Table of Contents Author Guidelines Submit a Manuscript
Parkinson’s Disease
Volume 2011 (2011), Article ID 716859, 11 pages
http://dx.doi.org/10.4061/2011/716859
Review Article

The Involvement of Neuroinflammation and Kynurenine Pathway in Parkinson's Disease

1Department of Pharmacology, School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia
2Experimental and Clinical Neuroscience (NiCE-CIBERNED), Department of Human Anatomy and Psychobiology, School of Medicine, University of Murcia, Murcia, Spain
3St Vincent's Centre for Applied Medical Research, Darlinghurst, NSW 2010, Australia

Received 1 December 2010; Accepted 31 January 2011

Academic Editor: Heinz Reichmann

Copyright © 2011 Anna Zinger et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. C. M. Tanner, “Epidemiology of Parkinson's disease,” Neurologic Clinics, vol. 10, no. 2, pp. 317–329, 1992. View at Google Scholar · View at Scopus
  2. J. Jankovic, “Parkinson's disease: clinical features and diagnosis,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 79, no. 4, pp. 368–376, 2008. View at Publisher · View at Google Scholar · View at Scopus
  3. D. J. Gelb, E. Oliver, and S. Gilman, “Diagnostic criteria for Parkinson disease,” Archives of Neurology, vol. 56, no. 1, pp. 33–39, 1999. View at Publisher · View at Google Scholar · View at Scopus
  4. E. Bezard, S. Dovero, C. Prunier et al., “Relationship between the appearance of symptoms and the level of nigrostriatal degeneration in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson's disease,” Journal of Neuroscience, vol. 21, no. 17, pp. 6853–6861, 2001. View at Google Scholar · View at Scopus
  5. T. Wichmann and M. R. DeLong, “Functional neuroanatomy of the basal ganglia in Parkinson's disease,” Advances in neurology, vol. 91, pp. 9–18, 2003. View at Google Scholar · View at Scopus
  6. M. G. Spillantini, R. A. Crowther, R. Jakes, M. Hasegawa, and M. Goedert, “α-synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with Lewy bodies,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 11, pp. 6469–6473, 1998. View at Publisher · View at Google Scholar · View at Scopus
  7. J. L. Montastruc, O. Rascol, and J. M. Senard, “Current status of dopamine agonists in Parkinson's disease management,” Drugs, vol. 46, no. 3, pp. 384–393, 1993. View at Google Scholar · View at Scopus
  8. A. H. V. Schapira, “Molecular and clinical pathways to neuroprotection of dopaminergic drugs in Parkinson disease,” Neurology, vol. 72, no. 7, pp. S44–S50, 2009. View at Publisher · View at Google Scholar · View at Scopus
  9. W. Dauer and S. Przedborski, “Parkinson's disease: mechanisms and models,” Neuron, vol. 39, no. 6, pp. 889–909, 2003. View at Publisher · View at Google Scholar · View at Scopus
  10. S. Przedborski, V. Jackson-Lewis, M. Vila et al., “Free radical and nitric oxide toxicity in Parkinson's disease,” Advances in neurology, vol. 91, pp. 83–94, 2003. View at Google Scholar · View at Scopus
  11. G. W. Kreutzberg, “Microglia: a sensor for pathological events in the CNS,” Trends in Neurosciences, vol. 19, no. 8, pp. 312–318, 1996. View at Publisher · View at Google Scholar · View at Scopus
  12. P. L. McGeer, S. Itagaki, B. E. Boyes, and E. G. McGeer, “Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains,” Neurology, vol. 38, no. 8, pp. 1285–1291, 1988. View at Google Scholar · View at Scopus
  13. A. Nimmerjahn, F. Kirchhoff, and F. Helmchen, “Neuroscience: resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo,” Science, vol. 308, no. 5726, pp. 1314–1318, 2005. View at Publisher · View at Google Scholar · View at Scopus
  14. B. Liu and J. S. Hong, “Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention,” Journal of Pharmacology and Experimental Therapeutics, vol. 304, no. 1, pp. 1–7, 2003. View at Publisher · View at Google Scholar · View at Scopus
  15. J. Gehrmann, Y. Matsumoto, and G. W. Kreutzberg, “Microglia: intrinsic immuneffector cell of the brain,” Brain Research Reviews, vol. 20, no. 3, pp. 269–287, 1995. View at Publisher · View at Google Scholar · View at Scopus
