Transplantation of dopamine-synthesizing cells—new therapy for Parkinson’s disease?

Comparison of strategies
  • W. H. Oertel
  • C. D. Marsden
Conference paper
Part of the Key Topics in Brain Research book series (KEYTOPICS)


In extensive research on rodents and in preliminary studies on nonhuman primates, allogeneic embryonic ventral mesencephalic grafts are superior to allogeneic adult adrenal medullary grafts in respect to intrastriatal graft survival and functional effectiveness in animal models of Parkinson syndrome. Intrastriatal grafting of Parkinson patients with their own adrenal medulla has so far given discrepant results. The adrenal medulla itself appears to be affected by Parkinson’s disease. Transplantation of embryonic ventral mesencephalic tissue raises ethical concern. Issues such as method of application, target areas and long term immunological graft-host reaction await further research in non-human primates. In the future, catecholamine-synthesizing cell lines may provide a valid alternative to presently considered donor tissue.


Nerve Growth Factor Nonhuman Primate Adrenal Medulla Donor Tissue Ventral Mesencephalon 
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.


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  1. Alexander GE, DeLong MR, Strick PL (1986) Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Ann Rev Neurosci 9: 357–381PubMedCrossRefGoogle Scholar
  2. Anderson DJ, Axel R (1986) A bipotential neuroendocrine precursor whose choice of cell fate is determined by NGF and glucocorticoids. Cell 47: 1079–1090PubMedCrossRefGoogle Scholar
  3. Backlund E-O, Granberg PO, Hamberger B, Knutsson E, Martensson A, Sedvall G, Seiger A, Olson L (1985) Transplantation of adrenal medullary tissue to striatum in parkinsonism. J Neurosurg 62: 169–173PubMedCrossRefGoogle Scholar
  4. Bakay RAE, Sweeney KM, Colbassani HJ, Collins DC (1988) Delayed stereo-tactic transplantation technique in primates. In: Gash DM, SladekJRJr (eds) Transplantation into the mammalian CNS: preclinical and clinical studies. Prog Brain Res 74 (in press)Google Scholar
  5. Ballard PA, Tertrud JW, Langston JW (1985) Permanent human parkinsonism due to 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine ( MPTP ). Neurology 35: 949–956Google Scholar
  6. Bankiewicz KS, Plunkett RJ, Oldfield EH, Jacobowitz DM, Porrino LJ, Vaidya U, Di Porzio U, Schuette WH, Markowitz A, London WT, Kopin IJ (1988) Transient and long term functional improvement by adrenal and fetal mesencephalic implants into caudate nuclei of MPTP parkinsonian monkeys. In: Gash DM, SladekJRJr (eds) Transplantation into the mammalian CNS: preclinical and clinical studies. Prog Brain Res 74 (in press)Google Scholar
  7. Barbin G, Katz DM, Chamak B, Glowinski J, Prochiantz A (1988) Brain astrocytes express region-specific surface glycoproteins in culture. Glia 1: 96–103PubMedCrossRefGoogle Scholar
  8. Berger B, Di Porzio MC, Daguet M-C, Gay M, Vigny A, Glowinski J, Prochiantz A (1982) Long-term development of mesencephalic dopaminergic neurons of mouse embryos in dissociated primary cultures: morphological and histochemical characteristics. Neuroscience 7: 193206Google Scholar
  9. Björklund A, Stenevi U (eds) (1985) Neural grafting in the mammalian CNS. Elsevier, AmsterdamGoogle Scholar
  10. Björklund A, Lindvall O, Isacson O, Brundin P, Wictorin K, Strecker RE, Clarke DJ, Dunnett SB (1987) Mechanisms of action of intracerebral neural implants: studies on nigral and striatal grafts to the lesioned striatum. Trends Neurosci 10: 509–516CrossRefGoogle Scholar
  11. Bohn MC, Cupit L, Marciano F, Gash DM (1987) Adrenal medulla grafts enhance recovery of striatal dopaminergic fibers. Science 237: 913–916PubMedCrossRefGoogle Scholar
