Changes in cytokines and neurotrophins in Parkinson’s disease

  • T. Nagatsu
  • M. Mogi
  • H. Ichinose
  • A. Togari
Conference paper


Degeneration of the dopamine (DA) neurons of the substantia nigra pars compacta and the resulting loss of nerve terminals accompanied by DA deficiency in the striatum are responsible for most of the movement disturbances called parkinsonism, observed in Parkinson’s disease (PD). One hypothesis of the cause of degeneration of the nigrostriatal DA neurons is that PD is caused by programmed cell death (apoptosis) due to increased levels of cytokines and/or decreased ones of neurotrophins. We and other workers found markedly increased levels of cytokines, such as tumor necrosis factor (TNF)-a, interleukin (IL)-1ß, IL-2, IL-4, IL-6, transforming growth factor (TFG)-a, TGF-131, and TGF-ß2, and decreased ones of neurotrophins, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), in the nigrostriatal DA regions and ventricular and lumbar cerebrospinal fluid of PD patients. Furthermore, the levels of TNF-a receptor Rl (TNF-R1, p55), bc1-2, soluble Fas (sFas), and the activities of caspase-1 and caspase-3 were also elevated in the nigrostriatal DA regions in PD. In experimental animal models of PD, IL-lß level was increased and NGF one decreased in the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian mice, and TNF-a level was increased in the substantia nigra and striatum of the 6-hydroxydopamine (6OHDA)-injected side of hemiparkinsonian rats. L-DOPA alone or together with 6OHDA does not increase the level of TNF-a in the brain in vivo. Increased levels of proinflammatory cytokines, cytokine receptors and caspase activities, and reduced levels of neurotrophins in the nigrostriatal region in PD patients, and in MPTP- and 6OHDA-produced parkinsonian animals suggest increased immune reactivity and programmed cell death (apoptosis) of neuronal and/or glial cells. These data indicate the presence of such proapoptotic environment in the substantia nigra in PD that may induce increased vulnerability of neuronal or glial cells towards a variety of neurotoxic factors. The probable causative linkage among the increased levels of proinflammatory cytokines and the decreased levels of neurotrophins, candidate parkinsonism-producing neurotoxins such as isoquinoline neurotoxins (Review; Nagatsu, 1997), and the genetic susceptibility to toxic factors, remains for further investigation in the molecular mechanism of PD. The increased cytokine levels, decreased


Nerve Growth Factor Substantia Nigra Neopterin Level Atypical Parkinsonism Parkinsonian Brain 


