Neural transplantation in animal models of multiple system atrophy: a review

  • G. K. Wenning
  • R. Granata
  • Z. Puschban
  • C. Scherfler
  • W. Poewe
Conference paper
Part of the 6th International Winter Conference on N eurodegeneration book series (NEURAL SUPPL, volume 55)


Multiple system atrophy of the striatonigral degeneration (MSA-SND) type is increasingly recognized as major cause of neurodegenerative parkinsonism. Due to combined degeneration of substantia nigra pars compacta (SNC) and of striatum, antiparkinsonian therapy based on levodopa substitution eventually fails in more than 90% of patients. Animal models of MSA-SND are urgently required as test-bed for the evaluation of novel therapeutic interventions in this disorder such as neurotrophic factor delivery and neuronal transplantation. A number of well established rodent and primate models of Parkinson’s (PD) and Huntington’s (HD) disease replicate either nigral (“PD-like”) or striatal (“HD-like”) pathology and may therefore provide a useful baseline for the development of MSA-SND models. Previous attempts to mimick MSA-SND pathology in rodents have included sequential injections of 6-hydroxydopamine (6OHDA) and quinolinic acid (QA) into medial forebrain bundle and ipsilateral striatum, respectively (“double toxin — double lesion” approach). Preliminary evidence in rodents subjected to such lesions indicates that embryonic transplantation may partially reverse behavioural abnormalities. Intrastriatal injections of mitochondrial toxins such as 3-nitropropionic acid (3NP) and l-methyl-4-phenylpyridinium (MPP+) in rodents result in (secondary) excitotoxic striatal lesions and subtotal neuronal degeneration of ipsilateral SNC, thus producing MSA-SND-like pathology by a simplified “single toxin — double lesion” approach. Comparative studies of human SND pathology and rodent striatonigral lesions are required in order to determine the rodent model(s) most closely mimicking the human disease process.


Multiple System Atrophy Quinolinic Acid Glial Cell Line Derive Neurotrophic Factor Intrastriatal Injection Striatal Lesion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Anderson KD, Panayotatos N, Coran TL, Lindsay RM, Wiegand SJ (1996) Ciliary neurotrophic factor protects striatal output neurons in an animal model of Huntington disease. Proc Natl Acad Sci USA 93: 7346–7351.PubMedCrossRefGoogle Scholar
  2. Beal MF, Kowall NW, Ellison DW, Mazurek MF, Swartz KJ, Martin JB (1986) Replication of the neurochemical characteristics of Huntington’s disease by quinolinic acid. Nature 321: 168–171.PubMedCrossRefGoogle Scholar
  3. Beal MF, Kowall NW, Swartz KJ, Ferrante RJ, Martin JB (1989) Differential sparing of somatostatin-neuropeptide Y and cholinergic neurons following striatal excitotoxic lesions. Synapse 3: 38–47.PubMedCrossRefGoogle Scholar
  4. Beal MF, Brouillet E, Jenkins BG, Ferrante RJ, Kowall NW, Miller JM, Storey E, Srivastava R, Rosen BR, Hyman BT (1993) Neurochemical and histologic characterization of striatal excitotoxic lesions produced by mitochondrial toxin 3-nitropropionic acid. J Neurosci 13: 4181–4192.PubMedGoogle Scholar
  5. Bloem BR, Irwin I, Buruma OJ, Haan J, Roos RA, Tetrud JW, Langston JW (1990) The MPTP model: versatile contributions to the treatment of idiopathic Parkinson’s disease. J Neurol Sci 97: 273–293.PubMedCrossRefGoogle Scholar
  6. Brouillet E, Hantraye P (1995) Effects of chronic MPTP and 3-nitropropionic acid in nonhuman primates. Curr Opin Neurol 8: 469–473.PubMedCrossRefGoogle Scholar
  7. Brundin P, Isacson O, Gage FH, Björklund A (1986) Intrastriatal grafting of dopaminecontaining neuronal cell suspensions: effects of mixing with target or non-target cells. Brain Res 389: 77–84.PubMedGoogle Scholar
