, Berlin, Heidelberg, pp. 91–105

  • 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 126:899–914

    Article  PubMed  CAS  Google Scholar 

  • Knyihar-Csillik E, Chadaide Z, Mihaly A, Krisztin-Peva B, Fenyo R, Vecsei 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 

  • Langston JW, Ballard PA Jr (1983) Parkinson’s disease in a chemist working with 1-methyl-4-phenyl-1, 2, 5, 6-tetrahydropyridine. N Engl J Med 309:310

    PubMed  CAS  Google Scholar 

  • Langston JW, Ballard P, Tetrud JW, Irwin I (1983) Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219:979–980

    Article  PubMed  CAS  Google Scholar 

  • Langston JW, Irwin I, Langston EB, Forno LS (1984) 1-Methyl-4-phenylpyridinium ion (MPP+): identification of a metabolite of MPTP, a toxin selective to the substantia nigra. Neurosci Lett 48:87–92

    Article  PubMed  CAS  Google Scholar 

  • Lee do Y, Lee KS, Lee HJ, Noh YH, Kim do H, Lee JY, Cho SH, Yoon OJ, Lee WB, Kim KY, Chung YH, Kim SS (2008) Kynurenic acid attenuates MPP(+)-induced dopaminergic neuronal cell death via a Bax-mediated mitochondrial pathway. Eur J Cell Biol 87:389–397

    Article  PubMed  CAS  Google Scholar 

  • Leon J, Vives F, Crespo E, Camacho E, Espinosa A, Gallo MA, Escames G, Acuna-Castroviejo D (1998a) Modification of nitric oxide synthase activity and neuronal response in rat striatum by melatonin and kynurenine derivatives. J Neuroendocrinol 10:297–302

    Article  PubMed  CAS  Google Scholar 

  • Leon J, Vives F, Gomez I, Camacho E, Gallo MA, Espinosa A, Escames G, Acuna-Castroviejo D (1998b) Modulation of rat striatal glutamatergic response in search for new neuroprotective agents: evaluation of melatonin and some kynurenine derivatives. Brain Res Bull 45:525–530

    Article  PubMed  CAS  Google Scholar 

  • Leon J, Macias M, Escames G, Camacho E, Khaldy H, Martin M, Espinosa A, Gallo MA, Acuna-Castroviejo D (2000) Structure-related inhibition of calmodulin-dependent neuronal nitric-oxide synthase activity by melatonin and synthetic kynurenines. Mol Pharmacol 58:967–975

    PubMed  CAS  Google Scholar 

  • Liu Y, Wong TP, Aarts M, Rooyakkers A, Liu L, Lai TW, Wu DC, Lu J, Tymianski M, Craig AM, Wang YT (2007) NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo. J Neurosci 27:2846–2857

    Article  PubMed  CAS  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  PubMed  CAS  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  PubMed  CAS  Google Scholar 

  • Marosi M, Nagy D, Farkas T, Kis Z, Rozsa E, Robotka H, Fulop F, Vecsei L, Toldi J (2010) A novel kynurenic acid analogue: a comparison with kynurenic acid. An in vitro electrophysiological study. J Neural Transm 117:183–188

    Article  PubMed  CAS  Google Scholar 

  • Matsumine H, Saito M, Shimoda-Matsubayashi S, Tanaka H, Ishikawa A, Nakagawa-Hattori Y, Yokochi M, Kobayashi T, Igarashi S, Takano H, Sanpei K, Koike R, Mori H, Kondo T, Mizutani Y, Schaffer AA, Yamamura Y, Nakamura S, Kuzuhara S, Tsuji S, Mizuno Y (1997) Localization of a gene for an autosomal recessive form of juvenile Parkinsonism to chromosome 6q25.2–27. Am J Hum Genet 60:588–596

    PubMed  CAS  Google Scholar 

  • McCormack AL, Thiruchelvam M, Manning-Bog AB, Thiffault C, Langston JW, Cory-Slechta DA, Di Monte DA (2002) Environmental risk factors and Parkinson’s disease: selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat. Neurobiol Dis 10:119–127

    Article  PubMed  CAS  Google Scholar 

  • McGeer PL, Itagaki S, Boyes BE, McGeer EG (1988) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 38:1285–1291

