NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-.

Cover of Madame Curie Bioscience Database

Madame Curie Bioscience Database [Internet].

Show details

Dopamine and Parkinson's Disease

.

Introduction

Movement control is accomplished by complex interactions among various groups of nerve cells in the central nervous system. One such important group of neurons is located in the substantia nigra in the ventral midbrain. Nigral neurons give rise to an extensive network of axonal processes that innervate the basal ganglia, establishing predominantly symmetrical synapses with dendritic spines and shafts of medium spiny projection neurons.1,2 Neurons of the substantia nigra communicate with neurons of the basal ganglia by liberating the neurotransmitter dopamine (DA). Such an interaction at the biochemical level is responsible for the fine tuning of an organism's movements.

Parkinson's disease or paralysis agitans3is a neurological disorder that affects movement control. In Parkinson's disease, neurons of the substantia nigra progressively degenerate4(Fig. 1); as a result, the amount of DA available for neurotransmission in the corpus striatum is lowered.5The biochemical imbalance manifests with typical clinical symptoms that include resting tremor, rigidity, bradykinesia, i.e., a gradual slowness of spontaneous movement, and loss of postural reflexes or, in other words, poor balance and motor coordination.6–9 An estimated half million people are affected with Parkinson's disease and related disorders in the United States.10

Figure 1. Appearance of normal (upper) and Parkinsonian (lower) human midbrain.

Figure 1

Appearance of normal (upper) and Parkinsonian (lower) human midbrain. Depigmentation of the substantia nigra is the main macroscopic neuropathological hallmark of Parkinson's disease. Magnification × 0.7. Courtesy Dr. Jans Muller.

Reductions in DA content and uptake indices have been documented in Parkinson's disease by a variety of techniques, including [3H]mazindol binding11 or computer-aided analyses of neuromelanin pigment12 in postmortem brain tissues, as well as positron emission tomography following the administration of 6-l-[18F]-fluorodopa or [11C]nomifensine as DA uptake tracers in vivo.13 A selective increase of N-methyl-d-aspartate (NMDA)-sensitive glutamate binding but not of (RS)-α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) and kainate occurs in the striatum of postmortem brain tissue from patients with Parkinson's disease.14

An important indirect action of DA in the striatum may actually be the tuning down of the cortical excitation of striatal neurons.15 Consequently, the impairment of dopaminergic neurotransmission that occurs in Parkinsonism may lead to an increase in the physiological state of corticostriatal glutamatergic transmission, which may further contribute towards reinforcing the imbalance between subsets of striata neuronal systems controlling the functional output of the basal ganglia, and the available evidence suggests an overactive striatal γ-aminobutyric acid (GABA) output, especially to the lateral segment of the globus pallidus.16

The commonest age of onset of idiopathic Parkinson's disease is during the fifth and sixth decades of life.6–10 The causes of cellular death in Parkinson's disease are only partially understood. An intracellular eosinophilic inclusion, the Lewy body, is found in neurons of the Parkinsonian substantia nigra (Fig. 2). The Lewy body consists of fibrillary elements that share common antigenic determinants with intermediate filaments.7

Figure 2. Lewy bodies are circular eosinophilic hyaline structures found in neurons of the substantia nigra and other brain areas in Parkinson's disease.

Figure 2

Lewy bodies are circular eosinophilic hyaline structures found in neurons of the substantia nigra and other brain areas in Parkinson's disease. The pigmented nigral neuron of the upper micrograph has an eccentric nucleus and an eosinophilic Lewy body (more...)

Research studies back several theories that are still being explored. It has been proposed that Parkinson's disease is a heterogeneous entity, in the etiology of which both environmental and genetic factors could play a role. The various theories implicate endogenous chemical reactions,17 exposure to specific environmental factors and neurotoxins,18 and genetically determined susceptibility or predisposition.19,20 In addition, there is a juvenile form of Parkinson's disease, i.e., characterized by an early onset, which is familial and clearly due to genetic factors.21–24 Any one or a combination of these theories may eventually prove to be the cause of Parkinson's disease.

The most effective mode of treatment has been the administration of the l-isomer of 3,4-dihydroxyphenylalanine (l-DOPA), a DA precursor.25 It is thought that certain anti-Parkinsonian agents may exert their clinical effects via blockade of NMDA receptors.26,27 In animal models of Parkinson's disease, NMDA and AMPA receptor antagonists were found to reverse Parkinsonian signs28 or potentiate the ability of l-DOPA to reverse akinesia and to alleviate muscular rigidity.29 Accordingly, the clinical use of NMDA antagonists has been considered for the symptomatic treatment of Parkinson's disease, based also on the observation that low doses of NMDA antagonists potentiate the therapeutic effects of DA agonists and on the hypothesis that even the beneficial effects of anticholinergic drugs may be mediated in part by NMDA receptor blockade.30 Polypharmacy with l-DOPA and a glutamate antagonist as adjuvant may be a realistic prospect in the pharmacological management of Parkinsonian symptoms, based on the pathophysiological hint that Parkinson's disease is a glutamate hyperactivity disorder.31 In addition, GABA receptor agonists have been used in clinical trials, where they are thought of having a dual action, depending on dose.32

Alternative neurosurgical procedures performed clinically to alleviate Parkinsonian symptoms include posteroventral pallidotomy33 and intrastriatal implantation of dopaminergic neurons that have the ability of releasing DA.34 The latter approach has been stimulated by studies showing that grafts of fetal mesencephalic DA neurons implanted into experimental models with DA deficiency counteract the behavioral effects caused by the lesion.35,36

Experimental Models of Parkinsonism in Laboratory Animals

The DA deficiency observed in the mesostriatal system in Parkinson's disease is the main event underlying the pathophysiology of the motoric symptomatology. Accordingly, appropriate experimental models in laboratory animals should feature the typical loss of DA neurons in the substantia nigra and an associated DA reduction in the corpus striatum in order to be useful in investigating ways of therapeutic intervention.