  8. Choi-Lundberg DL, Lin Q, Chang YN, Chiang YL, Hay CM, Mohajeri H, Davidson BL, Boh MC (1997) Dopaminergic neurons protected from degeneration by GDNF gene therapy. Science 275: 838–841.PubMedCrossRefGoogle Scholar
  9. Costantini LC, Snyder-Keller A (1997) Co-transplantation of fetal lateral ganglionic eminence and ventral mesencephalon can augment function and development of intrastriatal transplants. Exp Neurol 145: 214–227.PubMedCrossRefGoogle Scholar
  10. Costantini LC, Vozza BM, Snyder-Keller AM (1994) Enhanced efficacy of nigral-striatal cotransplants in bilaterally dopamine-depleted rats: an anatomical and behavioral analysis. Exp Neurol 127: 219–231.PubMedCrossRefGoogle Scholar
  11. Daniel SE (1992) Multiple system atrophy. In: Bannister R, Mathias C (eds) Autonomie failure — a textbook of clinical disorders of autonomie nervous system. Oxford Medical Publications, Oxford, pp 564–585.Google Scholar
  12. Deutch AY, Rosin DL, Goldstein M, Roth RH (1989) 3-Acetylpyridine-induced degeneration of the nigrostriatal dopamine system: an animal model of olivopontocerebellar atrophy-associated parkinsonism. Exp Neurol 105: 1–9.PubMedCrossRefGoogle Scholar
  13. Emerich DW, Winn SR, Hantraye PM, Peschanski M, Chen EY, Chu Y, McDermott P, Baetge EE, Kordower JH (1997) Protective effect of encapsulated cells producing neurotrophic factor CNTF in a monkey model of Huntington’s disease. Nature 386: 395–399.PubMedCrossRefGoogle Scholar
  14. Fearnley JM, Lees AJ (1990) Striatonigral degeneration. A clinicopathological study. Brain 113: 1823–1842.PubMedCrossRefGoogle Scholar
  15. Frim DM, Uhler TA, Galpern WR, Beal MF, Breakefield XO, Isacson O (1994) Implanted fibroblasts genetically engineered to produce brain-derived neurotrophic factor prevent 1-methyl-4-phenylpyridium toxicity to dopaminergic neurons in the rat. Proc Natl Acad Sci USA 91: 5104–5108.PubMedCrossRefGoogle Scholar
  16. Galpern WR, Frim DM, Tatter SB, Altar CA, Beal MF, Isacson O (1996) Cellmediated delivery of brain-derived neurotrophic factor enhances dopamine levels in an MPP+ rat model of substantia nigra degeneration. Cell Transplant 5: 225–232.PubMedCrossRefGoogle Scholar
  17. Gash DM, Zhang Z, Ovadi A, Cass WA, Yi A, Simmerman L, Russell D, Martin D, Lapchak PA, Collins F, Hoffer BJ, Gerhardt GA (1996) Functional recovery in parkinsonian monkeys treated with GDNF. Nature 380: 252–255.PubMedCrossRefGoogle Scholar
  18. Goto S, Hirano A, Matsumoto S (1989a) Subdivisional involvment of nigrostriatal loop in idiopathic Parkinson’s disease and striatonigral degeneration. Ann Neurol 26: 766–770.PubMedCrossRefGoogle Scholar
  19. Goto S, Hirano A, Rojas-Corona RR (1989b) Immunohistochemical visualization of afferent nerve terminals in human globus pallidus and ist alteration in neostriatal neurodegenerative disorders. Acta Neuropathol (Berl) 78: 543–550.CrossRefGoogle Scholar
  20. Hantraye P, Riche D, Maziere M, Isacson O (1990) A primate model of Huntington’s disease: behavioural and anatomical studies of unilateral excitotoxic lesions of the caudate-putamen in the baboon. Exp Neurol 108: 91–104.PubMedCrossRefGoogle Scholar
  21. Huang Q, Zhou D, Sapp E, Aizawa H, Ge P, Bird ED, Vonsattel JP, DiFiglia M (1995) Quinolinic acid-induced increases in calbindin D28k immunoreactivity in rat striatal neurons in vivo and in vitro mimic the pattern seen in Huntington’s disease. Neuroscience 65: 397–407.PubMedCrossRefGoogle Scholar
