Neurological Sciences

, Volume 32, Issue 1, pp 1–7 | Cite as

Role of glial cells in neurotoxin-induced animal models of Parkinson’s disease

  • Hironori Yokoyama
  • Hiroto Uchida
  • Hayato Kuroiwa
  • Jiro Kasahara
  • Tsutomu Araki
Review Article


Dopaminergic neurons are selectively vulnerable to oxidative stress and inflammatory attack. The neuronal cell loss in the substantia nigra is associated with a glial response composed markedly of activated microglia and, to a lesser extent, of reactive astrocytes although these glial responses may be the source of neurotrophic factors and can protect against oxidative stress such as reactive oxygen species and reactive nitrogen species. However, the glial response can also mediate a variety of deleterious events related to the production of pro-inflammatory, pro-oxidant reactive species, prostaglandins, cytokines, and so on. In this review, we discuss the possible protective and deleterious effects of glial cells in the neurodegenerative diseases and examine how these factors may contribute to the pathogenesis of Parkinson’s disease. This review suggests that further investigation concerning glial reaction in Parkinson’s disease may lead to disease-modifying therapeutic approaches and may contribute to the pathogenesis of this disease.


Parkinson’s disease Glia Oxidative stress Inflammation Cytokines Neurotrophic factors Neurodegeneration 



This study was supported in part by a Grant-in-Aid for Scientific Research (22590935) from the Ministry of Science and Education in Japan.

Conflict of interest

All authors have no conflict of interest.