Typically, three main experimental models have been used in the laboratory as dopaminergic phenocopies of Parkinson's disease to address cellular mechanisms of DA deficiency and restoration. Two of those models rely on selective neurotoxins to chemically destroy dopaminergic nigral neurons. The third model is the weaver mutant mouse (wv/wv), which has a genetic mutation that leads to mesencephalic DA neuron degeneration.37–41

  1. The local injection of 6-hydroxydopamine (6-OHDA) into the midbrain of rats and mice causes an acute degeneration of dopaminergic neurons42 (Fig. 3). The 6-OHDA molecule is recognized by nigral neurons as DA and is taken up by the cell; with its entrance in the cytoplasm, 6-OHDA expresses its toxicity and destroys monoaminergic cells selectively. Rats with unilateral 6-OHDA lesions of the substantia nigra present with a characteristic motor syndrome that includes rotation behavior ipsilaterally to the side of the lesion, either spontaneously or in response to DA-releasing agents such as amphetamine.43 The interruption of the nigrostriatal projection is associated with an increase in striatal DA receptors, a phenomenon referred to as denervation-induced supersensitivity.44
  2. The N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxin was accidentally found to cause a Parkinsonian syndrome in humans.45,46 MPTP-induced Parkinsonism presents with the typical clinical signs of tremor, rigidity and bradykinesia, just like idiopathic Parkinson's disease. The MPTP molecule seems to be selectively neurotoxic for humans and nonhuman primates. For that reason, it has been used in the laboratory to induce experimental Parkinsonism in monkeys. In vitro studies have shown that, once inside the cell, MPTP becomes oxidized to 1-methyl-4-phenylpyridine (MPP) through the action of the enzyme monoaminooxidase B. MPP is the form that is toxic to dopaminergic neurons.46
  3. The formation and maintenance of brain circuitry is in part regulated by an organism's genetics. Spontaneous heritable changes or mutations often take place in the genes. When a certain gene undergoes a mutation, the chromosome in which the gene is located may be abnormal in some functional aspect. Currently, more than 140 spontaneous mutations are known to affect the nervous system of laboratory mice. These mutant mice are valuable models for investigating various pathological conditions that modify brain function either during development or in adulthood. In the weaver mutant mouse, there is a selective decrease of neurons in the substantia nigra, resulting in a depletion of DA stores in the basal ganglia.47,48
Figure 3. Unilateral destruction of the substantia nigra in the laboratory mouse through local stereotactic injection of 6-hydroxydopamine.

Figure 3

Unilateral destruction of the substantia nigra in the laboratory mouse through local stereotactic injection of 6-hydroxydopamine. Micrographs from upper to lower correspond to coronal levels from rostral to caudal. Immunocytochemistry with antityrosine (more...)

A naturally occurring model of DA deficiency of genetic causes in rodents is particularly valuable, as it may shed new light on pathological mechanisms of degeneration related to Parkinson's disease and the application of techniques to restore lost function. Having a relatively short lifespan, the mouse avails itself of rigorous experimental analyses. Furthermore, there is the possibility of using large samples of animals with a consistent neurological defect to obtain biological, physiological and behavioral correlates of the restoration of lost function by means of various treatments. The weaver model is a valuable complement to the chemical models; its uniqueness lies in the fact that the mesostriatal DA depletion is progressive, taking place over several months, and incomplete, in contrast with the acute degeneration typical of the toxic models. Thus, laboratory studies in the weaver can address specific aspects of experimental interference with the chronic pathological central nervous system.

Graft-Assisted Neural Reconstruction (“Brainware Engineering”?)

As a rule, the genesis of neuronal populations, including midbrain DA cells, is concluded during embryonic life,49 and the regenerative capacity of the adult central nervous system is largely confined to compensatory fiber sprouting and not mitotic divisions of nerve cells.50,51 Therefore, neurons that die as a result of regressive phenomena can only be replaced through implantation of cells or tissues harvested from external sources.

In the past quarter of a century the field of neural transplantation has witnessed an unparalleled blooming. The publication of numerous books and periodicals attests to that effect.52–64Neural transplantation has been used successfully to effect cell replacement in conditions characterized by focal loss of a selective group of neurons both in laboratory animals and in clinical trials. The survival and growth of embryonic substantia nigra transplants in particular has been documented in rodents and in primates with lesions of the substantia nigra.34–36,38–41,47,65–84

Experiments in rodents have shown that it is possible to establish a terminal axonal network in the DA-denervated striatum by intracerebral grafting of fetal mesencephalic tissue.34–36,38,39,41,47,65–70The transplant-derived innervation leads to release of DA in the striatum as determined by methods of in vivo microdialysis71 and in vivo voltammetry.72 DA fibers from grafts form synaptic connections with striatal neurons of the host.73,74 The increase in DA D2 receptor binding, which occurs after 6-OHDA lesions in rats, can be normalized by nigral transplants.75 Mesencephalic grafts contain physiologically active neurons76 and restore specific behavioral functions.77–81

The precise mechanisms by which grafts promote a functional recovery are partially understood. It appears as if a multitude of trophic, neurohumoral and synaptic mechanisms may be responsible for such a recovery.82 Synaptic formation has been considered as one of the mechanisms underlying the recovery of function in the nigrostriatal system. Normal synaptogenesis is the result of a prolonged two-way communication between presynaptic and postsynaptic neuronal elements during development. In the case of neural grafting, however, embryonic donor tissue is led to develop inside an adult recipient brain. From both a theoretical and practical viewpoint, it is important to know the extent to which grafted cells mimic normal developmental patterns or participate in aberrant patterns of synaptic interactions with the denervated striatal cells of the adult recipient organisms.

