Journal of Neural Transmission

, Volume 119, Issue 2, pp 225–234

The role of kynurenines in the pathomechanism of amyotrophic lateral sclerosis and multiple sclerosis: therapeutic implications

  • Judit Füvesi
  • Cecilia Rajda
  • Krisztina Bencsik
  • József Toldi
  • László Vécsei
Basic Neurosciences, Genetics and Immunology - Review article
  • 346 Downloads

Abstract

Tryptophan is one of the essential amino acids, 80% of which is catabolised in the extrahepatic tissues by indoleamine-2,3-dioxygenase (IDO), the rate-limiting enzyme of the kynurenine pathway. Metabolites along the kynurenine pathway have been implicated to play a role in the pathomechanism of neuroinflammatory and neurodegenerative disorders. Changes in the concentration levels of kynurenines can shift the balance to pathological conditions. The ability to influence the metabolism towards the neuroprotective branch of the kynurenine pathway, i.e. towards kynurenic acid (KYNA) synthesis, may be one option in preventing neurodegenerative diseases. Three potential therapeutic strategies could be feasible to develop drugs to live up to expectations: (1) chemically related drugs with better bioavailability and higher affinity to the binding sites of excitatory receptors; (2) prodrugs of KYNA, which easily cross the blood–brain barrier combined with an inhibitor of organic acid transport for enhancement of the brain KYNA concentration; (3) inhibitors of enzymes of the kynurenine pathway. In this review, we focus on aspects of the pathomechanism and therapeutic possibilities of amyotrophic lateral sclerosis and multiple sclerosis that may be influenced by kynurenines.

Keywords

Neurodegeneration Inflammation Kynurenic acid Multiple sclerosis Amyotrophic lateral sclerosis 

References

  1. Alberati-Giani D, Ricciardi-Castagloni P, Köhler C, Cesura AM (1996) Regulation of the kynurenine metabolic pathway by interferon-γ in murine cloned macrophages and microglial cells. J Neurochem 66:996–1004PubMedCrossRefGoogle Scholar
  2. Amirkhani A, Rajda C, Arvidsson B, Bencsik K, Boda K, Seres E et al (2005) Interferon-beta affects the tryptophan metabolism in multiple sclerosis patients. Eur J Neurol 12:625–631PubMedCrossRefGoogle Scholar
  3. Beal MF, Vécsei L (1992) Excitatory amino acids in the pathogenesis of neurodegenerative disorders. In: Vécsei L, Freese A, Swartz KJ, Beal MF (eds) Neurological disorders: novel experimental and therapeutic strategies. Ellis Horwood, Chichester, pp 39–74Google Scholar
  4. Bensimon G, Lacomblez L, Meininger V, the ALS/Riluzole study group (1994) A controlled trial of riluzole in amyotrophic lateral sclerosis. N Engl J Med 330:585–591PubMedCrossRefGoogle Scholar
  5. Bordelon YM, Chesselet MF, Nelson D, Welsh F, Erecinska M (1997) Energetic dysfunction in quinolinic acid-lesioned rat striatum. J Neurochem 69:1629–1639PubMedCrossRefGoogle Scholar
  6. Braidy N, Grant R, Adams S, Brew BJ, Guillemin GJ (2009) Mechanism for quinolinic acid cytotoxicity in human astrocytes and neurons. Neurotox Res 16:77–86PubMedCrossRefGoogle Scholar
  7. Cammer W (2001) Oligodendrocyte killing by quinolinic acid in vitro. Brain Res 896:157–160PubMedCrossRefGoogle Scholar
  8. Carpenedo R, Pittaluga A, Cozzi A et al (2001) Presynaptic kynurenate-sensitive receptors inhibit glutamate release. Eur J Neurosci 13:2141–2147PubMedCrossRefGoogle Scholar
  9. Chari DM (2007) Remyelination in multiple sclerosis. Int Rev Neurobiol 79:589–620PubMedCrossRefGoogle Scholar
  10. Chen Y, Meininger V, Guillemin GJ (2009) Recent advances in the treatment of amyotrophic lateral sclerosis. Emphasis on kynurenine pathway inhibitors. Cent Nerv Syst Agents Med Chem 9:32–39PubMedCrossRefGoogle Scholar