  1. 1.
    Olanow CW, Schapira AH, Agid Y (2003) Neuroprotection for Parkinson’s disease: prospects and promises. Ann Neurol 53(Suppl 3):S1–S2CrossRefPubMedGoogle Scholar
  2. 2.
    Fahn S (2003) Description of Parkinson’s disease as a clinical syndrome. Ann NY Acad Sci 991:1–14CrossRefPubMedGoogle Scholar
  3. 3.
    Moore DJ, West AB, Dawson VL, Dawson TM (2005) Molecular pathophysiology of Parkinson’s disease. Annu Rev Neurosci 28:57–87CrossRefPubMedGoogle Scholar
  4. 4.
    McGeer PL, McGeer EG (2008) Glial reactions in Parkinson’s disease. Mov Disord 23:474–483CrossRefPubMedGoogle Scholar
  5. 5.
    Ransohoff RM, Perry VH (2009) Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol 27:119–145CrossRefPubMedGoogle Scholar
  6. 6.
    German DC, Manaye K, Smith WK et al (1989) Midbrain dopaminergic cell loss in Parkinson’s disease: computer visualization. Ann Neurol 26:507–514CrossRefPubMedGoogle Scholar
  7. 7.
    Ma Y, Dhawan V, Mentis M et al (2002) Parametric mapping of [18F]FPCIT binding in early stage Parkinson’s disease: a PET study. Synapse 45:125–133CrossRefPubMedGoogle Scholar
  8. 8.
    Langston SW, Altman NS, Hotchkiss JH (1993) Within and between sample comparisons of Gompertz parameters for Salmonella enteritidis and aerobic plate counts in chicken stored in air and modified atmosphere. Int J Food Microbiol 18:43–52CrossRefPubMedGoogle Scholar
  9. 9.
    Ballard PA, Tetrud JW, Langston JW (1985) Permanent human parkinsonism due to 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP): seven cases. Neurology 35:949–956PubMedGoogle Scholar
  10. 10.
    Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39:889–909CrossRefPubMedGoogle Scholar
  11. 11.
    Bové J, Prou D, Perier C, Przedborski S (2005) Toxin-induced models of Parkinson’s disease. NeuroRx 2:484–494CrossRefPubMedGoogle Scholar
  12. 12.
    Tipton KF, Singer TP (1993) Advances in our understanding of the mechanisms of the neurotoxicity of MPTP and related compounds. J Neurochem 61:1191–1206CrossRefPubMedGoogle Scholar
  13. 13.
    Gluck MR, Youngster SK, Ramsay RR et al (1994) Studies on the characterization of the inhibitory mechanism of 4’-alkylated 1-methyl-4-phenylpyridinium and phenylpyridine analogues in mitochondria and electron transport particles. J Neurochem 63:655–661CrossRefPubMedGoogle Scholar
  14. 14.
    Sriram K, Pai KS, Boyd MR, Ravindranath V (1997) Evidence for generation of oxidative stress in brain by MPTP: in vitro and in vivo studies in mice. Brain Res 749:44–52CrossRefPubMedGoogle Scholar
  15. 15.
    Zigmond MJ, Stricker EM (1989) Animal models of parkinsonism using selective neurotoxins: clinical and basic implications. Int Rev Neurobiol 31:1–79CrossRefPubMedGoogle Scholar
  16. 16.
    Heikkila RE, Manzino L, Cabbat FS, Duvoisin RC (1984) Protection against the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine by monoamine oxidase inhibitors. Nature 311:467–469CrossRefPubMedGoogle Scholar
  17. 17.
    Kurosaki R, Muramatsu Y, Kato H, Araki T (2004) Biochemical, behavioral and immunohistochemical alterations in MPTP-treated mouse model of Parkinson’s disease. Pharmacol Biochem Behav 78:143–153CrossRefPubMedGoogle Scholar
  18. 18.
    Yokoyama H, Takagi S, Watanabe Y et al (2008) Role of reactive nitrogen and reactive oxygen species against MPTP neurotoxicity in mice. J Neural Transm 115:831–842CrossRefPubMedGoogle Scholar
  19. 19.
    Lawson LJ, Perry VH, Dri P, Gordon S (1990) Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39:151–170CrossRefPubMedGoogle Scholar
  20. 20.
    Damier P, Hirsch EC, Zhang P et al (1993) Glutathione peroxidase, glial cells and Parkinson’s disease. Neuroscience 52:1–6CrossRefPubMedGoogle Scholar
  21. 21.
    Wilkin GP, Knott C (1999) Glia: a curtain raiser. Adv Neurol 80:3–7PubMedGoogle Scholar
  22. 22.
    Eddleston M, Mucke L (1993) Molecular profile of reactive astrocytes—implications for their role in neurologic disease. Neuroscience 54:15–36CrossRefPubMedGoogle Scholar
  23. 23.
    Gehrmann J, Matsumoto Y, Kreutzberg GW (1995) Microglia: intrinsic immuneffector cell of the brain. Brain Res Brain Res Rev 20:269–287CrossRefPubMedGoogle Scholar