  22. Javitch JA, D’Amato RJ, Strittmatter SM, Snyder SH (1985) Parkinsonism inducing neurotoxin, N-methyl-4-phenyl-l,2,3,6-tetrahydropyridine: uptake of the metabolite N-methyl-4-phenylpyridine by dopamine neurons explains selective toxicity. Proc Natl Acad Sci USA 82: 2173–2177.PubMedCrossRefGoogle Scholar
  23. Kato S, Nakamura H (1990) Cytoplasmic argyrophilic inclusions in neurons of pontine nuclei in patients with olivopontocerebellar atrophy: Immunohistochemical and ultrastructural studies. Acta Neuropathol (Berl) 79: 584–594.CrossRefGoogle Scholar
  24. Lantos PL (1997) Multiple system atrophy. Brain Pathol 7: 1293–1297.CrossRefGoogle Scholar
  25. Lapchak PL, Araujo DM, Hilt DC, Scheng J, Jiao S (1997) Adenoviral vector-mediated GDNF gene therapy in a rodent lesion model of late stage Parkinson’s disease. Brain Res 777: 153–160.PubMedCrossRefGoogle Scholar
  26. Martinez-Serrano A, Björklund A (1996) Protection of the neostriatum against excitotoxic damage by neurotrophin-producing, genetically modified neural stem cells. J Neurosci 16: 4604–4616.PubMedGoogle Scholar
  27. Nakao N, Brundi P (1997) Effects of alpha-phenyl-tert-butyl nitrone on neuronal survival and motor function following intrastriatal injections of quinolinate or 3-nitropropionic acid. Neuroscience 76: 749–761.PubMedCrossRefGoogle Scholar
  28. Olanow CW, Kordower JH, Freeman TB (1996) Fetal nigral transplantation as a therapy for Parkinson’s disease. Trends Neurosci 19: 102–109.PubMedCrossRefGoogle Scholar
  29. Papp MI, Lantos PL (1992) Accumulation of tubular structures in oligodendroglial and neuronal cells as the basic alteration in multiple system atrophy. J Neurol Sci 107: 172–182.PubMedCrossRefGoogle Scholar
  30. Papp MI, Lantos PL (1994) The distribution of oligodendroglial inclusions in multiple system atrophy and ist relevance to clinical symptomatology. Brain 117: 235–243.PubMedCrossRefGoogle Scholar
  31. Papp MI, Kahn JE, Lantos PL (1989) Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager Syndrom). J Neurol Sci 94: 79–100.PubMedCrossRefGoogle Scholar
  32. Perez-Navarro E, Arenas E, Reiriz J, Calvo N, Alberch J (1996) Glial cell line-derived neurotrophic factor protects striatal calbindin-immunoreactive neurons from excitotoxic damage. Neuroscience 75: 345–352.PubMedCrossRefGoogle Scholar
  33. Peschanski M, Cesaro P, Hantraye P (1996) What is needed versus what would be interesting to know bevor undertaking neural transplantation in patients with Huntington’s disease. Neuroscience 71: 899–900.PubMedCrossRefGoogle Scholar
  34. Pifl C, Giros B, Caron MG (1993) Dopamine transporter expression confers cytotoxicity to low doses of the parkinsonism-inducing neurotoxin l-methyl-4-phenylpyridinium. J Neurosci 13: 4246–4253.PubMedGoogle Scholar
  35. Probst-Cousin S, Rickert CH, Schmid KW, Gullotta F (1998) Cell death mechanisms in multiple system atrophy. J Neuropathol Exp Neurol 57: 814–821.PubMedCrossRefGoogle Scholar
  36. Quinn NP (1994) Multiple system atrophy. In: Marsden CD, Fahn S (eds) Movement disorders, vol 3. Butterworth-Heinemann, London, pp 262–281.Google Scholar
  37. Sauer H, Oertel WH (1994) Progressive degeneration of nigrostriatal dopaminergic neurons following intrastriatal terminal lesions with 6-hydroxydopamine: a combined retrograde tracing and immunocytochemical study in the rat. Neuroscience 59: 401–415.PubMedCrossRefGoogle Scholar
  38. Schulz JB, Hensha DR, Jenkin BG, Ferrant RJ, Kowal NW, Rose BR, Beal M (1994) 3-Acetylpyridine produces age-dependent excitotoxic lesions in the rat striatum. J Cereb Blood Flow Metab 14: 1024–1029.PubMedCrossRefGoogle Scholar
  39. Sonsalla PK, Giovanni A, Sieber BA, Donne KD, Manzino L (1992) Characteristics of dopaminergic neurotoxicity produced by MPTP and metamphetamine. Ann N Y Acad Sci 648: 229–238.PubMedCrossRefGoogle Scholar