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  1. Anglade P, Vyas S, Javoy-Agid F, Herreto MT, Michel PP, Marquez J, Mouatt-Prigent A, Ruberg M, Hirsch C, Agid Y (1997a) Apoptosis and autophagy in nigral neurons of patients with Parkinson’s disease. Histol Histopathol 12: 25–31Google Scholar
  2. Anglade P, Vyas S, Hirsch EC, Agid Y (1997b) Apoptosis in dopaminergic neurons of the human substantia nigra during normal aging. Histol Hisopathol 12: 603–610Google Scholar
  3. Aubin A, Curet O, Deffois A, Carter C (1998) Aspirin and salycylate protect against MPTP-induced dopamine depletion in mice. J Neurochem 71: 1635–1642PubMedCrossRefGoogle Scholar
  4. Banati RB, Daniel SE, Blunt SB (1998) Glial pathology but absence of apoptotic nigral neurons in long-standing Parkinson’s disease. Mov Disord 13: 221–227PubMedCrossRefGoogle Scholar
  5. Blum-Degan D, Müller T, Kuhn W, Gerlach M, Przuntek H, Riederer P (1995) Interleukin 113 and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer’s and de novo Parkinson’s disease patients. Neurosci Lett 202: 17–20CrossRefGoogle Scholar
  6. Boka G, Anglade P, Wallach D, Javoy-Agid F, Agid Y, Hirsch EC (1994) Immunocytochemical analysis of tumor necrosis factor and its receptor in Parkinson’s disease. Neurosci Lett 172: 151–154PubMedCrossRefGoogle Scholar
  7. Breitner JC (1996) The role of anti-inflammatory drugs in the prevention and treatment of Alzheimer’s disease. Ann Rev Med 47: 401–411PubMedCrossRefGoogle Scholar
  8. Burke RE, Kholodilov NG (1998) Programmed cell death: does it play a role in Parkinson’s disease? Ann Neurol 44 Suppl 1: S126–S133PubMedCrossRefGoogle Scholar
  9. Caparros-Lefebvre D, Elbaz A, the Caribbean Parkinsonism Study Group (1999) Possible relation of atypical parkinsonism in the French west indies with consumption of tropical plants and case-control study. Lancet 354: 281–286Google Scholar
  10. Dickson DW, Lee SC, Mattiace LA, Yen SH, Brosnan CF (1993) Microglia and cytokines in neurological diseases, with special reference to AIDS and Alzheimer’s disease. Glia 7: 76–82CrossRefGoogle Scholar
  11. Fan DS, Ogawa M, Ikeguchi K, Fujimoto K, Uraba M, Kume K, Nishizawa M, Matsushita N, Kiuchi K, Ichinose H, Nagatsu T, Kurzman GJ, Nakano I, Ozawa K (1996) Prevention of dopaminergic neuron death by adeno-associated virus vector-mediated GDNF gene transfer in rat mesencephalic cells in vitro. Neurosci Lett 248: 61–64CrossRefGoogle Scholar
  12. Foley P, Riederer P (1999) Pathogenesis and preclinical course of Parkinson’s disease. J Neural Transm Suppl 56: 31–74PubMedCrossRefGoogle Scholar
  13. Fujishiro K, Hagihara M, Takahashi A, Nagatsu T (1999) Concentrations of neopterin and biopterin in the cerebrospinal fluid of patients with Parkinson’s disease. Biochem Med Metab Biol 44: 97–100CrossRefGoogle Scholar
  14. Furukawa Y, Nishi K, Kondo T, Mizuno Y, Narabayashi H (1993) CSF biopterin levels and clinical features of patients with juvenile parkinsonism. Adv Neurol 60: 562–567PubMedGoogle Scholar
  15. Gash DM, Zhang Z, Ovadia A, Cass WA, Yi A, Simmerman L, Russel D, Martin D, Lapchak PA, Collins F, Hoffer BJ, Gerhardt GA (1996) Functional recovery in parkinsonian monkeys treated with GDNF. Nature 380: 252–255PubMedCrossRefGoogle Scholar
  16. Ichinose H, Ohye T, Takahashi E, Seki N, Hori T, Segawa M, Nomura Y, Endo K, Tanaka H, Tsuji S, Fujita K, Nagatsu T (1994) Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene. Nat Genet 8: 236–242PubMedCrossRefGoogle Scholar
  17. Ichinose H, Suzuki T, Inagaki H, Ohye T, Nagatsu T (1999a) Molecular genetics of dopa-responsive dystonia. Biol Chem 380: 1355–1364CrossRefGoogle Scholar
  18. Ichinose H, Ohye T, Suzuki T, Sumi-Ichinose C, Nomura T, Hagino Y, Nagatsu T (1999b) Molecular cloning of the human Nurr 1 gene: characterization of the human gene and cDNAs. Gene 230: 233–239CrossRefGoogle Scholar
  19. Jelliger KA (1999) Is there apoposis in Lewy body disease? Acta Neuropathol (Berl) 97: 413–415CrossRefGoogle Scholar
  20. Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N (1998) Mutation in the perkin gene cause autosomal recessive juvenile parkinsonism. Nature 329: 605–608Google Scholar
  21. Kosel S, Egensperger R, von-Eitzen U, Mehraein P, Graeber MB (1997) On the question of apoptosis in the parkinsonian substantia nigra. Acta Neuropathol (Berl) 93: 105–108CrossRefGoogle Scholar