  24. 24.
    Banati RB, Gehrmann J, Schubert P, Kreutzberg GW (1993) Cytotoxicity of microglia. Glia 7:111–118CrossRefPubMedGoogle Scholar
  25. 25.
    Forno LS, DeLanney LE, Irwin I et al (1992) Astrocytes and Parkinson’s disease. Prog Brain Res 94:429–436CrossRefPubMedGoogle Scholar
  26. 26.
    Mirza B, Hadberg H, Thomsen P, Moos T (2000) The absence of reactive astrocytosis is indicative of a unique inflammatory process in Parkinson’s disease. Neuroscience 95:425–432CrossRefPubMedGoogle Scholar
  27. 27.
    Giulian D, Woodward J, Young DG et al (1988) Interleukin-1 injected into mammalian brain stimulates astrogliosis and neovascularization. J Neurosci 8:2485–2490PubMedGoogle Scholar
  28. 28.
    Kohutnicka M, Lewandowska E, Kurkowska-Jastrzebska I et al (1988) Microglial and astrocytic involvement in a murine model of Parkinson’s disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Immunopharmacology 39:167–180CrossRefGoogle Scholar
  29. 29.
    Liberatore GT, Jackson-Lewis V, Vukosavic S et al (1999) Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Nat Med 5:1403–1409CrossRefPubMedGoogle Scholar
  30. 30.
    Aoki E, Yano R, Yokoyama H et al (2009) Role of nuclear transcription factor kappa B (NF-kappaB) for MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine)-induced apoptosis in nigral neurons of mice. Exp Mol Pathol 86:57–64CrossRefPubMedGoogle Scholar
  31. 31.
    Lindsay RM, Wiegand SJ, Altar CA, DiStefano PS (1994) Neurotrophic factors: from molecule to man. Trends Neurosci 17:182–190CrossRefPubMedGoogle Scholar
  32. 32.
    Tatton WG, Chalmers-Redman R, Brown D, Tatton N (2003) Apoptosis in Parkinson’s disease: signals for neuronal degradation. Ann Neurol 53(Suppl 3):S61–S70 (discussion S70–S72)CrossRefPubMedGoogle Scholar
  33. 33.
    Sawada M, Imamura K, Nagatsu T (2006) Role of cytokines in inflammatory process in Parkinson’s disease. J Neural Transm Suppl 70:373–381CrossRefPubMedGoogle Scholar
  34. 34.
    Mochizuki H, Mori H, Mizuno Y (1997) Apoptosis in neurodegenerative disorders. J Neural Transm Suppl 50:125–140PubMedGoogle Scholar
  35. 35.
    Tompkins MM, Basgall EJ, Zamrini E, Hill WD (1997) Apoptotic-like changes in Lewy-body-associated disorders and normal aging in substantia nigral neurons. Am J Pathol 150:119–131PubMedGoogle Scholar
  36. 36.
    Hunot S, Brugg B, Ricard D et al (1997) Nuclear translocation of NF-kappaB is increased in dopaminergic neurons of patients with Parkinson disease. Proc Natl Acad Sci USA 94:7531–7536CrossRefPubMedGoogle Scholar
  37. 37.
    Lin LF, Doherty DH, Lile JD et al (1993) GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 260:1130–1132CrossRefPubMedGoogle Scholar
  38. 38.
    Saavedra A, Baltazar G, Santos P et al (2006) Selective injury to dopaminergic neurons up-regulates GDNF in substantia nigra postnatal cell cultures: role of neuron-glia crosstalk. Neurobiol Dis 23:533–542CrossRefPubMedGoogle Scholar
  39. 39.
    Chen PS, Peng GS, Li G et al (2006) Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes. Mol Psychiatry 11:1116–1125CrossRefPubMedGoogle Scholar
  40. 40.
    Petrova P, Raibekas A, Pevsner J et al (2003) MANF: a new mesencephalic, astrocyte-derived neurotrophic factor with selectivity for dopaminergic neurons. J Mol Neurosci 20:173–188CrossRefPubMedGoogle Scholar
  41. 41.
    Hirsch EC, Hunot S, Damier P et al (1999) Glial cell participation in the degeneration of dopaminergic neurons in Parkinson’s disease. Adv Neurol 80:9–18PubMedGoogle Scholar
  42. 42.
    Chen Y, Vartiainen NE, Ying W et al (2001) Astrocytes protect neurons from nitric oxide toxicity by a glutathione-dependent mechanism. J Neurochem 77:1601–1610CrossRefPubMedGoogle Scholar
  43. 43.
    Dobrenis K (1998) Microglia in cell culture and in transplantation therapy for central nervous system disease. Methods 16:320–344CrossRefPubMedGoogle Scholar
  44. 44.
    Kim WG, Mohney RP, Wilson B et al (2000) Regional difference in susceptibility to lipopolysaccharide-induced neurotoxicity in the rat brain: role of microglia. J Neurosci 20:6309–6316PubMedGoogle Scholar
  45. 45.