  40. Spokes EG, Bannister R, Oppenheimer DR (1979) Multiple system atrophy with autonomie failure — clinical, histological and neurochemical observations on four cases. J Neurol Sci 43: 59–82.PubMedCrossRefGoogle Scholar
  41. Storey E, Hyman BT, Jenkins B, Brouillet E, Miller JM, Rosen BR, Beal MF (1992) 1-Methyl-4-phenylpyridinium produces excitotoxic lesions in rat striatum as a result of impairment of oxidative metabolism. J Neurochem 58: 1975–1978.PubMedCrossRefGoogle Scholar
  42. Sundstrom E, Goldstein M, Jonsson G (1986) Uptake inhibition protects nigro-striatal dopamine neurons from the neurotoxicity of l-methyl-4-phenylpyridine (MPP+) in mice. Eur J Pharmacol 131: 289–292.PubMedCrossRefGoogle Scholar
  43. Takada M, Kono T (1993) 3-Acetylpyridine neurotoxicity to the nigrostriatal dopamine system in mice. Neurosci Lett 161: 211–214.PubMedCrossRefGoogle Scholar
  44. Tison F, Wenning GK, Daniel SE, Quinn NP (1995) The pathophysiology of parkinsonism in multiple sytem atrophy. Eur J Neurol 2: 435–444.CrossRefGoogle Scholar
  45. Wenning GK, Ben-Shlomo Y, Magalhaes M, Daniel SE, Quinn NP (1994) Clinical features and natural history of multiple system atrophy. An analysis of 100 cases. Brain 117: 835–845.PubMedCrossRefGoogle Scholar
  46. Wenning GK, Granata R, Laboyrie PM, Quinn NP, Jenner P, Marsden CD (1996a) Reversal of behavioural abnormalities by fetal allografts in a novel rat model of striatonigral degeneration. Mov Disord 11: 522–532.PubMedCrossRefGoogle Scholar
  47. Wenning GK, Laboyrie P, Granata R, Quinn NP, Jenner P, Marsden CD (1996b) Reversal of behavioural abnormalities in a rat model of striatonigral degeneration following intrastriatal transplantation of pure mesencephalic and mesencephalic-striatal cografts. Mov Disord 11: 44 (abstract).Google Scholar
  48. Wenning GK, Tison F, Elliott L, Quinn NP, Daniel SE (1996c) Olivopontocerebellar pathology in multiple system atrophy. Mov Disord 11: 157–162.PubMedCrossRefGoogle Scholar
  49. Wenning GK, Odin P, Morrish P, Rehncrona S, Widner H, Brundin P, Rothwell JC, Brown R, Gustavii B, Hagell P, Jahanshahi M, Sawle G, Björklund A, Brooks DJ, Marsden CD, Quinn NP, Lindvall O (1997a) Short-and long-term survival and function of unilateral intrastriatal dopaminergic grafts in Parkinson’s disease. Ann Neurol 42: 95–107.PubMedCrossRefGoogle Scholar
  50. Wenning GK, Quinn NP (1997b) Parkinsonism. Multiple system atrophy. Baillieres Clin Neurol 6: 187–204.PubMedGoogle Scholar
  51. Winkler C, Sauer H, Lee CS, Björklund A (1996) Short-term GDNF treatment provides long-term rescue of lesioned nigral dopaminergic neurons in a rat model of Parkinson’s disease. J Neurosci 16: 7206–7215.PubMedGoogle Scholar
  52. Wüllner U, Young AB, Penney JB, Beal MF (1994) 3-Nitropropionic acid toxicity in the striatum. J Neurochem 63: 1772–1781.PubMedCrossRefGoogle Scholar
  53. Wüllner U, Weiler N, Groscurt P, Loschmann PA, Schulz JB, Müller I, Klockgether T (1997) Evidence for an active type of cell death with ultrastructural features distinct from apoptosis: the effects of 3-acetylpyridine neurotoxicity. Neuroscience 81: 721–734.PubMedCrossRefGoogle Scholar
  54. Yurek DM, Collier TJ, Sladek JR jr (1990) Embryonic mesencephalic and striatal cografts: development of grafted dopamine neurons and functional recovery. Exp Neurol 109:191–199.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag/Wien 1999

Authors and Affiliations

  • G. K. Wenning
    • 1
  • R. Granata
    • 1
  • Z. Puschban
    • 1
  • C. Scherfler
    • 1
  • W. Poewe
    • 1
  1. 1.Neurological Research Laboratory, Department of NeurologyUniversity HospitalInnsbruckAustria

Personalised recommendations