    PubMed  CAS  Google Scholar 

  • Meredith GE, Totterdell S, Beales M, Meshul CK (2009) Impaired glutamate homeostasis and programmed cell death in a chronic MPTP mouse model of Parkinson’s disease. Exp Neurol 219:334–340

    Article  PubMed  CAS  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  PubMed  CAS  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  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Mizuno Y, Sone N, Saitoh T (1987) Effects of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine and 1-methyl-4-phenylpyridinium ion on activities of the enzymes in the electron transport system in mouse brain. J Neurochem 48:1787–1793

    Article  PubMed  CAS  Google Scholar 

  • Mogi M, Harada M, Riederer P, Narabayashi H, Fujita K, Nagatsu T (1994) Tumor necrosis factor-alpha (TNF-alpha) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients. Neurosci Lett 165:208–210

    Article  PubMed  CAS  Google Scholar 

  • Mogi M, Harada M, Narabayashi H, Inagaki H, Minami M, Nagatsu T (1996) Interleukin (IL)-1 beta, IL-2, IL-4, IL-6 and transforming growth factor-alpha levels are elevated in ventricular cerebrospinal fluid in juvenile parkinsonism and Parkinson’s disease. Neurosci Lett 211:13–16

    Article  PubMed  CAS  Google Scholar 

  • Mortiboys H, Johansen KK, Aasly JO, Bandmann O (2010) Mitochondrial impairment in patients with Parkinson disease with the G2019S mutation in LRRK2. Neurology 75:2017–2020

    Article  PubMed  CAS  Google Scholar 

  • Nagatsu T, Sawada M (2005) Inflammatory process in Parkinson’s disease: role for cytokines. Curr Pharm Des 11:999–1016

    Article  PubMed  CAS  Google Scholar 

  • Nemeth H, Toldi J, Vecsei L (2006) Kynurenines, Parkinson’s disease and other neurodegenerative disorders: preclinical and clinical studies. J Neural Transm Suppl 70:285–304

    Google Scholar 

  • Nicklas WJ, Vyas I, Heikkila RE (1985) Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-1, 2, 5, 6-tetrahydropyridine. Life Sci 36:2503–2508

    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 42:1702–1706

    PubMed  CAS  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  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Ouattara B, Belkhir S, Morissette M, Dridi M, Samadi P, Gregoire L, Meltzer LT, Di Paolo T (2009) Implication of NMDA receptors in the antidyskinetic activity of cabergoline, CI-1041, and Ro 61–8048 in MPTP monkeys with levodopa-induced dyskinesias. J Mol Neurosci 38:128–142

    Article  PubMed  CAS  Google Scholar 

  • Papai Pariz F (1690) Pax corporis, az az az emberi testnek belső nyavalyáinak okairól, fészkeiről ‘s azoknak orvoslásának módgyáról való tracta…, (“Pax corporis, i.e. a teaching of the causes, sources and the methods of treatment of the internal diseases of the human body”). Nemethi Mihaly, Kolozsvár

  • Parkinson J (1817) An essay on the shaking palsy. Sherwood, Neely and Jones, London

    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  PubMed  CAS  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  PubMed  CAS  Google Scholar 

  • Plun-Favreau H, Klupsch K, Moisoi N, Gandhi S, Kjaer S, Frith D, Harvey K, Deas E, Harvey RJ, McDonald N, Wood NW, Martins LM, Downward J (2007) The mitochondrial protease HtrA2 is regulated by Parkinson’s disease-associated kinase PINK1. Nat Cell Biol 9:1243–1252

    Article  PubMed  CAS  Google Scholar 

  • Polymeropoulos MH, Higgins JJ, Golbe LI, Johnson WG, Ide SE, Di Iorio G, Sanges G, Stenroos ES, Pho LT, Schaffer AA, Lazzarini AM, Nussbaum RL, Duvoisin RC (1996) Mapping of a gene for Parkinson’s disease to chromosome 4q21–q23. Science 274:1197–1199