    Ouchi Y, Yoshikawa E, Sekine Y et al (2005) Microglial activation and dopamine terminal loss in early Parkinson’s disease. Ann Neurol 57:168–175CrossRefPubMedGoogle Scholar
  46. 46.
    Gerhard A, Pavese N, Hotton G et al (2006) In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson’s disease. Neurobiol Dis 21:404–412CrossRefPubMedGoogle Scholar
  47. 47.
    Koutsilieri E, Scheller C, Grünblatt E et al (2002) Free radicals in Parkinson’s disease. J Neurol 249(Suppl 2):II1–II5PubMedGoogle Scholar
  48. 48.
    Jenner P (2003) Oxidative stress in Parkinson’s disease. Ann Neurol 3(Suppl 3):S26–S36 (discussion S36–S38)CrossRefGoogle Scholar
  49. 49.
    Jana S, Maiti AK, Bagh MB et al (2007) 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 Res 1139:195–200CrossRefPubMedGoogle Scholar
  50. 50.
    McGeer PL, Schwab C, Parent A, Doudet D (2003) Presence of reactive microglia in monkey substantia nigra years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration. Ann Neurol 54:599–604CrossRefPubMedGoogle Scholar
  51. 51.
    Sugama S, Yang L, Cho BP et al (2003) Age-related microglial activation in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurodegeneration in C57BL/6 mice. Brain Res 964:288–294CrossRefPubMedGoogle Scholar
  52. 52.
    Cicchetti F, Brownell AL, Williams K et al (2002) Neuroinflammation of the nigrostriatal pathway during progressive 6-OHDA dopamine degeneration in rats monitored by immunohistochemistry and PET imaging. Eur J Neurosci 15:991–998CrossRefPubMedGoogle Scholar
  53. 53.
    Depino AM, Earl C, Kaczmarczyk E et al (2003) Microglial activation with atypical proinflammatory cytokine expression in a rat model of Parkinson’s disease. Eur J Neurosci 18:2731–2742CrossRefPubMedGoogle Scholar
  54. 54.
    Iravani MM, Kashefi K, Mander P et al (2002) Involvement of inducible nitric oxide synthase in inflammation-induced dopaminergic neurodegeneration. Neuroscience 110:49–58CrossRefPubMedGoogle Scholar
  55. 55.
    Arimoto T, Bing G (2003) Up-regulation of inducible nitric oxide synthase in the substantia nigra by lipopolysaccharide causes microglial activation and neurodegeneration. Neurobiol Dis 12:35–45CrossRefPubMedGoogle Scholar
  56. 56.
    Ryu JK, Shin WH, Kim J et al (2002) Trisialoganglioside GT1b induces in vivo degeneration of nigral dopaminergic neurons: role of microglia. Glia 38:15–23CrossRefPubMedGoogle Scholar
  57. 57.
    He Y, Le WD, Appel SH (2002) Role of Fcgamma receptors in nigral cell injury induced by Parkinson disease immunoglobulin injection into mouse substantia nigra. Exp Neurol 176:322–327CrossRefPubMedGoogle Scholar
  58. 58.
    Qin L, Wu X, Block ML et al (2007) Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 55:453–462CrossRefPubMedGoogle Scholar
  59. 59.
    Greenamyre JT, MacKenzie G, Peng TI, Stephans SE (1999) Mitochondrial dysfunction in Parkinson’s disease. Biochem Soc Symp 66:85–97PubMedGoogle Scholar
  60. 60.
    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 38:1285–1291PubMedGoogle Scholar
  61. 61.
    Burke RE, Antonelli M, Sulzer D (1998) Glial cell line-derived neurotrophic growth factor inhibits apoptotic death of postnatal substantia nigra dopamine neurons in primary culture. J Neurochem 71:517–525CrossRefPubMedGoogle Scholar
  62. 62.
    Kordower JH, Palfi S, Chen EY et al (1999) Clinicopathological findings following intraventricular glial-derived neurotrophic factor treatment in a patient with Parkinson’s disease. Ann Neurol 46:419–424CrossRefPubMedGoogle Scholar
  63. 63.
    Gash DM, Zhang Z, Ovadia A et al (1996) Functional recovery in parkinsonian monkeys treated with GDNF. Nature 380:252–255CrossRefPubMedGoogle Scholar
  64. 64.
    Eberhardt O, Coelln RV, Kugler S et al (2000) Protection by synergistic effects of adenovirus-mediated X-chromosome-linked inhibitor of apoptosis and glial cell line-derived neurotrophic factor gene transfer in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease. J Neurosci 20:9126–9134PubMedGoogle Scholar
  65. 65.
    Kordower JH, Emborg ME, Bloch J et al (2000) Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson’s disease. Science 290:767–773CrossRefPubMedGoogle Scholar