  16. G. M. Hayes, M. N. Woodroofe, and M. L. Cuzner, “Microglia express MHC class II in normal and demyelinating human white matter,” Annals of the New York Academy of Sciences, vol. 540, pp. 501–503, 1988. View at Google Scholar · View at Scopus
  17. K. Imamura, N. Hishikawa, M. Sawada, T. Nagatsu, M. Yoshida, and Y. Hashizume, “Distribution of major histocompatibility complex class II-positive microglia and cytokine profile of Parkinson's disease brains,” Acta Neuropathologica, vol. 106, no. 6, pp. 518–526, 2003. View at Publisher · View at Google Scholar · View at Scopus
  18. W. F. Hickey and H. Kimura, “Perivascular microglial cells of the CNS are bone marrow-derived and present antigen in vivo,” Science, vol. 239, no. 4837, pp. 290–292, 1988. View at Google Scholar · View at Scopus
  19. M. L. Block, L. Zecca, and J. S. Hong, “Microglia-mediated neurotoxicity: uncovering the molecular mechanisms,” Nature Reviews Neuroscience, vol. 8, no. 1, pp. 57–69, 2007. View at Publisher · View at Google Scholar · View at Scopus
  20. W. J. Streit, S. A. Walter, and N. A. Pennell, “Reactive microgliosis,” Progress in Neurobiology, vol. 57, no. 6, pp. 563–581, 1999. View at Publisher · View at Google Scholar · View at Scopus
  21. H. M. Gao and J. S. Hong, “Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression,” Trends in Immunology, vol. 29, no. 8, pp. 357–365, 2008. View at Publisher · View at Google Scholar · View at Scopus
  22. A. Castaño, A. J. Herrera, J. Cano, and A. Machado, “Lipopolysaccharide intranigral injection induces inflammatory reaction and damage in nigrostriatal dopaminergic system,” Journal of Neurochemistry, vol. 70, no. 4, pp. 1584–1592, 1998. View at Google Scholar · View at Scopus
  23. H. M. Gao, J. Jiang, B. Wilson, W. Zhang, J. S. Hong, and B. Liu, “Microglial activation-mediated delayed and progressive degeneration of rat nigral dopaminergic neurons: relevance to Parkinson's disease,” Journal of Neurochemistry, vol. 81, no. 6, pp. 1285–1297, 2002. View at Publisher · View at Google Scholar · View at Scopus
  24. H. M. Gao, B. Liu, W. Zhang, and J. S. Hong, “Critical role of microglial NADPH oxidase-derived free radicals in the in vitro MPTP model of Parkinson's disease,” The FASEB Journal, vol. 17, pp. 1954–1956, 2003. View at Google Scholar
  25. M. Gerlach, P. Riederer, H. Przuntek, and M. B. H. Youdim, “MPTP mechanisms of neurotoxicity and their implications for Parkinson's disease,” European Journal of Pharmacology, vol. 208, no. 4, pp. 273–286, 1991. View at Publisher · View at Google Scholar · View at Scopus
  26. D. C. Wu, V. Jackson-Lewis, M. Vila et al., “Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease,” Journal of Neuroscience, vol. 22, no. 5, pp. 1763–1771, 2002. View at Google Scholar · View at Scopus
  27. B. Liu, L. Du, and J. S. Hong, “Naloxone protects rat dopaminergic neurons against inflammatory damage through inhibition of microglia activation and superoxide generation,” Journal of Pharmacology and Experimental Therapeutics, vol. 293, no. 2, pp. 607–617, 2000. View at Google Scholar · View at Scopus
  28. H. Chen, S. M. Zhang, M. A. Hernán et al., “Nonsteroidal anti-inflammatory drugs and the risk of Parkinson disease,” Archives of Neurology, vol. 60, no. 8, pp. 1059–1064, 2003. View at Publisher · View at Google Scholar · View at Scopus
  29. H. Chen, E. Jacobs, M. A. Schwarzschild et al., “Nonsteroidal antiinflammatory drug use and the risk for Parkinson's disease,” Annals of Neurology, vol. 58, no. 6, pp. 963–967, 2005. View at Publisher · View at Google Scholar · View at Scopus
  30. H. Chen, E. J. O'Reilly, M. A. Schwarzschild, and A. Ascherio, “Peripheral inflammatory biomarkers and risk of Parkinson's disease,” American Journal of Epidemiology, vol. 167, no. 1, pp. 90–95, 2008. View at Publisher · View at Google Scholar · View at Scopus
  31. A. Gerhard, N. Pavese, G. Hotton et al., “In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson's disease,” Neurobiology of Disease, vol. 21, no. 2, pp. 404–412, 2006. View at Publisher · View at Google Scholar · View at Scopus