    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 402:108–112

    Article  PubMed  CAS  Google Scholar 

  • Reggiani A, Maraia G, Ceserani R, Gaviraghi G (1989) Effect of 7-chloro kynurenic acid on glycine modulation of the N-methyl-D-aspartate response in guinea-pig myenteric plexus. Eur J Pharmacol 168:123–127

    Article  PubMed  CAS  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)

  • Reynolds AD, Kadiu I, Garg SK, Glanzer JG, Nordgren T, Ciborowski P, Banerjee R, Gendelman HE (2008) Nitrated alpha-synuclein and microglial neuroregulatory activities. J Neuroimmune Pharmacol 3:59–74

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Roberts RC, Du F, McCarthy KE, Okuno E, Schwarcz R (1992) Immunocytochemical localization of kynurenine aminotransferase in the rat striatum: a light and electron microscopic study. J Comp Neurol 326:82–90

    Article  PubMed  CAS  Google Scholar 

  • Rodriguez MC, Obeso JA, Olanow CW (1998) Subthalamic nucleus-mediated excitotoxicity in Parkinson’s disease: a target for neuroprotection. Ann Neurol 44:S175–S188

    PubMed  CAS  Google Scholar 

  • Rodriguez-Oroz MC, Jahanshahi M, Krack P, Litvan I, Macias R, Bezard E, Obeso JA (2009) Initial clinical manifestations of Parkinson’s disease: features and pathophysiological mechanisms. Lancet Neurol 8:1128–1139

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  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  PubMed  CAS  Google Scholar 

  • Schuler F, Casida JE (2001) Functional coupling of PSST and ND1 subunits in NADH:ubiquinone oxidoreductase established by photoaffinity labeling. Biochim Biophys Acta 1506:79–87

    Article  PubMed  CAS  Google Scholar 

  • Schwarcz R (1993) Metabolism and function of brain kynurenines. Biochem Soc Trans 21:77–82

    PubMed  CAS  Google Scholar 

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

    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 303:1–10

    Article  PubMed  CAS  Google Scholar 

  • Silva-Adaya D, Perez-De La Cruz V, Villeda-Hernandez J, Carrillo-Mora P, Gonzalez-Herrera IG, Garcia E, Colin-Barenque L, Pedraza-Chaverri J, Santamaria 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. Neurotoxicol Teratol 33:303–312

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Stone TW, Darlington LG (2002) Endogenous kynurenines as targets for drug discovery and development. Nat Rev Drug Discov 1:609–620

    Article  PubMed  CAS  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  PubMed  CAS  Google Scholar 

  • Strauss KM, Martins LM, Plun-Favreau H, Marx FP, Kautzmann S, Berg D, Gasser T, Wszolek Z, Muller T, Bornemann A, Wolburg H, Downward J, Riess O, Schulz JB, Kruger R (2005) Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson’s disease. Hum Mol Genet 14:2099–2111

    Article  PubMed  CAS  Google Scholar 

  • Tavares RG, Tasca CI, Santos CE, Alves LB, Porciuncula LO, Emanuelli T, Souza DO (2002) Quinolinic acid stimulates synaptosomal glutamate release and inhibits glutamate uptake into astrocytes. Neurochem Int 40:621–627

    Article  PubMed  CAS  Google Scholar 

  • Tiszlavicz Z, Nemeth B, Fulop F, Vecsei L, Tapai K, Ocsovszky I, Mandi Y (2011) Different inhibitory effects of kynurenic acid and a novel kynurenic acid analogue on tumour necrosis factor-alpha (TNF-alpha) production by mononuclear cells, HMGB1 production by monocytes and HNP1–3 secretion by neutrophils. Naunyn Schmiedebergs Arch Pharmacol 383:447–455

    Article  PubMed  CAS  Google Scholar 

  • Ungerstedt U (1968) 6-Hydroxy-dopamine induced degeneration of central monoamine neurons. Eur J Pharmacol 5:107–110

    Article  PubMed  CAS  Google Scholar 

  • Valente EM, Bentivoglio AR, Dixon PH, Ferraris A, Ialongo T, Frontali M, Albanese A, Wood NW (2001) Localization of a novel locus for autosomal recessive early-onset parkinsonism, PARK6, on human chromosome 1p35–p36. Am J Hum Genet 68:895–900