  12. Brundin P, Nilsson OG, Gage FH, Björklund A (1985 a) Cyclosporin A increases survival of cross-species intrastriatal grafts of embryonic dopamine-containing neurons. Exp Brain Res 60: 204–208Google Scholar
  13. Brundin P, Barbin G, Isacson 0, Mallat M, Chamak B, Prochiantz A, Gage FH, Björklund A (1985 b) Survival of intracerebrally grafted rat dopamine neurons previously cultured in vitro. Neurosci Lett 61: 79–84Google Scholar
  14. Brundin P, Nilsson OG, Strecker RE, Lindvall O, Astedt B, Björklund A (1986) Behavioural effects of human fetal dopamine neurons grafted in a rat model of Parkinson’s disease. Exp Brain Res 65: 235–240PubMedCrossRefGoogle Scholar
  15. Brundin P, Barbin G, Strecker RE, Isacson O, Prochiantz A, Björklund A (1988 a) Survival and function of dissociated rat dopamine neurones grafted at different developmental stages or after being cultured in vitro. Develop Brain Res 39: 233–243Google Scholar
  16. Brundin P, Strecker RE, Widner H, Clarke DJ, Nilsson OG, Astedt B, Lindvall 0, Björldund A (1988 b) Human fetal dopamine neurons grafted in a rat model of Parkinson’s disease: immunological aspects, spontaneous and drug-induced behaviour, and dopamine release. Exp Brain Res 70: 192–208Google Scholar
  17. Brundin P, Strecker RE, Lindvall 0, Isacson 0, Nilsson OG, Barbin G, Prochiantz A, Forni C, Nieoullon A, Widner H, Gage FH, Björklund A (1988 c) Intracerebral grafting of dopamine neurons: experimental basis for clinical trials in patients with Parkinson’s disease. In: Gash DM, Sladek JR Jr (eds) Transplantation into the mammalian CNS: preclinical and clinical studies. Prog Brain Res 74 (in press)Google Scholar
  18. Burns RS, Chiueh CC, Markey SP, Ebert MH, Jacobowitz DM, Kopin IJ (1983) A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine. Proc Nat Acad Sci (USA) 80: 4546–4550Google Scholar
  19. Carmicheal SW, Wilson RJ, Brimijoin WS, Melton LJ III, Okazaki H, Yaksh TL, Ahlskog JE, Stoddard SL, Tyce GM (1988) Decreased catecholamines in the adrenal medulla of patients with Parkinsonism. New Engl J Med 318: 254Google Scholar
  20. Carvey PM, Kroin JS, Zhang TJ, O’Dorisio TM, Yaksh TL, McRea A, Dahlstrom A, Kao LC, Penn RD, Goetz CG, Tanner CM, Shannon KMGoogle Scholar
  21. Klawans HL (1988) Biochemical and immunochemical characterization of ventricular CSF from Parkinson’s disease (PD) patients with adrenal medulla transplants in the patients. Neurology 38 [Suppl] 1: 144Google Scholar
  22. Chamak B, Fellous A, Autillo-Touati, Barbin G, Prochiantz A (1987) Are neuronotrophic neuron-astrocyte interactions regionally specified? Ann NY Acad 495: 528–535CrossRefGoogle Scholar
  23. Collier TJ, Gallagher MJ, Sladek CD, Blanchard BC, Daley BF, Foster PN, Redmond DE Jr, Roth RH, SladekJRJr (1988) Cryopreservation of fetal rat and non-human primate mesencephalic neurons: viability in culture and neural transplantation. In: Gash DM, Sladek JR Jr (eds) Transplantation into the mammalian CNS: preclinical and clinical studies. Prog Brain Res 74Google Scholar
  24. Craig SP, Buckle VJ, Lamourous A, Mallet J, Craig I (1986) Localization of the human tyrosine hydroxylase gene to 11 p 15: gene duplication and evolution of metabolic pathways. Cytogenet Cell Genet 42: 29–32PubMedCrossRefGoogle Scholar
  25. Den Hartog Jager WA (1970) Histochemistry of adrenal bodies in Parkinson’s disease. Arch Neurol 23: 528–533Google Scholar
  26. Di Porzio U, Daguet MC, Glowinski J, Prochiantz A (1980) Effect of striatal cells on in vivo maturation of mesencephalic dopaminergic neurons grown in serum-free conditions. Nature 288: 370–373PubMedCrossRefGoogle Scholar