  32. P. L. McGeer and E. G. McGeer, “Glial reactions in Parkinson's disease,” Movement Disorders, vol. 23, no. 4, pp. 474–483, 2008. View at Publisher · View at Google Scholar · View at Scopus
  33. P. L. McGeer, C. Schwab, A. Parent, and D. Doudet, “Presence of reactive microglia in monkey substantia nigra years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration,” Annals of Neurology, vol. 54, no. 5, pp. 599–604, 2003. View at Publisher · View at Google Scholar · View at Scopus
  34. J. W. Langston, L. S. Forno, J. Tetrud, A. G. Reeves, J. A. Kaplan, and D. Karluk, “Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure,” Annals of Neurology, vol. 46, no. 4, pp. 598–605, 1999. View at Publisher · View at Google Scholar · View at Scopus
  35. C. Barcia, A. Sánchez Bahillo, E. Fernández-Villalba et al., “Evidence of active microglia in substantia nigra pars compacta of parkinsonian monkeys 1 year after MPTP exposure,” GLIA, vol. 46, no. 4, pp. 402–409, 2004. View at Publisher · View at Google Scholar · View at Scopus
  36. Y. S. Kim, D. H. Choi, M. L. Block et al., “A pivotal role of matrix metalloproteinase-3 activity in dopaminergic neuronal degeneration via microglial activation,” The FASEB Journal, vol. 21, no. 1, pp. 179–187, 2007. View at Publisher · View at Google Scholar · View at Scopus
  37. L. Zecca, F. A. Zucca, H. Wilms, and D. Sulzer, “Neuromelanin of the substantia nigra: a neuronal black hole with protective and toxic characteristics,” Trends in Neurosciences, vol. 26, no. 11, pp. 578–580, 2003. View at Publisher · View at Google Scholar · View at Scopus
  38. W. Zhang, T. Wang, Z. Pei et al., “Aggregated α-synuclein activates microglia: a process leading to disease progression in Parkinson's disease,” The FASEB Journal, vol. 19, no. 6, pp. 533–542, 2005. View at Publisher · View at Google Scholar · View at Scopus
  39. H. M. Gao, P. T. Kotzbauer, K. Uryu, S. Leight, J. Q. Trojanowski, and V. M. Y. Lee, “Neuroinflammation and oxidation/nitration of α-synuclein linked to dopaminergic neurodegeneration,” Journal of Neuroscience, vol. 28, no. 30, pp. 7687–7698, 2008. View at Publisher · View at Google Scholar · View at Scopus
  40. Y. S. Kim and T. H. Joh, “Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease,” Experimental and Molecular Medicine, vol. 38, no. 4, pp. 333–347, 2006. View at Google Scholar · View at Scopus
  41. C. C. Chao, S. Hu, T. W. Molitor, E. G. Shaskan, and P. K. Peterson, “Activated microglia mediate neuronal cell injury via a nitric oxide mechanism,” Journal of Immunology, vol. 149, no. 8, pp. 2736–2741, 1992. View at Google Scholar · View at Scopus
  42. P. Jenner, “Oxidative stress in Parkinson's disease,” Annals of Neurology, vol. 53, no. 3, pp. S26–S38, 2003. View at Publisher · View at Google Scholar · View at Scopus
  43. E. Koutsilieri, C. Scheller, E. Grünblatt, K. Nara, J. Li, and P. Riederer, “Free radicals in Parkinson's disease,” Journal of Neurology, vol. 249, supplement 2, pp. II1–II5, 2002. View at Google Scholar · View at Scopus
  44. S. Jana, A. K. Maiti, M. B. Bagh et al., “Dopamine but not 3,4-dihydroxy phenylacetic acid (DOPAC) inhibits brain respiratory chain activity by autoxidation and mitochondria catalyzed oxidation to quinone products: implications in Parkinson's disease,” Brain Research, vol. 1139, no. 1, pp. 195–200, 2007. View at Publisher · View at Google Scholar · View at Scopus
  45. D. T. Dexter, C. J. Carter, F. R. Wells et al., “Basal lipid peroxidation in substantia nigra is increased in Parkinson's disease,” Journal of Neurochemistry, vol. 52, no. 2, pp. 381–389, 1989. View at Google Scholar · View at Scopus
  46. R. N. Dilger and R. W. Johnson, “Aging, microglial cell priming, and the discordant central inflammatory response to signals from the peripheral immune system,” Journal of Leukocyte Biology, vol. 84, no. 4, pp. 932–939, 2008. View at Publisher · View at Google Scholar · View at Scopus