In the Parkinson's disease model, the growth of human fetal mesencephalic neurons after transplantation has been monitored in human-to-rat grafting experiments as well.83,84 Clinical trials with fetal mesencephalic grafts into the caudate nucleus or putamen have been reported in Parkinsonian patients in medical centers of several countries, including Sweden,85–100 England,101–112 Mexico,113,114 U.S.A.,115–131 Cuba,132 Russia,133 Czech Republic,134 Slovakia,135 Canada,136 Spain,137,138 China,139 Poland140 and France.141Such trials have been prompted by encouraging results from the extensive experimental results from studies in the rodent and primate models. Evidence for graft survival88,96,97,100,110,112,119,126,128,141and functional improvement of clinical signs85,113,115,141has been presented in several of those studies. Reported variations in the outcome of the procedure might relate among other factors to the technique and site of grafting, the age and method of preparation of donor tissue(s), the stage of advancement of the disease in the host, and the pharmacological scheme of patient treatment prior to the transplantation operation.

Clinical neural transplantation studies are monitored in the United States by the Registry Committee of the American Society for Neural Transplantation and Repair (ASNTR), which collects basic demographic, morbidity and mortality data and carries out efficacy evaluations.142 In the European Union, a concerted effort for the development of efficient, reliable, safe and ethically acceptable transplantation therapies for neurodegenerative diseases has been carried out by the Network of European CNS Transplantation and Restoration.143,144