  11. Chen Y, Stankovich R, Cullen KM, Meininger V, Garner B, Coggan S et al (2010) The kynurenine pathway and inflammation in amyotrophic lateral sclerosis. Neurotox Res 18:132–142PubMedCrossRefGoogle Scholar
  12. Chen Y, Brew B, Guillemin GJ (2011) Characterization of the kynurenine pathway in NSC-34 cell line: implications for amyotrophic lateral sclerosis. J Neurochem 118:816–825PubMedCrossRefGoogle Scholar
  13. Chiarugi A, Cozzi A, Ballerini C, Massacesi L, Moroni F (2001) Kynurenine 3-mono-oxygenase activity and neurotoxic kynurenine metabolites increase in the spinal cord of rats with experimental allergic encephalomyelitis. Neuroscience 102:687–695PubMedCrossRefGoogle Scholar
  14. Chun J, Hartung HP (2010) Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin Neuropharmacol 33:91–101PubMedCrossRefGoogle Scholar
  15. Comi G, Abramsky O, Arbizu T, Boyko A, Gold R, Havrdová E et al, LAQ/5063 Study Group (2010) Oral laquinimod in patients with relapsing-remitting multiple sclerosis: 36-week double-blind active extension of the multi-centre, randomized, double-blind, parallel-group placebo-controlled study. Mult Scler 16:1360–1366Google Scholar
  16. Comi G, Pulizzi A, Rovaris M, Abramsky O, Arbizu T, Boiko A, LAQ/5062 Study Group (2008) Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet 371:2085–2092Google Scholar
  17. Croitoru-Lamoury J, Lamoury FMJ, Caristo M, Suzuki K, Walker D et al (2011) Interferon-γ regulates the proliferation and differentiation of mesenchymal stem cells via activation of indoleamine 2,3 dioxygenase (IDO). PLoS ONE 6:e14698. doi:10.1371/journal.pone.0014698 PubMedCrossRefGoogle Scholar
  18. Espey MG, Chernyshev ON, Reinhard JF Jr, Namboodiri MA, Colton CA (1997) Activated human microglia produce the excitotoxin quinolinic acid. Neuroreport 8:431–434PubMedCrossRefGoogle Scholar
  19. Fallarino F, Grohmann U, Vacca C, Bianchi R, Orabona C, Spreca A et al (2002) T cell apoptosis by tryptophan catabolism. Cell Death Differ 9:1069–1077PubMedCrossRefGoogle Scholar
  20. Fernandez O (2011) Oral laquinimod treatment is multiple sclerosis. Neurologia 26:111–117PubMedCrossRefGoogle Scholar
  21. Flanagan EM, Erickson JB, Viveros OH, Chang SY, Reinhard JF Jr (1995) Neurotoxin quinolinic acid is selectively elevated in spinal cords of rats with experimental allergic encephalomyelitis. J Neurochem 64:1192–1196PubMedCrossRefGoogle Scholar
  22. Frumento G, Rotondo R, Tonetti M, Damonte G, Benatti U, Ferrara GB (2002) Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. J Exp Med 196:459–468PubMedCrossRefGoogle Scholar
  23. Füvesi J, Somlai C, Németh H, Varga H, Kis Z, Farkas T et al (2004) Comparative study on the effects of kynurenic acid and glucosamine-kynurenic acid. Pharmacol Biochem Behav 77:95–102PubMedCrossRefGoogle Scholar
  24. Gold R, Kappos L, Bar-Or A, Arnold D, Giovannoni G, Selmaj K et al (2011) Clinical efficacy of BG-12, an oral therapy, in relapsing-remitting multiple sclerosis: data from the phase 3 DEFINE trial. Mult Scler Suppl 10:34Google Scholar
  25. Graves MC, Fiala M, Dinglasan LA, Liu NQ, Sayre J et al (2004) Inflammation in amyotrophic lateral sclerosis spinal cord and brain is mediated by activated macrophages, mast cells and T cells. Amyotroph Lateral Scler Other Motor Neuron Disord 5:213–219PubMedCrossRefGoogle Scholar
  26. 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 102:103–111PubMedCrossRefGoogle Scholar