  47. Y. Huang, C. J. Henry, R. Dantzer, R. W. Johnson, and J. P. Godbout, “Exaggerated sickness behavior and brain proinflammatory cytokine expression in aged mice in response to intracerebroventricular lipopolysaccharide,” Neurobiology of Aging, vol. 29, no. 11, pp. 1744–1753, 2008. View at Publisher · View at Google Scholar · View at Scopus
  48. R. von Bernhardi, J. E. Tichauer, and J. Eugenín, “Aging-dependent changes of microglial cells and their relevance for neurodegenerative disorders,” Journal of Neurochemistry, vol. 112, no. 5, pp. 1099–1114, 2010. View at Publisher · View at Google Scholar · View at Scopus
  49. J. E. Merrill and E. N. Benveniste, “Cytokines in inflammatory brain lesions: helpful and harmful,” Trends in Neurosciences, vol. 19, no. 8, pp. 331–338, 1996. View at Publisher · View at Google Scholar · View at Scopus
  50. T. Nagatsu, M. Mogi, H. Ichinose, and A. Togari, “Cytokines in Parkinson's disease,” Journal of Neural Transmission. Supplementa, no. 58, pp. 143–151, 2000. View at Google Scholar · View at Scopus
  51. M. Mogi, M. Harada, P. Riederer, H. Narabayashi, K. Fujita, and T. Nagatsu, “Tumor necrosis factor-α (TNF-α) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients,” Neuroscience Letters, vol. 165, no. 1-2, pp. 208–210, 1994. View at Publisher · View at Google Scholar · View at Scopus
  52. G. Stypuła, J. Kunert-Radek, H. Stepien, K. Zylińska, and M. Pawlikowski, “Evaluation of interleukins, ACTH, cortisol and prolactin concentrations in the blood of patients with Parkinson's disease,” NeuroImmunoModulation, vol. 3, no. 2-3, pp. 131–134, 1996. View at Google Scholar · View at Scopus
  53. E. C. Hirsch, “Glial cells and Parkinson's disease,” Journal of Neurology, vol. 247, supplement 2, no. 2, pp. 58–62, 2000. View at Google Scholar · View at Scopus
  54. T. Nagatsu and M. Sawada, “Inflammatory process in Parkinson's disease: role for cytokines,” Current Pharmaceutical Design, vol. 11, no. 8, pp. 999–1016, 2005. View at Publisher · View at Google Scholar · View at Scopus
  55. P. Ravenscroft and J. Brotchie, “NMDA receptors in the basal ganglia,” Journal of Anatomy, vol. 196, no. 4, pp. 577–585, 2000. View at Publisher · View at Google Scholar · View at Scopus
  56. E. A. Waxman and D. R. Lynch, “N-methyl-D-aspartate receptor subtype mediated bidirectional control of p38 mitogen-activated protein kinase,” Journal of Biological Chemistry, vol. 280, no. 32, pp. 29322–29333, 2005. View at Publisher · View at Google Scholar · View at Scopus
  57. S. Kikuchi and S. U. Kim, “Glutamate neurotoxicity in mesencephalic dopaminergic neurons in culture,” Journal of Neuroscience Research, vol. 36, no. 5, pp. 558–569, 1993. View at Publisher · View at Google Scholar · View at Scopus
  58. B. P. Connop, R. J. Boegman, K. Jhamandas, and R. J. Beninger, “Excitotoxic action of NMDA agonists on nigrostriatal dopaminergic neurons: modulation by inhibition of nitric oxide synthesis,” Brain Research, vol. 676, no. 1, pp. 124–132, 1995. View at Publisher · View at Google Scholar · View at Scopus
  59. P. J. Hallett and D. G. Standaert, “Rationale for and use of NMDA receptor antagonists in Parkinson's disease,” Pharmacology & Therapeutics, vol. 102, no. 2, pp. 155–174, 2004. View at Publisher · View at Google Scholar · View at Scopus
  60. W. J. Schmidt, M. Bubser, and W. Hauber, “Behavioural pharmacology of glutamate in the basal ganglia,” Journal of Neural Transmission. Supplementa, no. 38, pp. 65–89, 1992. View at Google Scholar · View at Scopus
  61. H. Takeuchi, T. Mizuno, G. Zhang et al., “Neuritic beading induced by activated microglia is an early feature of neuronal dysfunction toward neuronal death by inhibition of mitochondrial respiration and axonal transport,” Journal of Biological Chemistry, vol. 280, no. 11, pp. 10444–10454, 2005. View at Publisher · View at Google Scholar · View at Scopus
  62. P. M. Mattila, J. O. Rinne, H. Helenius, and M. Röyttä, “Neuritic degeneration in the hippocampus and amygdala in Parkinson's disease in relation to Alzheimer pathology,” Acta Neuropathologica, vol. 98, no. 2, pp. 157–164, 1999. View at Publisher · View at Google Scholar · View at Scopus
