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Human fetal dopamine neurons grafted in a rat model of Parkinson's disease: immunological aspects, spontaneous and drug-induced behaviour, and dopamine release

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We have used a rat model of Parkinson's disease (PD) to address issues of importance for a future clinical application of dopamine (DA) neuron grafting in patients with PD. Human mesencephalic DA neurons, obtained from 6.5–8 week old fetuses, were found to survive intracerebral cell suspension xenografting to the striatum of rats immunosup-pressed with Cyclosporin A. The grafts produced an extensive new DA-containing terminal network in the previously denervated caudate-putamen, and they normalized amphetamine-induced, apomorphine-induced and spontaneous motor asymmetry in rats with unilateral lesions of the mesostriatal DA pathway. Grafts from an 11.5-week old donor exhibited a lower survival rate and smaller functional effects. As assessed with the intracerebral dialysis technique the grafted DA neurons were found to restore spontaneous DA release in the reinnervated host striatum to normal levels. The neurons responded with large increases in extracellular striatal DA levels after the intrastriatal administration of the DA-releasing agent d-amphetamine and the DA-reuptake blocker nomifensine, although not to the same extent as seen in striata with an intact mesostriatal DA system. DA fiber outgrowth from the grafts was dependent on the localization of the graft tissue. Thus, grafts located within the striatum gave rise to an extensive axonal network throughout the whole host striatum, whereas grafted DA neurons localized in the neocortex had their outgrowing fibers confined within the grafts themselves. In contrast to the good graft survival and behavioural effects obtained in immunosuppressed rats, there was no survival, or behavioural effects, of human DA neurons implanted in rats that did not receive immunosuppression. In addition, we found that all the graft recipients were immunized, having formed antibodies against antigens present on human T-cells. This supports the notion that the human neurons grafted to the non-immunosuppressed rats underwent immunological rejection. Based on an estimation of the survival rate and extent of fiber outgrowth from the grafted human fetal DA neurons, we suggest that DA neurons that can be obtained from one fetus may be sufficient to restore significant DA neurotransmission unilaterally, in one putamen, in an immunosuppressed PD patient.

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References

  • Abercrombie M (1946) Estimation of nuclear population from microtome sections. Anat Rec 94: 239–247

    Google Scholar 

  • Backlund E-O, Granberg P-O, Hamberger B, Knutsson E, Mårtensson A, Sedvall G, Seiger Å, Olson L (1985) Transplantation of adrenal medullary tissue to striatum in parkinsonism. First clinical trials. J Neurosurg 62: 169–173

    Google Scholar 

  • Bakay RA, Fiandaca MS, Barrow DL, Schiff A, Collins DC (1985) Preliminary report on the use of fetal tissue transplantation to correct MPTP-induced Parkinson-like syndrome in primates. Appl Neurophysiol 48: 358–361

    Google Scholar 

  • Bazelon M, Fenichel GM, Randall J (1967) Studies on neuromelanin. I. A melanin system in the human adult brainstem. Neurology 17: 512–519

    Google Scholar 

  • Björklund A, Stenevi U, Dunnett SB, Gage FH (1982) Cross-species neural grafting in a rat model of Parkinson's disease. Nature 298: 652–654

    Google Scholar 

  • Björklund A, Stenevi U, Schmidt RH, Dunnett SB, Gage FH (1983) 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

    Google Scholar 

  • Björklund A, Lindvall O (1984) Dopamine-containing systems in the CNS. In: Björklund A, Hökfelt T, Kuhar MJ (eds) Handbook of chemical neuroanatomy, Vol 2. Classical transmitters in the CNS. Elsevier, Amsterdam, pp 55–122

    Google Scholar 

  • Björklund A, Lindvall O, Isacson O, Brundin P, Wictorin K, Strecker RE, Dunnett SB (1987) Mechanisms of action of intracerebral neural implants. Trends Neurosci 10: 509–516

    Google Scholar 

  • Bolam JP, Freund T, Björklund A, Dunnett SB, Smith AD (1987) Synaptic input and local output of dopaminergic neurons in grafts that functionally reinnervate the host neostriatum. Exp Brain Res 68: 131–146

    Google Scholar 

  • Brundin P, Isacson O, Björklund A (1985a) Monitoring of cell viability in suspensions of embryonic CNS tissue and its use as a criterion for intracerebral graft survival. Brain Res 331: 251–259

