Transplantation of Human Dopaminergic Neurons in Parkinsonism: Experimental Reality and Future Clinical Feasibility

  • Ake Seiger
  • Lars Olson
  • Ingrid Stromberg
  • Marc Bygdeman
  • Menek Goldstein
  • Barry Hoffer


The extensive degeneration of mesostriatal dopamine (DA) neurons in patients with Parkinson’s disease lead to severe motor deficits with tremor, rigidity and hypokinesia. Levodopa treatment counteracts many of these symptoms for a few years, but patients invariably go into an end stage of severe “on-off” oscillations irrespective of further modulations of the medication (Marsden 1980). The need for a new and more effective long-term treatment of Parkinson’s disease is therefore urgent. After unilateral electrolytic lesions of the nigrostriatal pathway that cause degeneration of striatal DA terminals, rats become asymmetric and display a rotational behavior when given drugs that interfere with DA neurotransmission (Anden et al 1966). Animal models of Parkinson’s disease based on these observations have been available for almost 20 years. The first one was the 6-hydroxy-dopamine (6-OH-DA) lesion of the nigrostriatal pathway in rats (Ungerstedt 1971). By specific unilateral lesions of the DA system, rats have been produced whose asymmetric motor behavior can be quantified by a rotometer (Ungerstedt and Arbuthnott 1970). It was later shown that the transplantation of fetal syngeneic DA neuroblasts from substantia nigra to animals with such lesions resulted in a partial structural and functional restoration of the DA system in striatum (Perlow et al., 1979, Bjorklund and Stenevi 1979). Later modification of the procedure has improved reinnervation of striatum from the grafted DA neuroblasts leading to extensive functional restitution of the motor performance of the lesioned animals, (reviews see: Olson et al., 1985, Brundin et al., 1987).