  63. C. Ikonomidou and L. Turski, “Neurodegenerative disorders: clues from glutamate and energy metabolism,” Critical Reviews in Neurobiology, vol. 10, no. 2, pp. 239–263, 1996. View at Google Scholar · View at Scopus
  64. J. T. Greenamyre and C. F. O'Brien, “N-methyl-D-aspartate antagonists in the treatment of Parkinson's disease,” Archives of Neurology, vol. 48, no. 9, pp. 977–981, 1991. View at Google Scholar · View at Scopus
  65. D. Aarsland, C. Ballard, Z. Walker et al., “Memantine in patients with Parkinson's disease dementia or dementia with Lewy bodies: a double-blind, placebo-controlled, multicentre trial,” The Lancet Neurology, vol. 8, no. 7, pp. 613–618, 2009. View at Publisher · View at Google Scholar · View at Scopus
  66. L. Verhagen Metman, P. Del Dotto, P. van den Munckhof, J. Fang, M. M. Mouradian, and T. N. Chase, “Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson's disease,” Neurology, vol. 50, no. 5, pp. 1323–1326, 1998. View at Google Scholar · View at Scopus
  67. J. R. Moffett and M. A. Namboodiri, “Tryptophan and the immune response,” Immunology and Cell Biology, vol. 81, no. 4, pp. 247–265, 2003. View at Publisher · View at Google Scholar · View at Scopus
  68. A. L. Mellor, B. Baban, P. Chandler et al., “Cutting edge: induced indoleamine 2,3 dioxygenase expression in dendritic cell subsets suppresses T cell clonal expansion,” Journal of Immunology, vol. 171, no. 4, pp. 1652–1655, 2003. View at Google Scholar · View at Scopus
  69. D. H. Munn and A. L. Mellor, “IDO and tolerance to tumors,” Trends in Molecular Medicine, vol. 10, no. 1, pp. 15–18, 2004. View at Publisher · View at Google Scholar · View at Scopus
  70. G. J. Guillemin, D. G. Smith, G. A. Smythe, P. J. Armati, and B. J. Brew, “Expression of the kynurenine pathway enzymes in human microglia and macrophages,” Advances in Experimental Medicine and Biology, vol. 527, pp. 105–112, 2003. View at Google Scholar · View at Scopus
  71. G. J. Guillemin, S. J. Kerr, G. A. Smythe et al., “Kynurenine pathway metabolism in human astrocytes: a paradox for neuronal protection,” Journal of Neurochemistry, vol. 78, no. 4, pp. 842–853, 2001. View at Publisher · View at Google Scholar · View at Scopus
  72. G. J. Guillemin, K. M. Cullen, C. K. Lim et al., “Characterization of the kynurenine pathway in human neurons,” Journal of Neuroscience, vol. 27, no. 47, pp. 12884–12892, 2007. View at Publisher · View at Google Scholar · View at Scopus
  73. R. Owe-Young, N. L. Webster, M. Mukhtar et al., “Kynurenine pathway metabolism in human blood-brain-barrier cells: implications for immune tolerance and neurotoxicity,” Journal of Neurochemistry, vol. 105, no. 4, pp. 1346–1357, 2008. View at Publisher · View at Google Scholar · View at Scopus
  74. H. Q. Wu, P. Guidetti, J. H. Goodman et al., “Kynurenergic manipulations influence excitatory synaptic function and excitotoxic vulnerability in the rat hippocampus in vivo,” Neuroscience, vol. 97, no. 2, pp. 243–251, 2000. View at Publisher · View at Google Scholar · View at Scopus
  75. A. Chiarugi, E. Meli, and F. Moroni, “Similarities and differences in the neuronal death processes activated by 3OH-kynurenine and quinolinic acid,” Journal of Neurochemistry, vol. 77, no. 5, pp. 1310–1318, 2001. View at Publisher · View at Google Scholar · View at Scopus
  76. R. Schwarcz and R. Pellicciari, “Manipulation of brain kynurenines: glial targets, neuronal effects, and clinical opportunities,” Journal of Pharmacology and Experimental Therapeutics, vol. 303, no. 1, pp. 1–10, 2002. View at Publisher · View at Google Scholar · View at Scopus
  77. A. J. Smith, T. W. Stone, and R. A. Smith, “Neurotoxicity of tryptophan metabolites,” Biochemical Society Transactions, vol. 35, no. 5, pp. 1287–1289, 2007. View at Publisher · View at Google Scholar · View at Scopus
  78. A. J. Smith, R. A. Smith, and T. W. Stone, “5-hydroxyanthranilic acid, a tryptophan metabolite, generates oxidative stress and neuronal death via p38 activation in cultured cerebellar granule neurones,” Neurotoxicity Research, vol. 15, no. 4, pp. 303–310, 2009. View at Publisher · View at Google Scholar · View at Scopus