    Google Scholar 

  • Brundin P, Nilsson OG, Gage FH, Björklund A (1985b) Cyclosporin A increases survival of cross-species intrastriatal grafts of embryonic dopamine-containing neurons. Exp Brain Res 60: 204–208

    Google Scholar 

  • Brundin P, Nilsson OG, Strecker RE, Lindvall O, Åstedt B, Björklund A (1986) Behavioural effects of human fetal dopamine neurons grafted in a rat model of Parkinson's disease. Exp Brain Res 65: 235–240

    Google Scholar 

  • Brundin P, Björklund A (1987) Survival, growth and function of dopaminergic neurons grafted to the brain. In: Seil FJ, Herbet E, Carlson BM (eds) Neural regeneration. Progress in Brain Research, Vol 71. Elsevier, Amsterdam, pp 293–308

    Google Scholar 

  • Clarke DJ, Brundin P, Björklund A (1987) Grafting of human fetal dopamine neurons in a rat model of Parkinson's disease — a tyrosine hydroxylase immunocytochemical study. Br Pharmacol 92: 682P

  • Daniloff JK, Low WC, Bodony RP, Wells J (1985) Cross-species neural transplants: embryonic septal nuclei to the hippocampal formation of adult rats. Exp Brain Res 59: 73–82

    Google Scholar 

  • Dunnett SB, Björklund A, Stenevi U, Iversen SD (1981) Grafts of embryonic substantia nigra reinnervating the ventrolateral striatum ameliorate sensorimotor impairments and akinesia in rats with 6-OHDA lesions of the nigrostriatal pathway. Brain Res 229: 209–217

    Google Scholar 

  • Dunnett SB, Björklund A, Schmidt RH, Stenevi U, Iversen SD (1983) Intracerebral grafting of neuronal cell suspensions. IV. Behavioural recovery in rats with unilateral 6-OHDA lesions following implantation of nigral cell suspensions in different brain sites. Acta Physiol Scand Suppl 522: 29–37

    Google Scholar 

  • Dunnett SB, Whishaw IQ, Jones GH, Isacson O (1986) Effects of dopamine-rich grafts on conditioned rotation in rats with unilateral 6-OHDA lesions. Neurosci Lett 68: 127–133

    Google Scholar 

  • Dunnett SB, Whishaw IQ, Rogers DC, Jones GH (1987) Dopamine rich grafts ameliorate whole body motor as asymmetry and sensory neglect but not independent limb use in rats with 6-hydroxydopamine lesions. Brain Res 415: 63–87

    Google Scholar 

  • Freund TF, Bolam JP, Björklund A, Stenevi U, Dunnett SB, Powell JF, Smith AD (1985) Efferent synaptic connections of grafted dopaminergic neurons reinnervating the host neostriatum: a tyrosine hydroxylase immunocytochemical study. J Neurosci 5: 603–616

    Google Scholar 

  • Gage FH, Dunnett SB, Stenevi U, Björklund A (1983) Aged rats: recovery of motor impairments by intrastriatal nigral grafts. Science 221: 966–969

    Google Scholar 

  • Gazzara RA, Fisher RS, Howard SG (1986) The ontogeny of amphetamine-induced dopamine release in the caudate-putamen of rat. Dev Brain Res 28: 213–220

    Google Scholar 

  • German DC, Schlusselberg DS, Woodward DJ (1983) Three-dimensional computer reconstruction of midbrain dopaminergic neuronal populations from mouse to man. J Neural Transm 57: 243–254

    Google Scholar 

  • Herman J-P, Choulli K, Le Moal M (1985) Hyper-reactivity to amphetamine in rats with dopaminergic grafts. Exp Brain Res 60: 521–526

    Google Scholar 

  • Herman J-P, Choulli K, Geffard M, Nadaud D, Taghzouti K, Le Moal M (1986) Reinnervation of the nucleus accumbens and frontal cortex of the rat by dopaminergic grafts and effects on hoarding behavior. Brain Res 372: 210–216

    Google Scholar 

  • Jaeger CB (1985) Cytoarchitectonics of substantia nigra grafts: a light and electron microscopic study of immunocytochemically identified dopaminergic neurons and fibrous astrocytes. J Comp Neurol 231: 121–135