Parkinsonian Patient Rotational Behavior Functional Restoration Nigral Cell Nigrostriatal Dopamine System 
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. Anden N-E, Dahlstrom A., Fuxe K., Larsson K.: Functional role of the nigro-striatal dopamine neurons. Acta Pharmacol. Toxicol. 24: 263–274, 1966.CrossRefGoogle Scholar
  2. Allen, G. S., Burns, R. S. and Tulipan, N. B.: Human adrenal autografts as a potential therapy for Parkinson’s disease. Abstract. Transplantation into the mammalian CNS. Rochester, June 1987.Google Scholar
  3. Backay, R. A.E., Fiandaca, M.S., Barrow, D.L. et al: Preliminary report on the use of fetal tissue transplantation to correct MPTP-induced parkinson-like syndrome in primates. Appl. Neurophysiol. 48: 358–361, 1985.Google Scholar
  4. Backlund, E.O., Granberg, P.O., Hamberger, et al: Transplantation of adrenal medullary tissue to striatum in parkinsonism. First clinical trials. J. Neurosurg. 62: 169–173, 1985.PubMedCrossRefGoogle Scholar
  5. Bjorklund, A. and Stenevi, Reconstruction of the nigrostriatal dopamine pathway by intracerebral nigral transplants. Brain Res. 177: 555–560, 1979.PubMedCrossRefGoogle Scholar
  6. Bjorklund, A., Stenevi, U., Schmidt, R.H., Dunnett, S.B., and Gage, F.H.: Intracerebral grafting of neuronal cell suspensions. II. Survival and growth of nigral cell suspensions implanted in different brain sites. Acta Physiol. Scand. [Suppl] 522: 9–18, 1983.Google Scholar
  7. Brundin, P., Nilsson, O.G., Strecker, R.E., Lindvall, O., Astedt, B., Bjorklund, A.: Behavioral effects of human fetal dopamine neurons grafted in a rat model of Parkinson’s disease. Exp. Brain Res. 221: 235–240, 1986.Google Scholar
  8. Brundin, P., Strecker, R.E., Lindvall, O., et al: Intracerebral grafting of dopamine neurons: experimental basis for clinical trials in patients with Parkinson’s disease. In: Azmitia E, Bjorklund A (eds): Cell and tissue transplantation into the adult brain, New York, New York Academy of Sciences, pp. 473–495,1987.Google Scholar
  9. Burns, R.A., Markey, S.P., Phillips, J.M. and Chieuh, C.C.: The neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the monkey and man. Can. J. Neurol. Sci. 11: 166–168, 1984.PubMedGoogle Scholar
  10. Freed, W., Morihisa, J., Spoor, E., Hoffer, B., Olson, L., Seiger, A., and Wyatt, R.: Transplanted adrenal chromaffine cells in rat brain reduce lesion-induced rotational behavior. Nature 292: 351–352, 1981.PubMedCrossRefGoogle Scholar
  11. Hallman, H., Olson, L., and Jonsson, G.: Neurotoxicity of the meperidine analogue N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine on brain catecholamine neurons in the mouse. Eur. J. Pharmacol. 97: 133–137, 1984.PubMedCrossRefGoogle Scholar
  12. Heikkila, R.E., Hess, A., and Duvoisin, R.C.: Dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydiopyridine in mice. Science, 224: 1451–1453, 1984.PubMedCrossRefGoogle Scholar
  13. Jiao, Shou-shu, Zhang, W.C., Ding, M.C. and Sun, J.B.: The clinical study of adrenal medullary tissue transplantation to striatum in Parkinsonism. Abstract. Transplantation into the mammalian CNS, Rochester, June 1987.Google Scholar
  14. Langston, J.W., Ballard, P., Tetrud, J.W. and Irwin, I.: Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219: 979–980, 1983.PubMedCrossRefGoogle Scholar
  15. Lindvall, O., Backlund, E.-O., Farde, L., Sedvall, G., Freedman, R., Hoffer, B., Nobin, A., Seiger, A and Olson, L., Transplantation in Parkinson’s disease: two cases of adrenal grafts to the putamen. Ann. Neurol. 22. 457–468, 1987.PubMedCrossRefGoogle Scholar
  16. Madrazo, I., Drucker-Colin, R., Diaz, V., et al: Open microsurgical autograft of adrenal medulla to the right caudate nucleus in two patients with intractable Parkinson’s disease. N. Eng. J. Med. 316: 831–834, 1987.CrossRefGoogle Scholar
  17. Marsden, C.D.: “On-off” phenomena in Parkinson’s disease. In: Rinne UK, Klingler M., Stamm, G. (eds.): Parkinson’s Disease-Current Progress, Problems and Management. Amsterdam, Elsevier/NorthHolland, pp. 241–254,1980.Google Scholar
  18. Nobin, A. and Bjorklund, A.: Topography of the monoamine neuron systems in the human brain as revealed in fetuses. Acta Physiol. Scand. [Suppl.] 388: 1–40, 1973.Google Scholar
  19. Olson, L.: Fluorescence histochemical evidence for axonal growth and secretion from transplanted adrenal medullary tissue. Histochemie 22: 1–7, 1970.PubMedCrossRefGoogle Scholar