  79. S. Okuda, N. Nishiyama, H. Saito, and H. Katsuki, “3-hydroxykynurenine, an endogenous oxidative stress generator, causes neuronal cell death with apoptotic features and region selectivity,” Journal of Neurochemistry, vol. 70, no. 1, pp. 299–307, 1998. View at Google Scholar · View at Scopus
  80. T. W. Stone and M. N. Perkins, “Quinolinic acid: a potent endogenous excitant at amino acid receptors in CNS,” European Journal of Pharmacology, vol. 72, no. 4, pp. 411–412, 1981. View at Google Scholar · View at Scopus
  81. R. Schwarcz, W. O. Whetsell, and R. M. Mangano, “Quinolinic acid: an endogenous metabolite that produces axon-sparing lesions in rat brain,” Science, vol. 219, no. 4582, pp. 316–318, 1983. View at Google Scholar · View at Scopus
  82. G. J. Guillemin and B. J. Brew, “Implications of the kynurenine pathway and quinolinic acid in Alzheimer's disease,” Redox Report, vol. 7, no. 4, pp. 199–206, 2002. View at Publisher · View at Google Scholar · View at Scopus
  83. G. J. Guillemin, L. Wang, and B. J. Brew, “Quinolinic acid selectively induces apoptosis of human astocytes: potential role in AIDS dementia complex,” Journal of Neuroinflammation, vol. 2, article 16, 2005. View at Publisher · View at Google Scholar · View at Scopus
  84. A. Schurr, C. A. West, and B. M. Rigor, “Neurotoxicity of quinolinic acid and its derivatives in hypoxic rat hippocampal slices,” Brain Research, vol. 568, no. 1-2, pp. 199–204, 1991. View at Google Scholar · View at Scopus
  85. Y. M. Bordelon, M. F. Chesselet, D. Nelson, F. Welsh, and M. Erecińska, “Energetic dysfunction in quinolinic acid-lesioned rat striatum,” Journal of Neurochemistry, vol. 69, no. 4, pp. 1629–1639, 1997. View at Google Scholar · View at Scopus
  86. H. Baran, B. Kepplinger, M. Herrera-Marschitz, K. Stolze, G. Lubec, and H. Nohl, “Increased kynurenic acid in the brain after neonatal asphyxia,” Life Sciences, vol. 69, no. 11, pp. 1249–1256, 2001. View at Publisher · View at Google Scholar · View at Scopus
  87. N. Braidy, R. Grant, S. Adams, B. J. Brew, and G. J. Guillemin, “Mechanism for quinolinic acid cytotoxicity in human astrocytes and neurons,” Neurotoxicity Research, vol. 16, no. 1, pp. 77–86, 2009. View at Publisher · View at Google Scholar · View at Scopus
  88. G. J. Guillemin, K. M. Cullen, C. K. Lim et al., “Characterization of the kynurenine pathway in human neurons,” Journal of Neuroscience, vol. 27, no. 47, pp. 12884–12892, 2007. View at Publisher · View at Google Scholar · View at Scopus
  89. G. J. Guillemin, G. Smythe, O. Takikawa, and B. J. Brew, “Expression of indoleamine 2,3-dioxygenase and production of quinolinic acid by human microglia, astrocytes, and neurons,” GLIA, vol. 49, no. 1, pp. 15–23, 2005. View at Publisher · View at Google Scholar · View at Scopus
  90. P. Guidetti and R. Schwarcz, “3-hydroxykynurenine potentiates quinolinate but not NMDA toxicity in the rat striatum,” European Journal of Neuroscience, vol. 11, no. 11, pp. 3857–3863, 1999. View at Publisher · View at Google Scholar · View at Scopus
  91. W. M. H. Behan and T. W. Stone, “Enhanced neuronal damage by co-administration of quinolinic acid and free radicals, and protection by adenosine A2A receptor antagonists,” British Journal of Pharmacology, vol. 135, no. 6, pp. 1435–1442, 2002. View at Google Scholar · View at Scopus
  92. I. Ghorayeb, Z. Puschban, P. O. Fernagut et al., “Simultaneous intrastriatal 6-hydroxydopamine and quinolinic acid injection: a model of early-stage striatonigral degeneration,” Experimental Neurology, vol. 167, no. 1, pp. 133–147, 2001. View at Publisher · View at Google Scholar · View at Scopus
  93. M. G. Espey, O. N. Chernyshev, J. F. Reinhard, M. A. A. Namboodiri, and C. A. Colton, “Activated human microglia produce the excitotoxin quinolinic acid,” NeuroReport, vol. 8, no. 2, pp. 431–434, 1997. View at Google Scholar · View at Scopus
  94. M. P. Heyes, K. Saito, and S. P. Markey, “Human macrophages convert L-tryptophan into the neurotoxin quinolinic acid,” Biochemical Journal, vol. 283, no. 3, pp. 633–635, 1992. View at Google Scholar · View at Scopus