  22. Kotake Y, Tasaki Y, Makino Y, Ohta S, Hirobe M (1995) 1-Benzyl-1,2,3,4tetrahydroisoquinoline as a parkinsonism-inducing agent: a novel endogenous amine in mouse brain and parkinsonian brain. J Neurochem 65: 2633–2638PubMedCrossRefGoogle Scholar
  23. Levivier M, Przedborski S, Bencsics C, Kang UJ (1995) Intrastriatal implantation of fibroblasts genetically engineered to produce brain-derived neurotrophic factor prevents degeneration of dopaminergic neurons in a rat model of Parkinson’s disease. J Neurosci 15: 7810–7820PubMedGoogle Scholar
  24. Masliah E, Mallory M, Alford M, Tanaka S, Hansen LA (1998) Caspase dependent DNA fragmentation might be associated with excitotoxicity in Alzheimer’s disease. J Neuropathol Exp Neurol 57: 1041–1052PubMedCrossRefGoogle Scholar
  25. Matsubara K, Kobayashi S, Kobayashi Y, Yamashita K, Koide H, Hatta M, Iwamoto K, Tanaka O, Kimura K (1995) ß-Carbolinium cations, endogenous MPP+ analogs in the lumber cerebrospinal fluid of parkinsonian patients. Neurology 45: 2240–2245PubMedCrossRefGoogle Scholar
  26. McGeer PL, Itagaki S, Boyes BE, McGeer EG (1988) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s disease and Alzheimer’s disease brains. Neurology 38: 1285–1291PubMedCrossRefGoogle Scholar
  27. Mochizuki H, Goto K, Mori H, Mizuno Y (1996) Histochemical detection of apoptosis in Parkinson’s disease. J Neurol Sci 137: 120–123PubMedCrossRefGoogle Scholar
  28. Mogi M, Harada M, Riederer P, Narabayashi H, Fujita K, Nagatsu T (1994a) Tumor necrosis factor-a (TNF-a) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients. Neurosci Lett 165: 208–210CrossRefGoogle Scholar
  29. Mogi M, Harada M, Kondo T, Riederer P, Inagaki H, Minami M, Nagatsu T (1994b) Interleukin-1ß, interleukin-6, epidermal growth factor and transforming growth factor-a are elevated in the brain from parkinsonian patients. Neurosci Lett 180: 147–150CrossRefGoogle Scholar
  30. Mogi M, Harada M, Kondo T, Narabayashi H, Riederer P, Nagatsu T (1995a) Transforming growth factor-ß1 levels are elevated in the striatum and in ventricular cerebrospinal fluid in Parkinson’s disease. Neurosci Lett 193: 129–132CrossRefGoogle Scholar
  31. Mogi M, Harada M, Kondo T, Riederer P, Nagatsu T (1995b) Brain 132-microglobulin are elevated in the striatum in Parkinson’s disease. J Neural Transm [P-D Sect] 9: 87–92CrossRefGoogle Scholar
  32. Mogi M, Harada M, Narabayashi H, Inagaki H, Minami M, Nagatsu T (1996a) Interleukin (IL)-113, IL-2, IL-4, IL-6 and transforming growth factor-a levels are elevated in ventricular cerebrospinal fluid in juvenile parkinsonism and Parkinson’s disease. Neurosci Lett 211: 13–16CrossRefGoogle Scholar
  33. Mogi M, Harada M, Kondo T, Mizuno Y, Narabayashi H, Riederer P, Nagatsu T (1996b) bc1–2 Protein is increased in the brain from parkinsonian patients. Neurosci Lett 215: 1–2Google Scholar
  34. Mogi M, Harada M, Kondo T, Riederer P, Nagatsu T (1996c) Interleukin-2 but not basic fibroblast growth factor is elevated in parkinsonian brain. J Neural Transm 103: 1077–1081CrossRefGoogle Scholar
  35. Mogi M, Harada M, Kondo T, Mizuno Y, Narabayashi H, Riederer P, Nagatsu T (1996d) The soluble form of Fas molecule is elevated in parkinsonian brain tissues. Neurosci Lett 220: 195–198CrossRefGoogle Scholar
  36. Mogi M, Togari A, Ogawa M, Ikeguchi K, Shizuma N, Fan D-S, Nakano I, Nagatsu T (1998) Effects of repeated systemic administration of 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP) to mice on interleukin-113 and nerve growth factor in the striatum. Neurosci Lett 250: 25–28PubMedCrossRefGoogle Scholar
  37. Mogi M, Togari A, Tanaka K, Ogawa N, Ichinose H, Nagatsu T (1999a) Increase in level of tumor necrosis factor (TNF)-a in 6-hydroxydopamine-lesioned striatum in rats without influence of systemic L-DOPA on the TNF-a induction. Neurosci Lett 268: 101–104CrossRefGoogle Scholar
  38. Mogi M, Togari A, Kondo T, Mizuno Y, Komure O, Kuno S, Ichinose H, Nagatsu T (1999b) Brain-derived growth factor and nerve growth factor concentrations are decreased in the substantia nigra in Parkinson’s disease. Neurosci Lett 270: 45–48CrossRefGoogle Scholar
  39. Mogi M, Togari A, Kondo T, Mizuno Y, Komure O, Kuno S, Ichinose H, Nagatsu T (2000) Caspase activities and tumor necrosis factor R1 (p55) level are elevated in the substantia nigra from Parkinsonian brain. J Neural Transm 107: 335–341PubMedCrossRefGoogle Scholar