  27. Guillemin GJ, Kerr SJ, Pemberton LA, Smith DG, Smythe GA, Armati PJ, Brew BJ (2001a) IFN-beta1b induces kynurenine pathway metabolism in human macrophages: potential implications for multiple sclerosis treatment. J Interferon Cytokine Res 21:1097–1101PubMedCrossRefGoogle Scholar
  28. Guillemin GJ, Kerr SJ, Smythe GA et al (2001b) Kynurenine pathway metabolism in human astrocytes. J Neurochem 78:842–853PubMedCrossRefGoogle Scholar
  29. Guillemin GJ, Meininger V, Brew BJ (2005a) Implications for the kynurenine pathway and quinolinic acid in amyotrophic lateral sclerosis. Neurodegener Dis 2:166–176PubMedCrossRefGoogle Scholar
  30. Guillemin GJ, Wang L, Brew BJ (2005b) Quinolinic acid selectively induces apoptosis of human astrocytes: potential role in AIDS dementia complex. J Neuroinflammation 2:16PubMedCrossRefGoogle Scholar
  31. 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 67:353–368PubMedCrossRefGoogle Scholar
  32. Hartai Z, Klivenyi P, Janaky T, Penke B, Dux L, Vecsei L (2005) Kynurenine metabolism in multiple sclerosis. Acta Neur Scand 112:93–96CrossRefGoogle Scholar
  33. Henkel JS, Engelhardt JI, Siklos L, Simpson EP, Kim SH, Pan T et al (2004) Presence of dendritic cells, MCP-1, and activated microglia/macrophages in amyotrophic lateral sclerosis spinal cord tissue. Ann Neurol 55:221–235PubMedCrossRefGoogle Scholar
  34. Heyes MP, Saito K, Crowley JS, Davis LE, Memitrack MA, Der M et al (1992a) Quinolinic acid and kynurenine pathway metabolism in inflammatory and noninflammatory neurological disease. Brain 115:1249–1273PubMedCrossRefGoogle Scholar
  35. Heyes MP, Saito K, Markey SP (1992b) Human macrophages convert l-tryptophan into the neurotoxin quinolinic acid. Biochem J 283:633–635PubMedGoogle Scholar
  36. Hokari M, Wu HQ, Schwarcz R, Smith QR (1996) Facilitated brain uptake of 4-chlorokynurenine and conversion to 7-chlorokynurenic acid. Neuroreport 8:15–18PubMedCrossRefGoogle Scholar
  37. Ilzecka J, Kocki T, Stelmasiak Z, Turski WA (2003) Endogenous protectant kynurenic acid in amyotrophic lateral sclerosis. Acta Neurol Scand 107:412–418PubMedCrossRefGoogle Scholar
  38. Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert JR, Salazar AM et al (1996) Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol 39:285–294PubMedCrossRefGoogle Scholar
  39. Jhamandas KH, Boegman RJ, Beninger RJ, Miranda AF, Lipic KA (2000) Excitotoxicity of quinolinic acid: modulation by endogenous antagonists. Neurotoxic Res 2:139–155CrossRefGoogle Scholar
  40. Johnson JW, Ascher P (1987) Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 325:529–531PubMedCrossRefGoogle Scholar
  41. Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP et al (1995) Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology 45:1268–1276PubMedGoogle Scholar
  42. Kanki R, Nakamizo T, Yamashita H, Kihara T, Sawada H, Uemura K et al (2004) Effects of mitochondrial dysfunction on glutamate receptor-mediated neurotoxicity in cultured rat spinal motor neurons. Brain Res 1015:73–81PubMedCrossRefGoogle Scholar
  43. Kappos L, Radue EW, O’Connor P, Polman C, Hohlfeld R, Calabresi P, FREEDOMS Study Group et al (2010) A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 362:387–401PubMedCrossRefGoogle Scholar
  44. Kelly WJ, Burke RE (1996) Apoptotic neuron death in rat substantia nigra induced by striatal excitotoxic injury is developmentally dependent. Neurosci Lett 220:85–88PubMedCrossRefGoogle Scholar
  45. Kerr SJ, Armati PJ, Brew BJ (1995) Neurocytotoxicity of quinolinic acid in human brain cultures. J Neurovirol 1:375–380PubMedCrossRefGoogle Scholar
