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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

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