  20. Olson, L., Backlund, E.-O, Freed, W., Herrera-Marschitz, M., Hoffer, B., Seiger, A., Stromberg, I.: Transplantation of monoamine-producing cell systems in oculo and intracranially: Experiments in search of a treatment for Parkinson’s disease. In: Hope for a New Neurology (F. Nottebohm, ed.) Ann. N.Y. Acad. Sci. 1985, pp. 105–126.Google Scholar
  21. Olson, L., Backlund, E.O., Gerhardt, G., Hoffer, B., Lindvall, O., Rose, G., Seiger, A. and Stromberg I.: Nigral and adrenal grafts in parkinsonism: recent basic and clinical studies. In: Yahr M.D., Bergmann K.J. (eds.) Advances in neurology, Vol 45, Raven Press, New York, pp. 85–94, 1986.Google Scholar
  22. Olson, L., Boreus, L.O. and Seiger, A., Histochemical demonstration and mapping of 5-Hydroxytryptamine-and catecholamine-containing neuron systems in the fetal brain. Z. Anat. Entwickl. Gesch. 139: 259–282, 1973.CrossRefGoogle Scholar
  23. Olson, L., Seiger, A., Freedman, R., and Hoffer, B.: Chiomaffine cells can innervate brain tissue: Evidence from intraocular double grafts. Exp. Neurol., 70: 414–426, 1980.PubMedCrossRefGoogle Scholar
  24. Olson, L., Stromberg, I., Bygdeman, M., Granholm, A.-Ch., Hoffer, B., Freedman, R. and Seiger, A.: Human fetal tissues grafted to rodent hosts: structural and functional observations of brain, adrenal and heart tissues in oculo. Exp. Brain Res. 67: 163–178, 1987.PubMedCrossRefGoogle Scholar
  25. Perlow, M., Freed, W., Hoffer, B., Seiger, A., Olson, L. and Wyatt, R.: Brain grafts reduce motor abnormalities produced by destruction of nigrostriatal dopamine systems. Science 204: 643–647, 1979.PubMedCrossRefGoogle Scholar
  26. Redmond, D.E., Sladek, J.R. Jr., Roth, R.H., et al: Fetal neuronal grafts in monkeys given methylphenyltet-rahydropyridine. Lancet 1: 1125–1127, 1986.PubMedCrossRefGoogle Scholar
  27. Seiger, A., Bygdeman, M., Goldstein, M., Almqvist, P., Hoffer, Stromberg, I. and Olson, L.: Human fetal catecholamine-containing tissues grafted intraocularly and intracranially to immunocompromized rodent hosts. In: Transplantation into the mammalian CNS. Progr. Brain Res. (Sladek, JR and Gash DM, eds.), 1988, in press.Google Scholar
  28. Seiger, A., Stromberg, I. and Olson, L: Aspects of embryonic CNS transplantation. Int. Pediatr. 2:79–82,1987.Google Scholar
  29. Stromberg, I., Bygdeman, M., Goldstein, M., Seiger, A. and Olson, Human fetal substantia nigra grafted to the dopaminedenervated striatum of immunosuppressed rats: evidence for functional reinnervation. Neurosci. Lett. 71: 271–276, 1986.PubMedCrossRefGoogle Scholar
  30. Stromberg, I., Ebendal, T., Seiger, A., and Olson, L.,: Nerve fiber production by intraocular adrenal medullary grafts: stimulation by nerve growth factor or sympathetic denervation of the host iris. Cell Tissue Res. 241: 241–249, 1985a.PubMedCrossRefGoogle Scholar
  31. Stromberg, I., Herrera-Marschitz, M., Ungerstedt, U., Ebendal, T. and Olson, L.: Chronic implants of chromaffin tissue into the dopamine-denervated striatum. Effects of NGF on survival, fiber growth and rotational behavior. Exp. Brain Res. 60: 335–349, 1985b.PubMedCrossRefGoogle Scholar
  32. Stromberg, Johnson, Hoffer, B.J. and Olson, Reinnervation of the dopamine-denervated striatum by substantia nigra transplants: Immunohistochemical and electrophysiological correlates. Neuroscience 14: 981–990, 1985c.PubMedCrossRefGoogle Scholar
  33. Ungerstedt, Histochemical studies on the effects of intracerebral and intraventricular injections of 6-hydro-xydopamine on monoamine neurons in the rat brain. In: 6-Hydroxydopamine and catecholamine neurons, eds. T. Malmfors and H. Thoenen. North Holland Publishing Company, 1971.Google Scholar
  34. Ungerstedt, U. and Arbuthnott, G.W.: Quantitative recording of rotational behavior in rats after 6-hydroxydopamine lesions of the nigrostriatal dopamine system. Brain Res. 24: 485–493, 1970.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1988

Authors and Affiliations

  • Ake Seiger
    • 1
  • Lars Olson
    • 2
  • Ingrid Stromberg
    • 2
  • Marc Bygdeman
    • 3
  • Menek Goldstein
    • 4
  • Barry Hoffer
    • 5
  1. 1.Department of Neurological SurgeryUniversity of Miami, School of MedicineMiamiUSA
  2. 2.Department of Histology and NeurobiologyKarolinska InstituteStockholmSweden
  3. 3.Department of Obstetrics and GynecologyKarolinska InstituteStockholmSweden
  4. 4.Department of PsychiatryNew York University Medical CenterNewYorkUSA
  5. 5.Department of PharmacologyUniversity of Colorado Medical CenterDenverUSA

Personalised recommendations