References

1.
Pickel VM, Beckley SC, Joh TH. et al. Ultrastructural immunocytochemical localization of tyrosine hydroxylase in the neostriatum. Brain Res. 1981;225:373–385. [PubMed: 6118197]
2.
Freund TF, Powell JF, Smith AD. Tyrosine hydroxylase-immunoreactive boutons in synaptic contact with identified striatonigral neurons, with particular reference to dendritic spines. Neuroscience. 1984;13:1189–1215. [PubMed: 6152036]
3.
Parkinson J. An Essay on the Shaking Palsy. London: Sherwood, Neely, and Jones,1817 .
4.
Trétiakoff C. Contribution à l'étude de l'anatomie pathologique du locus niger de Sömmering. Paris: Université de Paris,1919 .
5.
Ehringer H, Hornykiewicz O. Verteilung von Noradrenalin und Dopamin (3-Hydroxytyramin) in Gehirn des Menschen und ihr Verhalten bei Erkrankungen des extrapyramidalen Systems. Klin Wochenschr. 1960;38:1236–1239. [PubMed: 13726012]
6.
Walton JN. Brain's Diseases of the Nervous System. Oxford: Oxford University Press,1977 .
7.
Wooten GF. Parkinsonism In: Pearlman AL, Collins RC, eds.Neurobiology of Disease New York Oxford: Oxford University Press,1990. 454–468.
8.
Rewcastle NB. Degenerative Diseases of the Central Nervous System In: Davis RL, Robertson DM, eds.Textbook of Neuropathology, 2nd edn Baltimore: Williams & Wilkins1991. 904–961.
9.
Fahn S. Parkinson's disease and other basal ganglion disorders In: Asbury AK, McKhann GM, McDonald WI, eds.Diseases of the Nervous System: Clinical Neurobiology, 2nd ed. Philadelphia: W.B. Saunders Co.1992. 1144–1158.
10.
American Academy of Neurology. Publication “Parkinson's Disease” (Brain Matters Series). St.Paul, MN1997 .
11.
Chinaglia G, Alvarez FJ, Probst A. et al. Mesostriatal and mesolimbic dopamine uptake binding sites are reduced in Parkinson's disease and progressive supranuclear palsy: A quantitative autoradiographic study using [3H]mazindol. Neuroscience. 1992;49:317–327. [PubMed: 1436470]
12.
German DC, Manaye K, Smith WK. et al. Midbrain dopaminergic cell loss in Parkinson's disease: Computer visualization. Ann Neurol. 1989;26:507–514. [PubMed: 2817827]
13.
Leenders KL, Salmon EP, Tyrrell P. et al. The nigrostriatal dopaminergic system assessed in vivo by positron emission tomography in healthy volunteer subjects and patients with Parkinson's disease. Arch Neurol. 1990;47:1290–1298. [PubMed: 2123623]
14.
Ulas J, Weihmuller FB, Brunner LC. et al. Selective increase of NMDA-sensitive glutamate binding in the striatum of Parkinson's disease, Alzheimer's disease, and mixed Parkinson's disease/Alzheimer's disease patients: An autoradiographic study. J Neurosci. 1994;14:6317–6324. [PubMed: 7965038]
15.
Nieoullon A, Kerkerian-Le Goff L. Cellular interactions in the striatum involving neuronal systems using “classical” neurotransmitters: Possible functional implications. Mov Disord. 1992;7:311–325. [PubMed: 1362449]
16.
Robertson RG, Clarke CA, Boyce S. et al. The role of striatopallidal neurones utilizing gamma-aminobutyric acid in the pathophysiology of MPTP-induced parkinsonism in the primate: Evidence from [3H]flunitrazepam autoradiography. Brain Res. 1990;531:95–104. [PubMed: 2289139]
17.
Carlsson A, Fornstedt B. Possible mechanisms underlying the special vulnerability of dopaminergic neurons. Acta Neurol Scand. 1991;84([Suppl 136]):16–18. [PubMed: 1801531]
18.
Calne S, Schoenberg B, Martin W. et al. Familial Parkinson's disease: Possible role of environmental factors. J Can Neurol Sci. 1987;14:303–305. [PubMed: 3664372]
19.
Golbe LI. The genetics of Parkinson's disease: A reconsideration. Neurology. 1990;40([Suppl 3]):714. [PubMed: 2215974]
20.
Golbe LI, Di Iorio G, Bonavita V. et al. A large kindred with autosomal dominant Parkinson's disease. Ann Neurol. 1990;27:276–282. [PubMed: 2158268]
21.
Martin WE, Resch JA, Baker AB. Juvenile Parkinsonism. Arch Neurol. 1971;25:494–500. [PubMed: 4398909]
22.
Yokochi M, Narabayashi H, Iizuka R. et al. Juvenile Parkinsonism--Some clinical, pharmacological, and neuropathological aspects. Adv Neurol. 1984;40:407–413. [PubMed: 6141711]
23.
Narabayashi H, Yokochi M, Iizuka R. et al. Juvenile Parkinsonism In: Vinken PJ, Bruyn GW, Klawans HL, eds.Handbook of Clinical Neurology Amsterdam: Elsevier1986. 49153–165.
24.
Matsumine H, Saito M, Shimoda-Matsubayashi S. et al. Localization of a gene for an autosomal recessive form of juvenile Parkinsonism to chromosome 6q25.2–27. Am J Hum Genet. 1997;60:588–596. [PMC free article: PMC1712507] [PubMed: 9042918]
25.
Cotzias GC, Papavasiliou PS, Gellene R. Modification of Parkinsonism: Chronic treatment with l-Dopa. N Engl J Med. 1969;280:337–345. [PubMed: 4178641]
26.
Lustig HS, von B Ahern K, Greenberg DA. Anti-Parkinsonian drugs and in vitro excitotoxicity. Brain Res. 1992;597:148–150. [PubMed: 1477727]
27.
Olney JW, Price MT, Labruyere J. et al. Anti-Parkinsonian agents are phencyclidine agonists and N-methyl-aspartate antagonists. Eur J Pharmacol. 1987;142:319–320. [PubMed: 2826182]
28.
Klockgether T, Turski L, Honoré T. et al. The AMPA receptor antagonist NBQX has antiparkinsonian effects in monoamine-depleted rats and MPTP-treated monkeys. Ann Neurol. 1991;30:717–723. [PubMed: 1662477]
29.
Klockgether T, Turski L. NMDA antagonists potentiate anti-Parkinsonian actions of l-dopa in monoamine-depleted rats. Ann Neurol. 1990;28:539–546. [PubMed: 2252365]
30.