  27. Di Porzio U, Rougon G, Novotny EA, Barker JL (1987) Dopaminergic neurons from embryonic mouse mesencephalon are enriched in culture through immunoreaction with monoclonal antibody to neural specific protein 4 and flow cytometry. Proc Nat Acad Sci (USA) 84: 7334–7338CrossRefGoogle Scholar
  28. Elsworth JD, Redmond DE Jr, Deutch AY, Collier TJ, SladekJRJr, Roth RH (1988) Dopamine production by fetal neuron transplants in the caudate nucleus of the MPTP-treated primate. In: Gash DM, Sladek JR Jr (eds) Transplantation into the mammalian CNS: preclinical and clinical studies. Prog Brain Res 74 (in press)Google Scholar
  29. Fiandaca MS, Bakay RAE, Sweeney KM, Chan WC (1988) Immunologic response to intracerebral fetal neural allografts in the rhesus monkey. In: Gash DM, SladekJRJr (eds) Transplantation into the mammalian CNS: preclinical and clinical studies. Prog Brain Res 74 (in press)Google Scholar
  30. Fine A, Oertel WH, Hunt S, Chong PN, Nomoto M, Waters CM, Temlett J, Dunett S, Annett L, Jenner P, Marsden CD (1988) Transplantation of embryonic marmoset dopaminergic neurons to the corpus striatum of marmosets rendered parkinsonian by MPTP. In: Gash DM, SladekJRJr (eds) Transplantation into the mammalian CNS: preclinical and clinical studies. Prog Brain Res 74 (in press)Google Scholar
  31. Freed WJ, Morihisa JM, Spoor E, Hoffer BJ, Olson L, Seiger A, Wyatt RJ (1981) Transplanted adrenal cromaffin cells in rat brain reduce lesion-induced rotational behavior. Nature 292: 351–352PubMedCrossRefGoogle Scholar
  32. Freed WJ, Karoum F, Spoor HE, Morihisa JM, Olson L, Wyatt RJ (1983) Catecholamine content of intracerebral adrenal medulla. Brain Res 269: 184–189PubMedCrossRefGoogle Scholar
  33. Freed WJ, Cannon-Spoor H, Krauthammer E ( 1986 a) Intrastriatal adrenal medulla grafts in rats. Long-term survival and behavioral effects. J Neurosurg 65: 664–670Google Scholar
  34. Freed WJ, Patel-Vaidya U, Geller HM (1986 b) Properties of PC 12 pheochromocytoma cells transplanted to the adult rat brain. Exp Brain Res 63: 557–566Google Scholar
  35. Gage FH, Wolff JA, Rosenberg MB, Xu L, Yee J-K, Shults C, Friedmann T (1987) Grafting genetically modified cells to the brain: possibilities for the future. Neuroscience 23: 795–807PubMedCrossRefGoogle Scholar
  36. Gash DM, Notter MFD, Okawara SH, Kraus AL, Joynt RJ (1986) Amitotic neuroblastoma cells used for neural implants in monkeys. Science 233: 1420–1422PubMedCrossRefGoogle Scholar
  37. Goetz CG, Tanner CM, Penn RD, Shannon KM, Klawans HL (1988) Efficacy of intrastriatal adrenal medulla transplant in Parkinson’s disease. Neurol 38 [Suppl] 1: 142Google Scholar
  38. Hefti F, Hartikka J, Schlumpf M (1985) Implantation of PC 12 cells into the corpus striatum of rats with lesions of the dopaminergic nigrostriatal neurons. Brain Res 348: 283–288PubMedCrossRefGoogle Scholar
  39. Jaeger CB (1985) Immunocytochemical study of PC 12 cells grafted to the brain of immature rats. Exp Brain Res 59: 615–624PubMedCrossRefGoogle Scholar
  40. Jaeger CB (1987) Morphological and immunocytochemical characteristics of PC 12 cell grafts in rat brain. Ann NY Acad Sci 495: 334–349PubMedCrossRefGoogle Scholar
  41. Kamo H, Kim SU, McGeer PL, Shin DH (1985) Transplantation of cultured fetal human adrenal chromaffin cells to rat brain. Neurosci Lett 57: 43–48PubMedCrossRefGoogle Scholar
  42. Kish SJ, Shannak K, Hornykiewicz 0 (1988) Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson’s disease. New Engl J Med 318: 876–880Google Scholar
  43. Kordower JH, Notter MFD, Yeh HH, Gash DM (1987) An in vivo and in vitro assessment of differentiated neuroblastoma cells as a source of donor tissue for transplantation. Ann NY Acad Sci 495: 606–621PubMedCrossRefGoogle Scholar
  44. Langston JW, Ballard P, Tertrud JW, Irwin I (1983) Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219: 979–980PubMedCrossRefGoogle Scholar