  46. Kiss C, Vécsei L (2009) Kynurenines in the brain: preclinical and clinical studies, therapeutic considerations. In: Lajtha A (ed) Handbook of neurochemistry and molecular neurobiology, 3rd edn. Springer, Heidelberg, pp 91–105CrossRefGoogle Scholar
  47. Kiss C, Ceresoli-Borroni G, Guidetti P, Zielke CL, Zielke HR, Schwarcz R (2003) Kynurenate production by cultured human astrocytes. J Neural Transm 110:1–14PubMedGoogle Scholar
  48. Kwidzinski E, Bechmann I (2007) IDO expression in the brain: a double-edged sword. J Mol Med 85:1351–1359PubMedCrossRefGoogle Scholar
  49. Kwidzinski E, Bunse J, Aktas O, Richter D, Mutlu L, Zipp F et al (2005) Indolamine 2,3-dioxygenase is expressed in the CNS and down-regulates autoimmune inflammation. FASEB J 19:1347–1349PubMedGoogle Scholar
  50. Lee GK, Park HJ, Macleod M, Chandler P, Munn DH, Mellor AL (2002) Tryptophan deprivation sensitizes activated T cells to apoptosis prior to cell division. Immunology 107:452–460PubMedCrossRefGoogle Scholar
  51. Lehrmann E, Molinari A, Speciale C, Schwarcz R (2001) Immunohistochemical visualization of newly formed quinolate in the normal and excitotoxically lesioned rat striatum. Exp Brain Res 141:389–397PubMedCrossRefGoogle Scholar
  52. Linker RA, Lee DH, Ryan S, van Dam AM, Conrad R, Bista P et al (2011) Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 134:678–692PubMedCrossRefGoogle Scholar
  53. Lovas G, Szilagyi N, Majtenyi K, Palkovits M, Komoly S (2000) Axonal changes in chronic demyelinated cervical spinal cord plaques. Brain 123:308–317PubMedCrossRefGoogle Scholar
  54. Lublin FD, Reingold SC (1996) Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 46:907–911PubMedGoogle Scholar
  55. Lublin FD, Whitaker JN, Eidelman BH, Miller AE, Arnason BG, Burks JS (1996) Management of patients receiving interferon beta-1b for multiple sclerosis: report of a consensus conference. Neurology 46:12–18PubMedGoogle Scholar
  56. Macaya A, Munell F, Gubits RM, Burke RE (1994) Apoptosis in substantia nigra following developmental striatal excitotoxic injury. Proc Natl Acad Sci USA 91:8117–8121PubMedCrossRefGoogle Scholar
  57. Malpass K (2011) The kynurenine pathway—promising new targets and therapies for neurodegenerative disease. Nat Rev Neurol 7:417PubMedCrossRefGoogle Scholar
  58. Mándi Y, Vécsei L (2011) The kynurenine system and immunoregulation. J Neural Transm. doi:10.1007/s00702-011-0681-y (online first™)
  59. Marosi M, Nagy D, Farkas T, Kis Z, Rózsa E, Robotka H et al (2010) A novel kynurenic acid analogue: a comparison with kynurenic acid. An in vitro electrophysiological study. J Neural Transm 117:183–188PubMedCrossRefGoogle Scholar
  60. Matysiak M, Stasiołek M, Orłowski W, Jurewicz A, Janczar S, Raine CS, Selmaj K (2008) Stem cells ameliorate EAE via an indoleamine 2,3-dioxygenase (IDO) mechanism. J Neuroimmunol 193:12–23PubMedCrossRefGoogle Scholar
  61. McGeer PL, McGeer EG (2002) Inflammatory processes in amyotrophic lateral sclerosis. Muscle Nerve 26:459–470PubMedCrossRefGoogle Scholar
  62. Miller DH, Khan OA, Sheremata WA, Blumhardt LD, Rice GP, Libonati MA, International Natalizumab Multiple Sclerosis Trial Group et al (2003) A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 348:15–23PubMedCrossRefGoogle Scholar
  63. Monaco F, Fumero S, Mondino A, Mutani R (1979) Plasma and cerebrospinal fluid tryptophan in multiple sclerosis and degenerative diseases. J Neurol Neurosurg Psychiatry 42:640–641PubMedCrossRefGoogle Scholar
  64. Munn DH, Zhou M, Attwood JT et al (1998) Prevention of allogenic fetal rejection by tryptophan catabolism. Science 281:1122–1124CrossRefGoogle Scholar