Greenamyre JT, O'Brien CF. N-methyl-d-aspartate antagonists in the treatment of Parkinson's disease. Arch Neurol. 1991;48:977–981. [PubMed: 1835370]
31.
Starr MS. Glutamate/dopamine D1/D2balance in the basal ganglia and its relevance to Parkinson's disease. Synapse. 1995;19:264–293. [PubMed: 7792721]
32.
Bartholini G, Scatton B, Zivkovic B. et al. GABA receptor agonists and extrapyramidal motor function: Therapeutic implications for Parkinson's disease. Adv Neurol. 1987;45:79–83. [PubMed: 3030072]
33.
Laitinen LV, Bergenheim AT, Hariz MI. Leksell's posteroventral pallidotomy in the treatment of Parkinson's disease. J Neurosurg. 1992;76:53–61. [PubMed: 1727169]
34.
Olson L. On the use of transplants to counteract the symptoms of Parkinson's disease: Background, experimental models, and possible clinical applications In: Cotman CW, ed.Synaptic Plasticity New York: Guilford Press1986. 485–505.
35.
Björklund A, Stenevi U. Reconstruction of the nigrostriatal dopamine pathway by intracerebral nigral transplants. Brain Res. 1979;177:555–560. [PubMed: 574053]
36.
Perlow MJ, Freed WJ, Hoffer BJ. et al. Brain grafts reduce motor abnormalities produced by destruction of nigrostriatal dopamine system. Science. 1979;204:643–647. [PubMed: 571147]
37.
Zigmond MJ, Stricker EM. Animal models of Parkinsonism using selective neurotoxins: Clinical and basic implications. Int Rev Neurobiol. 1989;31:1–79. [PubMed: 2689379]
38.
Brundin P, Duan W -M, Sauer H. Functional effects of mesencephalic dopamine neurons and adrenal chromaffin cells grafted to the rodent striatum In: Dunnett SB, Björklund A, eds.Functional Neural Transplantation New York: Raven Press,1994. 9–46.
39.
Witt TC, Triarhou LC. Transplantation of mesencephalic cell suspensions from wild-type and heterozygous Weaver mice into the denervated striatum: Assessing the role of graft-derived dopaminergic dendrites in the recovery of function. Cell Transplant. 1995;4:323–333. [PubMed: 7640872]
40.
Bakay R A E, Fiandaca MS, Barrow DL. et al. Preliminary report on the use of fetal tissue transplantation to correct MPTP-induced Parkinson-like syndrome in primates. Appl Neurophysiol. 1985;48:358–361. [PubMed: 3879797]
41.
Triarhou LC, Low WC, Doucet G. et al. The weaver mutant mouse as a model for intrastriatal grafting of fetal dopamine neurons In: Hefti F, Weiner WJ, eds.Progress in Parkinson's Disease Research 2 Mt. Kisco, New York: Futura Publishing Company1992. 383–393.
42.
Ungerstedt U. 6-Hydroxydopamine-induced degeneration of central monoamine neurons. Eur J Pharmacol. 1968;5:107–110. [PubMed: 5718510]
43.
Ungerstedt U, Arbuthnott GW. Quantitative recording of rotational behavior in rats after 6-hydroxydopamine lesions of the nigrostriatal dopamine system. Brain Res. 1970;24:485–493. [PubMed: 5494536]
44.
Marshall JF, Ungerstedt U. Supersensitivity to apomorphine following destruction of the ascending dopamine neurons: Quantification using the rotational model. Eur J Pharmacol. 1977;41:361–367. [PubMed: 557411]
45.
Burns RS, Chiueh CC, Markey SP. et al. 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 Natl Acad Sci USA. 1983;80:4546–4550. [PMC free article: PMC384076] [PubMed: 6192438]
46.
Langston JW. MPTP and Parkinson's disease. Trends Neurosci. 1985;8:79–83.
47.
Triarhou LC, Low WC, Ghetti B. Transplantation of ventral mesencephalic anlagen to hosts with genetic nigrostriatal dopamine deficiency. Proc Natl Acad Sci USA. 1986;83:8789–8793. [PMC free article: PMC387017] [PubMed: 2877463]
48.
Triarhou LC. Weaver gene expression in central nervous system In: Conn PM, ed.Gene Expression in Neural Tissues San Diego: Academic Press1992. 209–227.
49.
Taber Pierce E. Time of origin of neurons in the brain stem of the mouse. Prog Brain Res. 1973;40:53–65. [PubMed: 4802670]
50.
Cotman CW. Synaptic Plasticity. New York: Guilford Press1986.
51.
Baudry M, Thompson RF, Davis JL. Synaptic Plasticity: Molecular, Cellular, and Functional Aspects. Cambridge, MA: MIT Press1993.
52.
Wallace RB, Das GD., eds.Neural Tissue Transplantation Research. New York-Berlin-Heidelberg-Tokyo: Springer-Verlag1983.
53.
Sladek J R Jr, Gash DM., eds.Neural Transplants: Development and Function. New York: Raven Press,1984.
54.
Björklund A, Stenevi U., eds.Neural Grafting in the Mammalian CNS. Amsterdam: Elsevier;1985.
55.
Azmitia EC, Björklund A., eds.Cell and Tissue Transplantation into the Adult Brain. New York: The New York Academy of Sciences1987.
56.
Gash DM, Sladek J R Jr., eds.Transplantation into the Mammalian CNS. Amsterdam-New York-Oxford: Elsevier1988.
57.
Dunnett SB, Richards S -J., eds.Neural Transplantation: From Molecular Basis to Clinical Applications. Amsterdam-New York-Oxford: Elsevier1990.
58.
Lindvall O, Björklund A, Widner H., eds.Intracerebral Transplantation in Movement Disorders: Experimental Basis and Clinical Experiences. Amsterdam-London-New York-Tokyo: Elsevier1991.
59.
Dunnett SB, Björklund A., eds.Neural Transplantation: A Practical Approach. Oxford-New York-Tokyo: Oxford University Press1992.
60.
Dunnett SB, Björklund A., eds.Functional Neural Transplantation. New York: Raven Press,1994.
61.
Sanberg PR, Wictorin K, Isacson O. Cell Transplantation for Huntington's Disease. Austin, TX: RG Landes Co.1994.
62.
Vrbová G, Clowry G, Nógrádi A. et al. Transplantation of Neural Tissue into Spinal Cord. Austin, TX: RG Landes Co.1994.
63.
Triarhou LC. Neural Transplantation in Cerebellar AtaxiaAustin, TX: RG Landes Co.1997.