    Google Scholar 

  • Kamo H, Kim SU, McGeer PL, Shin DH (1985) Transplantation of human fetal adrenal chromaffin cells to rat brain. Neurosci Lett 57: 43–48

    Google Scholar 

  • Kamo H, Kirn SU, McGeer PL, Shin DH (1986) Functional recovery in a rat model of Parkinson's disease following transplantation of cultured human sympathetic neurons. Brain Res 397: 372–376

    Google Scholar 

  • Kamo H, Kim SU, McGeer PL, Araki M, Tomimoto H, Kimura H (1987) Transplantation of cultured human spinal cord cells into the rat motor cortex: use of Phaseolus vulgaris leucoagglutinin as a cell marker. Neurosci Lett 76: 163–167

    Google Scholar 

  • Krupp P, Gülich A, Timonen P (1986) Side effects and safety of sandimmune in long-term treatment of renal transplant patients. Transplant Proc 17: 991–992

    Google Scholar 

  • Leenders KL, Aquilonius S-M, Bergström K, Bjurling P, Crossman AR, Eckernäs S-A, Gee AG, Hartvig P, Lundquist H, Långström B, Rimland A, Tedroff J (1988) Unilateral MPTP lesion in a rhesus monkey: effects on the striatal dopaminergic system measured in vivo with PET using various novel tracers. Brain Res (in press)

  • Lindvall O, Backlund E-O, Farde L, Sedvall G, Freedman R, Hoffer B, Nobin A, Seiger Å, Olson L (1987a) Transplantation in Parkinson's disease: two cases of adrenal medullary grafts to the putamen. Ann Neurol 22: 457–468

    Google Scholar 

  • Lindvall O, Dunnett SB, Brundin P, Björklund A (1987b) Transplantation of catecholamine-producing cells to the basal ganglia in Parkinson's disease: experimental and clinical studies. In: Rose C (ed) Parkinson's disease; clinical and experimental advances. John Libbey and Company Ltd, London, pp 135–152

    Google Scholar 

  • Lorén I, Björklund A, Falck B, Lindvall O (1980) The aluminium-formaldehyde (ALFA) method for improved visualization of catecholamines. I. A detailed account of the methology for central nervous tissue using paraffin, cryostat or Vibratome sections. J Neurosci Meth 2: 277–300

    Google Scholar 

  • Low WC, Lewis PR, Bunch ST (1983) Embryonic neural transplants across a major histocompatibility barrier: survival and specificity of innervation. Brain Res 262: 328–333

    Google Scholar 

  • Madrazo I, Drücker-Colin R, Diaz V, Martinez-Marta J, Torres C, Becerril JJ (1987) Open microsurgical autograft of adrenal medulla to the right caudate nucleus in Parkinson's disease: a report of two cases. N Engl J Med 326: 831–834

    Google Scholar 

  • Mahalik TJ, Finger TE, Strömberg I, Olson L (1985) Substantia nigra transplants into denervated striatum of the rat: ultrastructure of graft and host interconnections. J Comp Neurol 240: 60–70

    Google Scholar 

  • Mason DW, Charlton HM, Jones AJ, Lavy CB, Puklavec M, Simmonds SJ (1986a) The fate of allogeneic and xenogeneic neuronal tissue transplanted into the third ventricle of rodents. Neuroscience 19: 685–694

    Google Scholar 

  • Mason DW, Morris PJ (1986b) Effector mechanisms in allograft rejection. Ann Rev Immunol 4: 119–145

    Google Scholar 

  • Maiorca R, Cristenelli L, Scolari F, Sandrini S, Savoldi S, Brunori G, Prati E, Lojacono L, Salerni B, Tonini G (1985) Cyclosporine toxicity can be minimized by careful monitoring of blood levels. Transplant Proc 17: 54–59

    Google Scholar 

  • Möller G (1961) Demonstration of mouse isoantigens at the cellular level by the fluorescent antibody technique. J Exp Med 114: 415–434

    Google Scholar 

  • Nikodejevec B, Snoh S, Daly JW, Creveling CR (1970) CatecholO-methyltransferase. II. A new class of inhibitors of catechol-O-methyltransferase: 3,5-Dihydroxy-4-methoxybenzoic acid and related compounds. J Pharmacol Exp Ther 174: 83–93

    Google Scholar 

  • Nyberg P, Nordberg A, Wester P, Winblad B (1983) Dopaminergic deficiency is more pronounced in putamen than in nucleus caudatus in Parkinson's disease. Neurochem Pathol 1: 193–202