  65. Okuno E, Nakamura M, Schwarcz R (1991) Two kynurenine aminotransferases in human brain. Brain Res 542:307–312PubMedCrossRefGoogle Scholar
  66. Paterson PY (1980) Experimental allergic encephalomyelitis and autoimmune disease. Prog Clin Biol Res 49:19–36PubMedGoogle Scholar
  67. Paty DW, Li DK (1993) Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. UBC MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group. Neurology 43:662–667PubMedGoogle Scholar
  68. Platten M, Ho PP, Youssef S, Fontoura P, Garren H, Hur EM et al (2005) Treatment of autoimmune neuroinflammation with a synthetic tryptophan metabolite. Science 310:850–855PubMedCrossRefGoogle Scholar
  69. Polman C, Barkhof F, Sandberg-Wollheim M, Linde A, Nordle O, Nederman T, Laquinimod in Relapsing MS Study Group (2005) Treatment with laquinimod reduces development of active MRI lesions in relapsing MS. Neurology 64:987–991Google Scholar
  70. Polman CH, O’Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH et al, AFFIRM Investigators (2006) A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 354:899–910Google Scholar
  71. Prescott C, Weeks AM, Staley KJ, Partin KM (2006) Kynurenic acid has a dual action on AMPA receptor responses. Neurosci Lett 402:109–112CrossRefGoogle Scholar
  72. PRISMS Study Group (1998) Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet 352:1498–1504CrossRefGoogle Scholar
  73. Rajda C, Bergquist J, Vecsei L (2007) Kynurenines, redox disturbances and neurodegeneration in multiple sclerosis. J Neural Transm Suppl 72:323–329PubMedCrossRefGoogle Scholar
  74. Reder AT, Ebers G, Cutter G, Kremenchutzky M, Goodin D, Oger J et al (2010a) Survival analysis 21 years after the initiation of the pivotal interferon beta-1b trial in patients with RRMS. Mult Scler 16:S318Google Scholar
  75. Reder AT, Ebers GC, Traboulsee A, Li D, Langdon D, Goodin DS et al (2010b) Cross-sectional study assessing long-term safety of interferon-beta-1b for relapsing-remitting MS. Neurology 74:1877–1885PubMedCrossRefGoogle Scholar
  76. Rejdak K, Bartosik-Psujek H, Dobosz B, Kocki T, Grieb P, Giovannoni G et al (2002) Decreased level of kynurenic acid in cerebrospinal fluid of relapsing-onset multiple sclerosis patients. Neurosci Lett 331:63–65PubMedCrossRefGoogle Scholar
  77. Rejdak K, Petzold A, Kocki T, Kurzepa J, Grieb P, Turski WA, Stelmasiak Z (2007) Astrocytic activation in relation to inflammatory markers during clinical exacerbation of relapsing-remitting multiple sclerosis. J Neural Transm 114:1011–1015PubMedCrossRefGoogle Scholar
  78. Rios C, Santamaria A (1991) Quinolinic acid is a potent lipid peroxidant in rat brain homogenates. Neurochem Res 16:1139–1143PubMedCrossRefGoogle Scholar
  79. Robotka H, Németh H, Somlai C, Vécsei 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 513:75–80PubMedCrossRefGoogle Scholar
  80. Ropper AH, Samuels MA (2009) Adams and Victor’s principles of neurology, 9th edn. McGraw Hill, New York, pp 1011–1080Google Scholar
  81. Rozsa E, Robotka H, Vecsei L, Toldi J (2008) The Janus-face kynurenic acid. J Neural Transm 115:1087–1091PubMedCrossRefGoogle Scholar
  82. Rudick RA, Fisher E, Lee JC, Simon J, Jacobs L (1999) Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Multiple Sclerosis Collaborative Research Group. Neurology 53:1698–1704PubMedGoogle Scholar
  83. Sargsyan SA, Monk PN, Shaw PJ (2005) Microglia as potential contributors to motor neuron injury in amyotrophic lateral sclerosis. Glia 51:241–253PubMedCrossRefGoogle Scholar
  84. 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 257:221–239PubMedCrossRefGoogle Scholar