64.
Freed WJ. Neural Transplantation: An IntroductionCambridge, MA: MIT Press2000.
65.
Stenevi U, Björklund A, Svendgaard N -A. Transplantation of central and peripheral monoamine neurons to the adult rat brain: Techniques and conditions for survival. Brain Res. 1976;114:1–20. [PubMed: 963534]
66.
Björklund A, Dunnett SB, Stenevi U. et al. Reinnervation of the denervated striatum by substantia nigra transplants: Functional consequences as revealed by pharmacological and sensorimotor testing. Brain Res. 1980;199:307–333. [PubMed: 7417786]
67.
Schmidt RH, Ingvar M, Lindvall O. et al. Functional activity of substantia nigra grafts reinnervating the striatum: Neurotransmitter metabolism and [14C]2-deoxy-d-glucose autoradiography. J Neurochem. 1982;38:737–748. [PubMed: 6120214]
68.
Jaeger CB. Cytoarchitectonics of substantia nigra grafts: A light and electron microscopic study of immunocytochemically identified dopaminergic neurons and fibrous astrocytes. J Comp Neurol. 1985;231:121–135. [PubMed: 3968226]
69.
Strömberg I, Johnson S, Hoffer BJ. et al. Reinnervation of dopamine-denervated striatum by substantia nigra transplants: Immunohistochemical and electrophysiological correlates. Neuroscience. 1985;14:981–990. [PubMed: 2860618]
70.
Brundin P, Björklund A. Survival, growth and function of dopaminergic neurons grafted to the brain. Prog Brain Res. 1987;71:293–308. [PubMed: 3588950]
71.
Zetterström T, Brundin P, Gage FH. et al. Spontaneous release of dopamine from intrastriatal nigral grafts as monitored by the intracerebral dialysis technique. Brain Res. 1986;362:344–349. [PubMed: 2417666]
72.
Rose G, Gerhardt G, Strömberg I. et al. Monoamine release from dopamine-depleted rat caudate nucleus reinnervated by substantia nigra transplants: An in vivo electrochemical study. Brain Res. 1985;341:92–100. [PubMed: 4041791]
73.
Freund TF, Bolam JP, Björklund A. et al. Efferent synaptic connections of grafted dopaminergic neurons reinnervating the host neostriatum: A tyrosine hydroxylase immunocytochemical study. J Neurosci. 1985;5:603–616. [PubMed: 2857778]
74.
Mahalik TJ, Finger TE, Strömberg I. et al. Substantia nigra transplants into denervated striatum of the rat: Ultrastructure of graft and host interconnections. J Comp Neurol. 1985;240:60–70. [PubMed: 2865279]
75.
Freed WJ, Ko GN, Niehoff DL. et al. Normalization of spiroperidol binding in the denervated rat striatum by homologous grafts of substantia nigra. Science. 1983;222:937–939. [PubMed: 6635666]
76.
Arbuthnott G, Dunnett SB, MacLeod N. Electrophysiological properties of single units in dopamine-rich mesencephalic transplants in rat brain. Neurosci Lett. 1985;57:205–210. [PubMed: 2993967]
77.
Björklund A, Schmidt RH, Stenevi U. Functional reinnervation of the neostriatum in the adult rat by use of intraparenchymal grafting of dissociated cell suspensions from the substantia nigra. Cell Tissue Res. 1980;212:39–45. [PubMed: 6254660]
78.
Björklund A, Stenevi U, Dunnett SB. et al. Functional reactivation of the deafferented neostriatum by nigral transplants. Nature (Lond) 1981;289:497–499. [PMC free article: PMC100331] [PubMed: 6258079]
79.
Dunnett SB, Björklund A, Stenevi U. et al. Behavioural recovery following transplantation of substantia nigra in rats subjected to 6-OHDA lesions of the nigrostriatal dopamine pathway. I. Unilateral lesions. Brain Res. 1981;215:147–161. [PubMed: 7260584]
80.
Dunnett SB, Björklund A, Stenevi U. et al. Behavioural recovery following transplantation of substantia nigra in rats subjected to 6-OHDA lesions of the nigrostriatal dopamine pathway.II. Bilateral lesions. Brain Res. 1981;229:457–470. [PubMed: 6796197]
81.
Brundin P, Isacson O, Gage FH. et al. The rotating 6-hydroxydopamine-lesioned mouse as a model for assessing functional effects of neuronal grafting. Brain Res. 1986;366:346–349. [PubMed: 3084035]
82.
Björklund A, Lindvall O, Isacson O. et al. Mechanisms of action of intracerebral neural implants: Studies on nigral and striatal grafts to the lesioned striatum. Trends Neurosci. 1987;10:509–516.
83.
Brundin P, Nilsson OG, Strecker RE. et al. Behavioural effects of human fetal dopamine neurons grafted in a rat model of Parkinson's disease. Exp Brain Res. 1986;65:235–240. [PubMed: 3542544]
84.
Clarke DJ, Brundin P, Strecker RE. et al. Human fetal dopamine neurons grafted in a rat model of Parkinson's disease: Ultrastructural evidence for synapse formation using tyrosine hydroxylase immunocytochemistry. Exp Brain Res. 1988;73:115–126. [PubMed: 3145209]
85.
Lindvall O, Rehncrona S, Gustavii B. et al. Fetal dopamine-rich mesencephalic grafts in Parkinson's disease. Lancet. 1988;2:1483–1484. [PubMed: 2904587]
86.
Lindvall O, Rehncrona S, Brundin P. et al. Human fetal dopamine neurons grafted into the striatum in two patients with severe Parkinson's disease: A detailed account of methodology and a 6-month follow-up. Arch Neurol. 1989;46:615–631. [PubMed: 2786405]
87.
Lindvall O. Transplantation into the human brain: Present status and future possibilities. J Neurol Neurosurg Psychiat. 1989;Suppl:39–54. [PMC free article: PMC1033308] [PubMed: 2666578]
88.
Lindvall O, Brundin P, Widner H. et al. Grafts of fetal dopamine neurons survive and improve motor function in Parkinson's disease. Science. 1990;247:574–577. [PubMed: 2105529]
89.