  45. Lindvall O, Backlund E-O, Farde L, Sedvall G, Freedman R, Hoffer B, Nobin A, Seiger A, Olson L (1987) Transplantation in Parkinson’s disease: two cases of adrenal medullary grafts to the putamen. Ann Neurol 22: 457468Google Scholar
  46. Madrazo I, Drucker-Colin R, Diaz V, Martinez-Mata J, Torres C, Becerril JJ (1987) Open microsurgical autograft of adrenal medulla to the right caudate nucleus in two patients with intractable Parkinson’s disease. New Engl J Med 316: 831–834PubMedCrossRefGoogle Scholar
  47. Madrazo I, Leon V, Torres C, del Aguilera C, Varela G, Alvarez F, Fraga A, Drucker-Colin R, Ostrosky F, Skurovich M, Franco R (1988) Transplantation of fetal substantia nigra and adrenal medulla to the caudate nucleus in two patients with Parkinson’s disease. New Engl J Med 318: 51PubMedGoogle Scholar
  48. Mason DW, Charlton HM, Jones AJ, Lavy CBD, Puklavec M, Simmonds SJ (1986) The fate of allogeneic and xenogeneic neuronal tissue transplanted into the third ventricle of rodents. Neuroscience 19: 685–694PubMedCrossRefGoogle Scholar
  49. Miller WC, DeLong MR (1988) Parkinsonian symptomatology. An anatomical and physiological analysis. Ann NY Acad Sci 515: 287–302CrossRefGoogle Scholar
  50. Morihisa JM, Nakamura RK, Freed WJ, Mishkin M, Wyatt RJ (1984): Adrenal medulla grafts survive and exhibit catecholamine-specific fluorescence in the primate brain. Exp Neurol 84: 643–653PubMedCrossRefGoogle Scholar
  51. Müller TH, Unsicker K (1986) Nerve growth factor and dexamethasone modulate synthesis and storage of catecholamines in cultured rat adrenal medullary cells: dependence on postnatal age. J Neurochem 46: 516–524PubMedCrossRefGoogle Scholar
  52. Nishino H, Ono T, Takahashi J, Kimura M, Shiosaka S, Tohyama M (1986) Transplants in the peri-and intraventricular region grow better than those in the central parenchyma of the caudate. Neurosci Lett 64: 184190Google Scholar
  53. Olanow CW, Cahill D, Cox C (1988): Autologous transplantation of adrenal medulla to caudate nucleus in Parkinson’s disease. Neurol 38 [Suppl] 1: 142Google Scholar
  54. Olson L, Backlund E-O, Gerhardt G, Hoffer B, Lindvall O, Rose G, Seiger A, Stromberg I (1986) Nigral and adrenal grafts in Parkinsonism: recent basic and clinical studies. In: Yahr MD, Bergmann KJ (eds) Parkinson’s disease. Adv Neurol 45: 85–94Google Scholar
  55. Patel-Vaidya U, Wells MR, Freed WJ (1985) Survival of dissociated adrenal chromaffin cells of rat and monkey transplanted into rat brain. Cell Tiss Res 240: 281–285CrossRefGoogle Scholar
  56. Peterson DI, Price ML, Small CS, Linda L (1988) Autopsy findings in a patient that had an adrenal-to-brain transplant for Parkinson’s disease. Neurol 38 [Suppl] 1: 144Google Scholar
  57. Pezzolli G, Goodman R, Ferrante C, Silani V, Yebenes J, Truong D, Jackson-Lewis V, Fahn S (1988) Human fetal adrenal medullary cells reduce experimental parkinsonism in monkey. In: Gash DM, Sladek JR Jr (eds) Transplantation into the mammalian CNS: preclinical and clinical studies. Prog Brain Res 74 (in press)Google Scholar
  58. Prochiantz A, Di Porzio U, Dato A, Berger B, Glowinski J (1979 a) In vitro maturation of mesencephalic dopaminergic neurons from embryos is enhanced in presence of their striatal target cells. Proc Nat Acad Sci (USA) 76: 5387–5391Google Scholar
  59. Prochiantz A, Daguet MC, Herbet A, Glowinski J (1979 b) Specific stimulation of in vitro maturation of mesencephalic dopaminergic neurons by striatal membranes. Nature 293: 570–572Google Scholar
  60. Redmond E, Sladek JR Jr, Roth RH, Collier TJ, Elsworth JD, Deutch AY, Haber S (1986) Fetal neuronal grafts in monkeys given methylphenyltetrahydropyridine. Lancet is 1125–1127Google Scholar