  66. 66.
    Frim DM, Uhler TA, Galpern WR et al (1994) Implanted fibroblasts genetically engineered to produce brain-derived neurotrophic factor prevent 1-methyl-4-phenylpyridinium toxicity to dopaminergic neurons in the rat. Proc Natl Acad Sci USA 91:5104–5108CrossRefPubMedGoogle Scholar
  67. 67.
    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
  68. 68.
    Przedborski S, Jackson-Lewis V, Djaldetti R et al (2000) The parkinsonian toxin MPTP: action and mechanism. Restor Neurol Neurosci 16:135–142PubMedGoogle Scholar
  69. 69.
    Schulz JB, Lindenau J, Seyfried J, Dichgans J (2000) Glutathione, oxidative stress and neurodegeneration. Eur J Biochem 267:4904–4911CrossRefPubMedGoogle Scholar
  70. 70.
    Benazzouz A, Piallat B, Ni ZG et al (2000) Implication of the subthalamic nucleus in the pathophysiology and pathogenesis of Parkinson’s disease. Cell Transplant 9:215–221PubMedGoogle Scholar
  71. 71.
    DeLong MR (1990) Primate models of movement disorders of basal ganglia origin. Trends Neurosci 13:281–285CrossRefPubMedGoogle Scholar
  72. 72.
    Yamada T, McGeer PL, McGeer EG (1992) Lewy bodies in Parkinson’s disease are recognized by antibodies to complement proteins. Acta Neuropathol 84:100–104CrossRefPubMedGoogle Scholar
  73. 73.
    Yamada T, McGeer PL, McGeer EG (1992) Some immunohistochemical features of argyrophilic grain dementia with normal cortical choline acetyltransferase levels but extensive subcortical pathology and markedly reduced dopamine. J Geriatr Psychiatry Neurol 5:3–13PubMedGoogle Scholar
  74. 74.
    Hisahara S, Okano H, Miura M (2003) Caspase-mediated oligodendrocyte cell death in the pathogenesis of autoimmune demyelination. Neurosci Res 46:387–397CrossRefPubMedGoogle Scholar
  75. 75.
    Melcangi RC, Magnaghi V, Cavarretta I et al (1998) Effects of steroid hormones on gene expression of glial markers in the central and peripheral nervous system: variations induced by aging. Exp Gerontol 33:827–836CrossRefPubMedGoogle Scholar
  76. 76.
    Tanaka J, Okuma Y, Tomobe K, Nomura Y (2005) The age-related degeneration of oligodendrocytes in the hippocampus of the senescence-accelerated mouse (SAM) P8: a quantitative immunohistochemical study. Biol Pharm Bull 28:615–618CrossRefPubMedGoogle Scholar
  77. 77.
    Irving EA, Yatsushiro K, McCulloch J, Dewar D (1997) Rapid alteration of tau in oligodendrocytes after focal ischemic injury in the rat: involvement of free radicals. J Cereb Blood Flow Metab 17:612–622CrossRefPubMedGoogle Scholar
  78. 78.
    McCracken E, Fowler JH, Dewar D et al (2002) Grey matter and white matter ischemic damage is reduced by the competitive AMPA receptor antagonist, SPD 502. J Cereb Blood Flow Metab 22:1090–1097CrossRefPubMedGoogle Scholar
  79. 79.
    Gresle MM, Jarrott B, Jones NM, Callaway JK (2006) Injury to axons and oligodendrocytes following endothelin-1-induced middle cerebral artery occlusion in conscious rats. Brain Res 1110:13–22CrossRefPubMedGoogle Scholar
  80. 80.
    Dewar D, Dawson D (1995) Tau protein is altered by focal cerebral ischaemia in the rat: an immunohistochemical and immunoblotting study. Brain Res 684:70–78CrossRefPubMedGoogle Scholar
  81. 81.
    Imai H, Masayasu H, Dewar D et al (2001) Ebselen protects both gray and white matter in a rodent model of focal cerebral ischemia. Stroke 32:2149–2154CrossRefPubMedGoogle Scholar
  82. 82.
    Vlkolinský R, Cairns N, Fountoulakis M, Lubec G (2001) Decreased brain levels of 2′, 3′-cyclic nucleotide-3′-phosphodiesterase in Down syndrome and Alzheimer’s disease. Neurobiol Aging 22:547–553CrossRefPubMedGoogle Scholar
  83. 83.
    Takagi S, Hayakawa N, Kimoto H et al (2007) Damage to oligodendrocytes in the striatum after MPTP neurotoxicity in mice. J Neural Transm 114:1553–1557CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Hironori Yokoyama
    • 1
  • Hiroto Uchida
    • 1
  • Hayato Kuroiwa
    • 1
  • Jiro Kasahara
    • 1
  • Tsutomu Araki
    • 1
  1. 1.Department of Neurobiology and Therapeutics, Graduate School and Faculty of Pharmaceutical SciencesThe University of TokushimaTokushimaJapan

Personalised recommendations