Brundin P, Odin P, Widner H. Promising new results with transplantation of nerve cells to the brain in Parkinson disease. Lakartidningen. 1990;87:3761–3763. [PubMed: 2233056]
90.
Brundin P, Björklund A, Lindvall O. Practical aspects of the use of human fetal brain tissue for intracerebral grafting. Prog Brain Res. 1990;2:707–714. [PubMed: 2290974]
91.
Lindvall O, Rehncrona S, Brundin P. et al. Neural transplantation in Parkinson's disease: The Swedish experience. Prog Brain Res. 1990;82:729–734. [PubMed: 2290977]
92.
Lindvall O. Prospects of transplantation in human neurodegenerative diseases. Trends Neurosci. 1991;14:376–384. [PubMed: 1721746]
93.
Lindvall O, Björklund A, Widner H., eds.Intracerebral Transplantation in Movement Disorders: Experimental Basis and Clinical Experiences. Amsterdam: Elsevier,1991.
94.
Widner H, Brundin P, Rehncrona S. et al. Transplanted allogeneic fetal dopamine neurons survive and improve motor function in idiopathic Parkinson's disease. Transplant Proc. 1991;23:793–795. [PubMed: 1990693]
95.
Lindvall O. Transplants in Parkinson's disease. Eur Neurol. 1991;31([Suppl 1]):17–27. [PubMed: 1855521]
96.
Lindvall O, Widner H, Rehncrona S. et al. Transplantation of fetal dopamine neurons in Parkinson's disease: One-year clinical and neurophysiological observations in two patients with putaminal implants. Ann Neurol. 1992;31:155–165. [PubMed: 1575454]
96.
Widner H, Tetrud J, Rehncrona S. et al. Bilateral fetal mesencephalic grafting in two patients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) N Engl J Med. 1992;327:1556–1563. [PubMed: 1435882]
98.
Widner H, Tetrud J, Rehncrona S. et al. Fifteen months' follow-up on bilateral embryonic mesencephalic grafts in two cases of severe MPTP-induced Parkinsonism. Adv Neurol. 1993;60:729–733. [PubMed: 8420218]
99.
Widner H, Rehncrona S. Transplantation and surgical treatment of Parkinsonian syndromes. Curr Opin Neurol Neurosurg. 1993;6:344–349. [PubMed: 8507904]
100.
Lindvall O, Sawle G, Widner H. et al. Evidence for long-term survival and function of dopaminergic grafts in progressive Parkinson's disease. Ann Neurol. 1994;35:172–180. [PubMed: 8109898]
101.
Hitchcock ER, Clough C, Hughes R. et al. Embryos and Parkinson's disease. Lancet. 1988;1:1274. [PubMed: 2897530]
102.
Hitchcock ER, Kenny BG, Clough CG. et al. Stereotactic implantation of foetal mesencephalon (STIM): the UK experience. Prog Brain Res. 1990;82:723–728. [PubMed: 2290976]
103.
Quinn NP. The clinical application of cell grafting techniques in patients with Parkinson's disease. Prog Brain Res. 1990;82:619–625. [PubMed: 2290963]
104.
Hitchcock ER, Kenny BG, Clough CG. et al. Stereotactic implantation of foetal mesencephalon (STIM): The UK experience. Prog Brain Res. 1990;82:723–728. [PubMed: 2290976]
105.
Henderson B T H, Kenny BG, Hitchcock ER. et al. A comparative evaluation of clinical rating scales and quantitative measurements in assessment pre and post striatal implantation of human foetal mesencephalon in Parkinson's disease. Acta Neurochir Suppl (Wien) 1991;52:48–50. [PubMed: 1792966]
106.
Henderson BT, Clough CG, Hughes RC. et al. Implantation of human fetal ventral mesencephalon to the right caudate nucleus in advanced Parkinson's disease. Arch Neurol. 1991;48:822–827. [PubMed: 1898256]
107.
Hitchcock ER, Kenny BG, Henderson B T H. et al. A series of experimental surgery for advanced Parkinson's disease by foetal mesencephalic transplantation. Acta Neurochir Suppl (Wein) 1991;52:54–57. [PubMed: 1792968]
108.
Hitchcock ER. Neural implants and recovery of function: Human work. Adv Exp Med Biol. 1992;325:67–78. [PubMed: 1337822]
109.
Sinden JD, Patel SN, Hodges H. Neural transplantation: Problems and prospects for therapeutic application. Curr Opin Neurol Neurosurg. 1992;5:902–908. [PubMed: 1361375]
110.
Sawle GV, Bloomfield PM, Björklund A. et al. Transplantation of fetal dopamine neurons in Parkinson's disease: PET [18F]6-L-fluorodopa studies in two patients with putaminal implants. Ann Neurol. 1992;31:166–173. [PubMed: 1575455]
111.
Henderson B, Good PA, Hitchcock ER. et al. Visual evoked cortical responses and electroretinograms following implantation of human fetal mesencephalon to the right caudate nucleus in Parkinson's disease. J Neurol Sci. 1992;107:183–190. [PubMed: 1564516]
112.
Sawle GV, Myers R. The role of positron emission tomography in the assessment of human neurotransplantation. Trends Neurosci. 1993;16:172–176. [PubMed: 7685938]
113.
Madrazo I, León V, Torres C. et al. Transplantation of fetal substantia nigra and adrenal medulla to the caudate nucleus in two patients with Parkinson's disease. N Engl J Med. 1988;318:51. [PubMed: 3336384]
114.
Madrazo I, Franco-Bourland R, Ostrosky-Solis F. et al. Neural transplantation (auto-adrenal, fetal nigral and fetal adrenal) in Parkinson's disease: The Mexican experience. Prog Brain Res. 1990;82:593–602. [PubMed: 1981281]
115.
Freed CR, Breeze RE, Rosenberg NL. et al. Transplantation of human fetal dopamine cells for Parkinson's disease: Results at 1 year. Arch Neurol. 1990;47:505–512. [PubMed: 2334298]
116.
Freed CR, Breeze RE, Rosenberg NL. et al. Therapeutic effects of human fetal dopamine cells transplanted in a patient with Parkinson's disease. Prog Brain Res. 1990;82:715–721. [PubMed: 2290975]
117.
Fiandaca MS. Brain grafting for Parkinson's disease. Transplantation. 1991;51:549–556. [PubMed: 2006508]
118.