  61. Riederer P, Rausch WD, Birkmayer W, Jellinger K, Seemann D (1978) CNS modulation of adrenal tyrosine hydroxylase in Parkinson’s disease and metabolic encephalopathies. J Neural Transm [Suppl] 14: 121Google Scholar
  62. Rydel RE, Greene LA (1987) Acidic and basic fibroblast growth factors promote stable neurite outgrowth and neuronal differentiation in cultures of PC 12 cells. J Neurosci 7: 3639–3653PubMedGoogle Scholar
  63. Schmidt RH, Björklund A, Stenevi U, Dunnett SB, Gage FH (1983) Activity of intrastriatal nigral suspension implants as assessed by measurements of dopamine synthesis and metabolism. Acta Physiol Scand [Suppl] 522: 19–28Google Scholar
  64. Seeger RC, Rayner SA, Banerjee A, Chung H, Lang WE, Neustein HB, Benedict WF (1977) Morphology, growth, chromosomal pattern and fibrinolytic activity of two new human neuroblastoma lines. Cancer Res 37: 1364–1367PubMedGoogle Scholar
  65. Silani V, Pezzolli G, Motti E, Ferrante C, Falini A, Pizzuti A, Zecchinelli A, Moggio M, Buscaglia M, Scarlato G (1988) Human fetal chromaffin cells for neurotransplantation in parkinsonian patients. In: Gash DM, Sladek JR Jr (eds) Transplantation into the mammalian CNS: preclinical and clinical studies. Prog Brain Res, 74 (in press)Google Scholar
  66. SladekJRJr, Redmond DE Jr, Roth RH, Elsworth JD, Deutch AY, Haber SN, Blount J, Collier TJ (1988) Long term reversal of MPTP-induced parkinsonism in primates with fetal dopamine nerve cell transplants. In: Gash DM, SladekJRJr (eds) Transplantation into the mammalian CNS: preclinical and clinical studies. Prog Brain Res 74 (in press)Google Scholar
  67. Sladek JR Jr, Gash DM (1988) Nerve-cell grafting in Parkinson’s disease. Review article. J Neurosurg 68: 337–351Google Scholar
  68. Strecker RE, Sharp T, Brundin P, Zetterström T, Ungerstedt U, Björklund A (1987) Autoregulation of dopamine release and metabolism by intrastriatal nigral grafts as revealed by intracerebral dialysis. Neuroscience 22: 169–178PubMedCrossRefGoogle Scholar
  69. Strömberg I, Herrera-Marschitz M, Ungerstedt U, Ebendal T, Olson L (1985) Chronic implants of chromaffin tissue into the dopamine-denervated striatum. Effects of NGF on graft survival, fiber growth and rotational behavior. Exp Brain Res 60: 335–349Google Scholar
  70. Strömberg I, Bygdeman M, Goldstein M, Seiger A, Olson L (1986) Human fetal substantia nigra grafted to the dopamine-denervated striatum of immunosuppressed rats: evidence for functional reinnervation. Neurosci Lett 71: 271–276PubMedCrossRefGoogle Scholar
  71. Tanner CM, Goetz CG, Gilley DW, Shannon KM, Stebbins GT, Klawans HL, Wilson RS, Penn RM (1988) Behavioral aspects of intrastriatal adrenal medulla transplant surgery in Parkinson’s disease (PD). Neurology 38 [Suppl] 1: 143Google Scholar
  72. Ungerstedt U, Arbuthnott GW (1970) Quantitative recording of rotational behavior in rats after 6-hydroxy-dopamine lesions of the nigrostriatal dopamine system. Brain Res 24: 485–493PubMedCrossRefGoogle Scholar
  73. Vines G (1988) First British implant of fetal tissue. New Scientist: 22Google Scholar
  74. Widner H, Brundin P, Björklund A, Möller E (1987) Immunological aspects of neural grafting in the mammalian central nervous system. In: Gash DM, Sladek JR Jr (eds) Transplantation into the mammalian CNS: pre-clinical and clinical studies. Prog Brain Res 74 (in press)Google Scholar

Copyright information

© Springer-Verlag/Wien 1989

Authors and Affiliations

  • W. H. Oertel
    • 1
  • C. D. Marsden
    • 2
  1. 1.Department of NeurologyKlinikum Grosshadern, University of MunichFederal Republic of Germany
  2. 2.Institute of Neurology, University Department of Clinical NeurologyThe National Hospital for Nervous DiseasesLondonUK

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