  95. H. E. Scharfman, P. S. Hodgkins, S. C. Lee, and R. Schwarcz, “Quantitative differences in the effects of de novo produced and exogenous kynurenic acid in rat brain slices,” Neuroscience Letters, vol. 274, no. 2, pp. 111–114, 1999. View at Publisher · View at Google Scholar · View at Scopus
  96. A. F. Miranda, R. J. Boegman, R. J. Beninger, and K. Jhamandas, “Protection against quinolinic acid-mediated excitotoxicity in nigrostriatal dopaminergic neurons by endogenous kynurenic acid,” Neuroscience, vol. 78, no. 4, pp. 967–975, 1997. View at Publisher · View at Google Scholar · View at Scopus
  97. R. Carpenedo, A. Pittaluga, A. Cozzi et al., “Presynaptic kynurenate-sensitive receptors inhibit glutamate release,” European Journal of Neuroscience, vol. 13, no. 11, pp. 2141–2147, 2001. View at Publisher · View at Google Scholar · View at Scopus
  98. R. C. Roberts, K. E. McCarthy, F. Du, E. Okuno, and R. Schwarcz, “Immunocytochemical localization of the quinolinic acid synthesizing enzyme, 3-hydroxyanthranilic acid oxygenase, in the rat substantia nigra,” Brain Research, vol. 650, no. 2, pp. 229–238, 1994. View at Publisher · View at Google Scholar · View at Scopus
  99. R. Schwarcz, F. Du, W. Schmidt et al., “Kynurenic acid: a potential pathogen in brain disorders,” Annals of the New York Academy of Sciences, vol. 648, pp. 140–153, 1992. View at Google Scholar · View at Scopus
  100. A. C. Foster, A. Vezzani, E. D. French, and R. Schwarcz, “Kynurenic acid blocks neurotoxicity and seizures induced in rats by the related brain metabolite quinolinic acid,” Neuroscience Letters, vol. 48, no. 3, pp. 273–278, 1984. View at Publisher · View at Google Scholar · View at Scopus
  101. K. Jhamandas, R. J. Boegman, R. J. Beninger, and M. Bialik, “Quinolinate-induced cortical cholinergic damage: modulation by tryptophan metabolites,” Brain Research, vol. 529, no. 1-2, pp. 185–191, 1990. View at Google Scholar · View at Scopus
  102. U. Testa, F. Louache, M. Titeux, P. Thomopoulos, and H. Rochant, “The iron-chelating agent picolinic acid enhances transferrin receptors expression in human erythroleukaemic cell lines,” British Journal of Haematology, vol. 60, no. 3, pp. 491–502, 1985. View at Google Scholar
  103. F. Molina-Holgado, R. C. Hider, A. Gaeta, R. Williams, and P. Francis, “Metals ions and neurodegeneration,” BioMetals, vol. 20, no. 3-4, pp. 639–654, 2007. View at Publisher · View at Google Scholar · View at Scopus
  104. G. J. Guillemin, S. J. Kerr, L. A. Pemberton et al., “IFN-β induces kynurenine pathway metabolism in human macrophages: potential implications for multiple sclerosis treatment,” Journal of Interferon and Cytokine Research, vol. 21, no. 12, pp. 1097–1101, 2001. View at Publisher · View at Google Scholar · View at Scopus
  105. R. J. Beninger, A. M. Colton, J. L. Ingles, K. Jhamandas, and R. J. Boegman, “Picolinic acid blocks the neurotoxic but not the neuroexcitant properties of quinolinic acid in the rat brain: evidence from turning behaviour and tyrosine hydroxylase immunohistochemistry,” Neuroscience, vol. 61, no. 3, pp. 603–612, 1994. View at Publisher · View at Google Scholar
  106. R. Owe-Young, N. L. Webster, M. Mukhtar et al., “Kynurenine pathway metabolism in human blood-brain-barrier cells: implications for immune tolerance and neurotoxicity,” Journal of Neurochemistry, vol. 105, no. 4, pp. 1346–1357, 2008. View at Publisher · View at Google Scholar · View at Scopus
  107. T. Ogawa, W. R. Matson, M. F. Beal et al., “Kynurenine pathway abnormalities in Parkinson's disease,” Neurology, vol. 42, no. 9, pp. 1702–1706, 1992. View at Google Scholar · View at Scopus
  108. M. Flint Beal, W. R. Matson, E. Storey et al., “Kynurenic acid concentrations are reduced in Huntington's disease cerebral cortex,” Journal of the Neurological Sciences, vol. 108, no. 1, pp. 80–87, 1992. View at Publisher · View at Google Scholar · View at Scopus
  109. E. Knyihár-Csillik, B. Csillik, M. Pákáski et al., “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, vol. 126, no. 4, pp. 899–914, 2004. View at Publisher · View at Google Scholar