    Google Scholar 

  • Pearson J, Goldstein M, Markey K, Brandeis L (1983) Human brainstem catecholamine neuronal anatomy as indicated by immunocytochemistry with antibodies to tyrosine hydroxylase. Neuroscience 8: 3–32

    Google Scholar 

  • Peuler JD, Johnson GA (1977) Simultaneous single isotope radioenzymatic assay of plasma norepinephrine, epinephrine and dopamine. Life Sci 21: 625–636

    Google Scholar 

  • Ryffel B (1982) Experimental toxicological studies with cyclosporin A. In: White DJG (ed) Cyclosporin A. Elsevier, Amsterdam, pp 45–75

    Google Scholar 

  • Schmidt RH, Ingvar M, Lindvall O, Stenevi U, Björklund A (1982) Functional activity of substantia nigra grafts reinnervating the striatum: neurotransmitter metabolism and [14C]2-deoxy-D-glucose autoradiography. J Neurochem 38: 737–748

    Google Scholar 

  • Sharp T, Zetterström T, Ungerstedt U (1986) An in vivo study of dopamine release and metabolism in rat brain regions using intracerebral dialysis. J Neurochem 47: 113–122

    Google Scholar 

  • Sladek JR Jr, Collier TJ, Haber SN, Roth RH, Redmond DE Jr (1986) Survival and growth of fetal catecholamine neurons grafted into primate brain. Brain Res Bull 1: 809–818

    Google Scholar 

  • 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: 169–178

    Google Scholar 

  • 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: 335–349

    Google Scholar 

  • Strömberg I, Bygdeman M, Goldstein M, Seiger Å, Olson L (1986) Human fetal substantia nigra grafted to the dopamine denervated striatum of immunosuppressed rats: evidence for functional reinnervation. Neurosci Lett 71: 271–276

    Google Scholar 

  • van den Pol AN, Herbst R, Powell JF (1984) Tyrosine hydroxylase-immunoreactive neurons in the hypothalamus: a light and electron microscopic study. Neuroscience 13: 1117–1156

    Google Scholar 

  • 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: 485–493

    Google Scholar 

  • Ungerstedt U (1984) Measurement of neurotransmitter release by intracranial dialysis. In: Marsden CA (ed) Measurement of neurotransmitter release in vivo. John Wiley and Sons Ltd, New York, pp 81–105

    Google Scholar 

  • Widner H, Brundin P, Björklund A, Möller E (1988) Immunological aspects of neural grafting in the mammalian central nervous system. Progr Brain Res (in press)

  • Wells J, Vietje PB, Wells DG, Boucher M, Bodony RP (1986) Xenografts of brain cells labelled in cell suspensions show growth and differentiation in septo-hippocampal transplants. Brain Res 383: 333–338

    Google Scholar 

  • Zetterström T, Brundin P, Gage FH, Sharp T, Isacson O, Dunnett SB, Ungerstedt U, Björklund A (1986) In vivo measurement of spontaneous release and metabolism of dopamine from intrastriatal nigral grafts using intracerebral dialysis. Brain Res 362: 344–349

    Google Scholar 

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Authors and Affiliations

  1. Department of Medical Cell Research, University of Lund, Biskopsgatan 5, S-22362, Lund, Sweden

    P. Brundin, R. E. Strecker, O. G. Nilsson, O. Lindvall & A. Björklund

  2. Department of Neurology, University of Lund, Biskopsgatan 5, S-22362, Lund, Sweden

    H. Widner & O. Lindvall

  3. Department of Obstetrics and Gynaecology, University of Lund, Biskopsgatan 5, S-22362, Lund, Sweden

    B. Åstedt

  4. Department of Clinical Immunology, Karolinska Institutet, Huddinge University Hospital, S-14186, Huddinge, Sweden

    H. Widner

  5. Department of Pharmacology, University of Oxford, Oxford, UK

    D. J. Clarke

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  1. P. Brundin
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  4. D. J. Clarke
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  5. O. G. Nilsson
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  7. O. Lindvall
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  8. A. Björklund
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Brundin, P., Strecker, R.E., Widner, H. et al. 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, 192–208 (1988). https://doi.org/10.1007/BF00271860

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  • DOI: https://doi.org/10.1007/BF00271860

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