    Article  PubMed  CAS  Google Scholar 

  • van Duijn CM, Dekker MC, Bonifati V, Galjaard RJ, Houwing-Duistermaat JJ, Snijders PJ, Testers L, Breedveld GJ, Horstink M, Sandkuijl LA, van Swieten JC, Oostra BA, Heutink P (2001) Park7, a novel locus for autosomal recessive early-onset parkinsonism, on chromosome 1p36. Am J Hum Genet 69:629–634

    Article  PubMed  Google Scholar 

  • Varga G, Erces D, Fazekas B, Fulop M, Kovacs T, Kaszaki J, Fulop F, Vecsei L, Boros M (2010) N-Methyl-d-aspartate receptor antagonism decreases motility and inflammatory activation in the early phase of acute experimental colitis in the rat. Neurogastroenterol Motil 22:217–225 (e68)

    Article  PubMed  CAS  Google Scholar 

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

    Google Scholar 

  • Wang J, Simonavicius N, Wu X, Swaminath G, Reagan J, Tian H, Ling L (2006) Kynurenic acid as a ligand for orphan G protein-coupled receptor GPR35. J Biol Chem 281:22021–22028

    Article  PubMed  CAS  Google Scholar 

  • Wolf H (1974) The effect of hormones and vitamin B6 on urinary excretion of metabolites of the kynurenine pathway. Scand J Clin Lab Invest Suppl 136:1–186

    PubMed  CAS  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  PubMed  CAS  Google Scholar 

  • Yang H, Zhou HY, Li B, Niu GZ, Chen SD (2007) Downregulation of parkin damages antioxidant defenses and enhances proteasome inhibition-induced toxicity in PC12 cells. J Neuroimmune Pharmacol 2:276–283

    Article  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  PubMed  CAS  Google Scholar 

  • Zadori D, Klivenyi P, Vamos E, Fulop F, Toldi J, Vecsei L (2009) Kynurenines in chronic neurodegenerative disorders: future therapeutic strategies. J Neural Transm 116:1403–1409

    Article  PubMed  CAS  Google Scholar 

  • Zadori D, Ilisz I, Klivenyi P, Szatmari I, Fulop F, Toldi J, Vecsei L, Peter A (2011a) Time-course of kynurenic acid concentration in mouse serum following the administration of a novel kynurenic acid analog. J Pharm Biomed Anal 55:540–543

    Article  PubMed  CAS  Google Scholar 

  • Zadori D, Klivenyi P, Plangar I, Toldi J, Vecsei L (2011b) Endogenous neuroprotection in chronic neurodegenerative disorders: with particular regard to the kynurenines. J Cell Mol Med 15:701–717

    Article  PubMed  CAS  Google Scholar 

  • Zadori D, Nyiri G, Szonyi A, Szatmari I, Fulop F, Toldi J, Freund TF, Vecsei L, Klivenyi P (2011c) Neuroprotective effects of a novel kynurenic acid analogue in a transgenic mouse model of Huntington’s disease. J Neural Transm 118:865–875

    Article  PubMed  CAS  Google Scholar 

  • Zhang W, Wang T, Pei Z, Miller DS, Wu X, Block ML, Wilson B, Zhang W, Zhou Y, Hong JS, Zhang J (2005) Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease. FASEB J 19:533–542

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by grants ETT 026-04 and TÁMOP-4.2.1/B-09/1/KONV-2010-0005. The project “TÁMOP-4.2.1/B-09/1/KONV-2010-0005—Creating the Center of Excellence at the University of Szeged” is supported by the European Union and co-financed by the European Regional Development Fund.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

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

    Dénes Zádori, Péter Klivényi & László Vécsei

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

    József Toldi

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

    Ferenc Fülöp

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  1. Dénes Zádori
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  2. Péter Klivényi
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  4. Ferenc Fülöp
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  5. László Vécsei
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Correspondence to László Vécsei.

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Zádori, D., Klivényi, P., Toldi, J. et al. Kynurenines in Parkinson’s disease: therapeutic perspectives. J Neural Transm 119, 275–283 (2012). https://doi.org/10.1007/s00702-011-0697-3

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  • DOI: https://doi.org/10.1007/s00702-011-0697-3

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