Spencer DD, Robbins RJ, Naftolin F. et al. Unilateral transplantation of human fetal mesencephalic tissue into the caudate nucleus of patients with Parkinson's disease. N Engl J Med. 1992;327:1541–1548. [PubMed: 1435880]
119.
Freed CR, Breeze RE, Rosenberg NL. et al. Survival of implanted fetal dopamine cells and neurologic improvement 12 to 46 months after transplantation for Parkinson's disease. N Engl J Med. 1992;327:1549–1555. [PubMed: 1435881]
120.
Bakay R A E. Central nervous system grafting: Animal and clinical results. Stereotact Funct Neurosurg. 1992;58:67–78. [PubMed: 1439352]
121.
Thompson L. Fetal transplants show promise. Science. 1992;257:868–870. [PubMed: 1502548]
122.
Langston JW, Widner H, Goetz CG. et al. Core assessment program for intracerebral transplantation (CAPIT) Mov Disord. 1992;7:2–13. [PubMed: 1557062]
123.
Goetz CG, De Long MR, Penn RD. et al. Neurosurgical horizons in Parkinson's disease. Neurology. 1993;43:1–7. [PubMed: 8423869]
124.
Freed CR, Breeze RE, Rosenberg NL. et al. Embryonic dopamine cell implants as a treatment for the second phase of Parkinson's disease: Replacing failed nerve terminals. Adv Neurol. 1993;60:721–728. [PubMed: 8420217]
125.
Redmond D E Jr, Robbins RJ, Naftolin F. et al. Cellular replacement of dopamine deficit in Parkinson's disease using human fetal mesencephalic tissue: Preliminary results in four patients. Res Publ Assoc Res Nerv Ment Dis. 1993;71:325–359. [PubMed: 8417471]
126.
Rauch RA, Markham CH, Rand RW. et al. MR imaging findings after transplant surgery for Parkinson disease. J Magn Reson Imaging. 1994;4:19–24. [PubMed: 8148551]
127.
Freeman TB, Olanow CW, Hauser RA. et al. Bilateral fetal nigral transplantation into the postcommissural putamen in Parkinson's disease. Ann Neurol. 1995;38:379–388. [PubMed: 7668823]
128.
Kordower JH, Freeman TB, Snow BJ. et al. Neuropathological evidence of graft survival and striatal reinnervation after the transplantation of fetal mesencephalic tissue in a patient with Parkinson's disease. N Engl J Med. 1995;332:1118–1124. [PubMed: 7700284]
129.
Price LH, Spencer DD, Marek KL. et al. Psychiatric status after human fetal mesencephalic tissue transplantation in Parkinson's disease. Biol Psychiat. 1995;38:498–505. [PubMed: 8562661]
130.
Olanow CW, Kordower JH, Freeman TB. Fetal nigral transplantation as a therapy for Parkinson's disease. Trends Neurosci. 1996;19:102–109. [PubMed: 9054056]
131.
Kopyov OV, Jacques DS, Lieberman A. et al. Clinical study of fetal mesencephalic intracerebral transplants for the treatment of Parkinson's disease. Cell Transplantation. 1996;5:327–337. [PubMed: 8689043]
132.
Molina H, Quiñones R, Alvarez L. et al. Transplantation of human fetal mesencephalic tissue in caudate nucleus as treatment for Parkinson's disease: The Cuban experience. Restor Neurol. 1991;4:99–110.
133.
Bekhtereva NP, Gilerovich EG, Gurchin FA. et al. Transplantation of embryonal nerve tissues in the treatment of Parkinson disease. Zh Nevropatol Psikhiatr SS Korsakova. 1990;90:10–13. [PubMed: 1963958]
134.
Subrt O, Tichy M, Vladyka V. et al. Grafting of fetal dopamine neurons in Parkinson's disease: The Czech experience with severe akinetic patients. Acta Neurochir Suppl (Wien) 1991;52:51–53. [PubMed: 1792967]
135.
Marsala J, Zigova T, Badonic T. et al. Neurotransplantation, critical analysis and perspectives. Bratisl Lek Listy. 1992;93:111–122. [PubMed: 1525684]
136.
Jones D. Halifax hospital first in Canada to proceed with controversial fetal-tissue transplant. Can Med Assoc J. 1992;146:389–391. [PMC free article: PMC1488249] [PubMed: 1544055]
137.
Lopez-Lozano JJ, Brera B, Bravo G. et al. Neural transplants in Parkinson's disease. CPH Neural Transplantation Group. Transplant Proc. 1993;25:1005–1011. [PubMed: 8442023]
138.
Lopez-Lozano JJ, Bravo G, Brera B. et al. Long-term follow-up in 10 Parkinson's disease patients subjected to fetal brain grafting into a cavity in the caudate nucleus: The Clinica Puerta de Hierro experience. CPH Neural Transplantation Group. Transplant Proc. 1995;27:1395–1400. [PubMed: 7878925]
139.
Iacono RP, Tang ZS, Mazziotta JC. et al. Bilateral fetal grafts for Parkinson's disease: 22 months' results. Stereotact Funct Neurosurg. 1992;58:84–87. [PubMed: 1439354]
140.
Zabek M, Mazurowski W, Dymecki J. et al. Transplantation of fetal dopaminergic cells in Parkinson disease. Neurol Neurochir Pol. 1992;Suppl 1:13–19. [PubMed: 1407286]
141.
Remy P, Samson Y, Hantraye P. et al. Clinical correlates of [18F]fluorodopa uptake in five grafted parkinsonian patients. Ann Neurol. 1995;38:580–588. [PubMed: 7574454]
142.
Goetz CG, Bakay R A E, Fine A. et al. American Society for Neural Transplantation Registry for fetal mesencephalic implants: Demographic and baseline data. Abstr Am Soc Neural Transpl. 1996;3:25.
143.
Boer GJ. Ethical guidelines for the use of human embryonic or fetal tissue for experimental and clinical neurotransplantation and research. Network of European CNS Transplantation and Restoration (NECTAR) J Neurol. 1994;242:1–13. [PubMed: 7897446]
144.
Wolfslast G. Legal aspects of neurotransplantation. Zentralbl Neurochir. 1995;56:210–214. [PubMed: 8571703]
Copyright © 2000-2013, Landes Bioscience.
Bookshelf ID: NBK6271
PubReader format: click here to try

Views

  • PubReader
  • Print View
  • Cite this Page

Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...