  40. Nagatsu T (1991) Genes for human catecholamine-synthesizing enzymes. Neurosci Res 12: 315–345PubMedCrossRefGoogle Scholar
  41. Nagatsu T (1993) Biochemical aspects of Parkinson’s disease. Adv Neurol 60: 165–174PubMedGoogle Scholar
  42. Nagatsu T (1997) Isoquinoline neurotoxins and Parkinson’s disease. Neurosci Res 29: 99–111PubMedCrossRefGoogle Scholar
  43. Nagatsu T, Mogi M, Ichinose H, Togari A, Riederer P (1999) Cytokines in Parkinson’s disease. NeuroSci News 2: 88–90Google Scholar
  44. Naoi M, Maruyama Y, Dostert P, Hashizume Y, Nakahara D, Takahashi T, Ota M (1996) Dopamine-derived endogenous 1(R),2(N)-dimethyl-6,7-dihydroxy-1,2,3,4tetrahydroisoquinoline, N-methyl-(R)-salsolinol, induced parkinsonism in rats: biochemcal, pathological and behavioral studies. Brain Res 707: 285–295CrossRefGoogle Scholar
  45. Naoi M, Maruyama W, Kasamatsu T, Dostert P (1998) Oxidation of Nmethyl(R)salsolinol: involvement to neurotoxicity and neuroprotection by endogenous catechol isoquinolines. J Neural Transm Suppl 52: 125–138PubMedCrossRefGoogle Scholar
  46. Olanow CW, Kordower JH, Freeman TB (1996) Fetal nigral transplantation as a therapy for Parkinson’s disease. Trends Neurosci 19: 102–109PubMedCrossRefGoogle Scholar
  47. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Sternroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, brio GD, Golie LI, Nussbaum RL (1997) Mutation of the a-synuclein gene identified in families with Parkinson’s disease. Science 276: 2045–2047PubMedCrossRefGoogle Scholar
  48. Sacco J, Agnello D, Sottocorno M, Lozza G, Monopoll A, Vilia P, Ghezzl P (1998) Nonsteroidal anti-inflammatory drugs increase tumor necrosis factor production in the periphery but not in the central nervous system in mice and rats. J Neurochem 71: 2063–2070PubMedCrossRefGoogle Scholar
  49. Segawa M, Hosaka A, Miyagawa F, Nomura Y, Imai H (1976) Hereditary progressive dystonia with marked diurnal fluctuation. Adv Neurol 14: 215–233PubMedGoogle Scholar
  50. Snyder SH, Lai MM, Burnett PE (1998) Immunophilins in the nervous system. Neuron 21: 283–294PubMedCrossRefGoogle Scholar
  51. Spina MB, Squinto SP, Miller J, Lindsay RM, Hyman C (1992) Brain-derived neurotrophic factor protects dopamine neurons against 6-hydroxydopamine and Nmethylpyridinium ion activity: involvement of the glutathione system. J Neurochem 59: 99–106PubMedCrossRefGoogle Scholar
  52. Stadtmann C, Bruck W, Bancher C, Jellinger K, Lassmann H (1998) Alzheimer disease: DNA fragmentation indicates increased neuronal vulnerability, but not apoptosis. J Neuropathol Exp Neurol 57: 456–464CrossRefGoogle Scholar
  53. Stern G (1996) Parkinson’s disease: the apoptosis hypothesis. Adv Neurol 69: 101–107 Stewart WF, Kawas C, Corrada M, Metter EJ (1997) Risk of Alzheimer’s disease and duration of NSAID use. Neurology 48: 101–107Google Scholar
  54. Takahashi H, Levine RA, Galloway MP, Snow BJ, Calne DB, Nygaard TG (1994) Biochemical and fluorodopa positron emmision tomograph findings in an asymptomatic carrier of the gene for dopa-responsive dystonia. Ann Neurol 35: 354–356PubMedCrossRefGoogle Scholar
  55. Tatton NA, Maclean-Fraser A, Tatton WG, Perl DP, Olanow CW (1998) A fluorescent double-labeling method to detect and confirm apoptotic nuclei in Parkinson’s disease. Ann Neurol 44 Suppl 1: S142–S148Google Scholar
  56. Vawter MP, Dillon-Carter O, Tourtellotte WW, Carvey P, Freed WJ (1996) TGFßl and TGF132 concentrations are elevated in Parkinson’s disease in ventricular cerebrospinal fluid. Exp Neurol 142: 313–322PubMedCrossRefGoogle Scholar
  57. Wullner U, Kornhuber J, Weller M, Schulz JB, Loschmann PA, Riederer P, Klockgether T (1999) Cell death and apoptosis regulating proteins in Parkinson’s disease¡ªa cautionary note. Acta Neuropathol (Berl) 97: 408–412CrossRefGoogle Scholar
  58. Yurek DM, Lu W, Hipkens S, Wiegand SJ (1996) BDNF enhances the functional reinner-vation of the striatum by grafted fetal DA neurons. Exp Neurol 137: 105–118PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2000

Authors and Affiliations

  • T. Nagatsu
    • 1
  • M. Mogi
    • 2
  • H. Ichinose
    • 1
  • A. Togari
    • 2
  1. 1.Institute for Comprehensive Medical ScienceGraduate School of Medicine, Fujita Health UniversityToyoake, AichiJapan
  2. 2.Department of PharmacologySchool of Dentistry, Aichi-Gakuin UniversityNagoya, AichiJapan

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