  85. Simon JH, Jacobs LD, Campion M, Wende K, Simonian N, Cookfair DL et al (1998) Magnetic resonance studies of intramuscular interferon beta-1a for relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group. Ann Neurol 43:79–87PubMedCrossRefGoogle Scholar
  86. Spreux-Varoquaux O, Bensimon G, Lacomblez L, Salachas F, Pradat PF, LeForestier N et al (2002) Glutamate levels in cerebrospinal fluid in amyotrophic lateral sclerosis: a reappraisal using a new HPLC method with coulometric detection in a large cohort of patients. J Neurol Sci 193:73–78PubMedCrossRefGoogle Scholar
  87. Stone TW (1993) Neuropharmacology of quinolinic and kynurenic acids. Pharmacol Rev 45:310–379Google Scholar
  88. Stone TW (2000) Development and therapeutic potential of kynurenic acid and kynurenine derivatives for neuroprotection. Tips 21:149–154PubMedGoogle Scholar
  89. Stone TW (2001a) Endogenous neurotoxins from tryptophan. Toxicon 39:61–73PubMedCrossRefGoogle Scholar
  90. Stone TW (2001b) Kynurenic acid antagonists and kynurenine pathway inhibitors. Exp Opin Investig Drugs 10:633–645CrossRefGoogle Scholar
  91. Tavares RG, Tasca CI, Santos CE, Wajner M, Souza DO, Dutra-Filho CS (2000) Quinolinic acid inhibits glutamate uptake into synaptic vesicles from rat brain. Neuroreport 11:249–253PubMedCrossRefGoogle Scholar
  92. The IFNB Multiple Sclerosis Study Group (1993) Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 43:655–661Google Scholar
  93. Thomas SR, Witting PK, Stocker R (1996) 3-Hydroxyanthranilic acid is an efficient, cell derived co-antioxidant for α-tocopherol, inhibiting human low density lipoprotein and plasma lipid peroxidation. J Biol Chem 271:32714–32721PubMedCrossRefGoogle Scholar
  94. Vamos E, Pardutz A, Klivenyi P, Toldi J, Vecsei L (2009) The role of kynurenines in disorders of the central nervous system: possibilities for neuroprotection. J Neurol Sci 283:21–27PubMedCrossRefGoogle Scholar
  95. Vécsei L, Miller J, MacGarvey U, Beal MF (1992) Kynurenine and probenecid inhibit pentylenetetrazol- and NMDLA-induced seizures and increase kynurenic acid concentrations in the brain. Brain Res Bull 28:233–238PubMedCrossRefGoogle Scholar
  96. Vincent AM, Backus C, Taubman AA, Feldman EL (2005) Identification of candidate drugs for the treatment of ALS. Amyotroph Lateral Scler 6:29–36CrossRefGoogle Scholar
  97. Whetsell WO, Schwarcz R (1989) Prolonged exposure to submicromolar concentrations of quinolinic acid causes excitotoxic damage in organotypic cultures of rat corticostriatal system. Neurosci Lett 97:271–275PubMedCrossRefGoogle Scholar
  98. 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 365:111–118PubMedCrossRefGoogle Scholar
  99. Zádori D, Nyiri G, Szonyi A, Szatmári I, Fülöp F, Toldi J et al (2011a) Neuroprotective effects of a novel kynurenic acid analogue in a transgenic mouse model of Huntington’s disease. J Neural Transm 118:865–875PubMedCrossRefGoogle Scholar
  100. Zádori D, Klivényi P, Plangár I, Toldi J, Vécsei L (2011b) Endogenous neuroprotection in chronic neurodegenerative disorders: with particular regard to the kynurenines. J Cell Mol Med 15:701–717PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Judit Füvesi
    • 1
  • Cecilia Rajda
    • 1
  • Krisztina Bencsik
    • 1
  • József Toldi
    • 2
    • 3
  • László Vécsei
    • 1
    • 3
  1. 1.Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical CentreUniversity of SzegedSzegedHungary
  2. 2.Department of Physiology, Anatomy and Neuroscience, Faculty of Natural SciencesUniversity of SzegedSzegedHungary
  3. 3.Neuroscience Research Group of the Hungarian Academy of Sciences, University of SzegedSzegedHungary

Personalised recommendations