  110. M. Merino, M. L. Vizuete, J. Cano, and A. Machado, “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+,” Journal of Neurochemistry, vol. 73, no. 2, pp. 750–757, 1999. View at Publisher · View at Google Scholar · View at Scopus
  111. Z. Hartai, P. Klivenyi, T. Janaky, B. Penke, L. Dux, and L. Vecsei, “Kynurenine metabolism in plasma and in red blood cells in Parkinson's disease,” Journal of the Neurological Sciences, vol. 239, no. 1, pp. 31–35, 2005. View at Publisher · View at Google Scholar · View at Scopus
  112. S. Fukui, R. Schwarcz, S. I. Rapoport, Y. Takada, and Q. R. Smith, “Blood-brain barrier transport of kynurenines: implications for brain synthesis and metabolism,” Journal of Neurochemistry, vol. 56, no. 6, pp. 2007–2017, 1991. View at Publisher · View at Google Scholar · View at Scopus
  113. M. C. Barth, N. Ahluwalia, T. J. T. Anderson et al., “Kynurenic acid triggers firm arrest of leukocytes to vascular endothelium under flow conditions,” Journal of Biological Chemistry, vol. 284, no. 29, pp. 19189–19195, 2009. View at Publisher · View at Google Scholar · View at Scopus
  114. H. Németh, J. Toldi, and L. Vécsei, “Kynurenines, Parkinson's disease and other neurodegenerative disorders: preclinical and clinical studies,” Journal of Neural Transmission. Supplementa, no. 70, pp. 285–304, 2006. View at Google Scholar
  115. S. Fujigaki, K. Saito, K. Sekikawa et al., “Lipopolysaccharide induction of indoleamine 2,3-dioxygenase is mediated dominantly by an IFN-γ-independent mechanism,” European Journal of Immunology, vol. 31, no. 8, pp. 2313–2318, 2001. View at Publisher · View at Google Scholar · View at Scopus
  116. T. W. Stone and L. G. Darlington, “Endogenous kynurenines as targets for drug discovery and development,” Nature Reviews Drug Discovery, vol. 1, no. 8, pp. 609–620, 2002. View at Publisher · View at Google Scholar · View at Scopus
  117. L. McNally, Z. Bhagwagar, and J. Hannestad, “Inflammation, glutamate, and glia in depression: a literature review,” CNS Spectrums, vol. 13, no. 6, pp. 501–510, 2008. View at Google Scholar · View at Scopus
  118. H. Q. Wu, S. C. Lee, and R. Schwarcz, “Systemic administration of 4-chlorokynurenine prevents quinolinate neurotoxicity in the rat hippocampus,” European Journal of Pharmacology, vol. 390, no. 3, pp. 267–274, 2000. View at Publisher · View at Google Scholar · View at Scopus
  119. T. W. Stone, “Development and therapeutic potential of kynurenic acid and kynurenine derivatives for neuroprotection,” Trends in Pharmacological Sciences, vol. 21, no. 4, pp. 149–154, 2000. View at Publisher · View at Google Scholar · View at Scopus
  120. M. Platten, P. P. Ho, and L. Steinman, “Anti-inflammatory strategies for the treatment of multiple sclerosis—tryptophan catabolites may hold the key,” Drug Discovery Today: Therapeutic Strategies, vol. 3, no. 3, pp. 401–408, 2006. View at Publisher · View at Google Scholar
  121. M. Platten, P. P. Ho, S. Youssef et al., “Treatment of autoimmune neuroinflammation with a synthetic tryptophan metabolite,” Science, vol. 310, no. 5749, pp. 850–855, 2005. View at Publisher · View at Google Scholar · View at Scopus
  122. C. W. Ritchie, A. I. Bush, and C. L. Masters, “Metal-protein attenuating compounds and Alzheimer's disease,” Expert Opinion on Investigational Drugs, vol. 13, no. 12, pp. 1585–1592, 2004. View at Publisher · View at Google Scholar · View at Scopus
  123. J. R. Moffett, T. Els, M. G. Espey, S. A. Walter, W. J. Streit, and M. A. A. Namboodiri, “Quinolinate immunoreactivity in experimental rat brain tumors is present in macrophages but not in astrocytes,” Experimental Neurology, vol. 144, no. 2, pp. 287–301, 1997. View at Publisher · View at Google Scholar · View at Scopus
  124. M. Hamann, S. E. Sander, and A. Richter, “Effects of the kynurenine 3-hydroxylase inhibitor Ro 61-8048 after intrastriatal injections on the severity of dystonia in the dt mutant,” European Journal of Pharmacology, vol. 586, no. 1–3, pp. 156–159, 2008. View at Publisher · View at Google Scholar · View at Scopus