Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuronal properties of the human globus pallidus (GP) are not known. Since GP is the major output of the basal ganglia, it may be involved in the pathophysiology of Parkinson's disease. We studied 12 patients with medically resistant Parkinson's disease by using single cell recording of the GP during stereotaxic pallidotomy to define neuronal firing rate and its modulation during active and passive movements. Different frequency and pattern of single cell activity was found in globus pallidus externus compared with globus pallidus internus. Discharge rates of 19% of GP cells were modulated by passive contralateral movements. Pallidal units were most often related solely to single joint movement. Different patterns of activity in relation to the two different movements of the same joint were often observed. We identified somatotopically arranged cell clusters that alter discharge rate with related movements. These findings suggest at least a partial somatotopic organization of the human GP and similarity with experimental results in both healthy and MPTP monkeys, providing a rationale for surgical or pharmacological targeting of GP for treating Parkinson's disease.
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PMID:Neurophysiological properties of pallidal neurons in Parkinson's disease. 817 4

The survival of ventral mesencephalic substantia nigra (SN) dopamine neurons, which degenerate in Parkinson's disease, is enhanced by glial cells in vitro. The recent isolation of glial cell line-derived growth factor (GDNF), a molecule with apparently selective effects on dopamine (DA) neurons in vitro, raises the question of whether this factor is found in normal brain cells. In this study, the polymerase chain reaction (PCR) was employed to determine the regional distribution and cellular localization of GDNF in the rat central nervous system. GDNF was expressed by SN and basal forebrain Type 1 (T1) astrocytes, with trace transcript levels present in cortical T1 astrocytes. Neuronal cultures of embryonic SN also expressed GDNF. Regionally, postnatal striatum contained the highest GDNF mRNA levels in vivo under the PCR conditions employed. Our data suggest a role for GDNF in both local and target-derived support of DA neurons, as well as potential involvement in the support of other neuronal populations in vivo.
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PMID:Regional and cell-specific expression of GDNF in rat brain. 828 32

Neuronal loss in the substantia nigra of patients with Parkinson's disease (PD) does not occur evenly throughout the nucleus: the ventrolateral part of the substantia nigra degenerates more severely, whereas the medial part is relatively preserved. This pattern of nigral neuronal loss is compatible with the uneven loss of dopamine in the striatum (the putamen more affected than the caudate nucleus). The predominant loss of ventrolateral nigrostriatal projections in PD, leading to substantial loss of dopamine especially in the putamen, is thought to contribute to the motor symptoms of the patients. On the other hand, the more medial nigral projections may be involved in the cognitive symptoms of patients. Selegiline (L-deprenyl) has been shown to delay the need to initiate levodopa therapy in early PD, and selegiline has also been suggested to increase the survival of PD patients. These observations have led to the proposal of selegiline's neuron-saving effect in PD. There is some pathological evidence supporting the better survival of nigral neurons in PD patients treated with selegiline as compared with those without such treatment. Further studies are, however, needed to elucidate this question more clearly.
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PMID:Nigral degeneration in Parkinson's disease. 830 5

Nigrostriatal dopaminergic neurons play an essential role in the central regulation of motor functions. These functions are initiated through the release of dopamine from axon terminals in the striatum or from dendrites in the substantia nigra (SN) and are terminated by the reuptake of dopamine by the sodium- and chloride-dependent dopamine transporter (DAT). DAT also can transport dopamine neurotoxins and has been implicated in the selective vulnerability of nigrostriatal dopaminergic neurons in major models of Parkinson's disease. We have used electron microscopic immunocytochemistry with an N-terminal domain anti-peptide antibody to examine the subcellular distribution of DAT in the rat SN and dorsolateral striatum. In the SN, immunogold labeling for DAT was localized to cytoplasmic surfaces of plasma membranes and smooth endoplasmic reticulum of dendrites and dendritic spines, few of which contained synaptic vesicles. Neuronal perikarya in the SN contained immunogold-labeled pleomorphic electron-lucent tubulovesicles but showed immunolabeling of plasma membranes only rarely. Axon terminals in the striatum contained extensive immunogold labeling of cytoplasmic surfaces of plasma membranes near aggregates of synaptic vesicles and less frequent labeling of intervaricose segments of plasma membrane or small electron-lucent vesicles. In sections dually labeled for DAT and the catecholamine-synthesizing enzyme tyrosine hydroxylase, both markers were colocalized in most profiles in the SN and striatum. These findings support the proposed topological model for DAT and suggest that this transporter is strategically located to facilitate uptake of dopamine and neurotoxins into distal dendritic and axonal processes of nigrostriatal dopaminergic neurons.
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PMID:The dopamine transporter is localized to dendritic and axonal plasma membranes of nigrostriatal dopaminergic neurons. 855 28

Neuronal transplantation of dopaminergic embryonic ventral mesencephalic cells aims at replacing the lost striatal dopamine in Parkinson's disease. Functional effects of intrastriatal ventral mesencephalic transplants are reflected in improvements of bradykinesia and rigidity. However, a more widespread clinical application critically depends on further technical refinements, specifically in the area of improved survival of the grafted ventral mesencephalic dopamine neurones. This review highlights some of the progress made in the field of ventral mesencephalic transplantation in animal models of Parkinson's disease and also discusses issues and results obtained by our own research group in Munich. Thus we studied whether cryo- or neuroprotective additives during cryopreservation of ventral mesencephalic tissue can improve survival of such tissue/cells following transplantation. Concerning immunological aspects we studied the effects of pooled or co-transplanted embryonic tissue on survival and function of grafts and whether immunosuppression with cyclosporine A has beneficial effects. Possible neurotoxic effects of cyclosporine A were considered in a separate study. Finally, we established in vivo voltammetry to measure dopamine release from the graft and effects of the grafts on related parts of the dopaminergic system in the living animal. In the clinic we employed guidelines for preoperative patient evaluation and respective tests are described.
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PMID:[Neuronal transplantation in animal models of Parkinson disease: in vivo voltammetry, tissue cryopreservation and immunology]. 857 94

Neuronal death associated with plaque and tangle formation characteristic of Alzheimer's disease (AD) may result from an underlying defect of intracellular protein catabolism. In an attempt to identify the proteolytic enzyme types responsible for aberrant protein processing, we have composed the levels of activity of proline endopeptidase in brain tissue samples (grey/white matter) from frontal, parietal, temporal and occipital lobes, from normal control cases, and cases with AD, Lewy body dementia (LBD), Parkinson's disease (PD) and Huntington's disease (HD). The activity of proline endopeptidase was significantly reduced in AD to approximately 65% of that of corresponding control tissue-this is of note since previous biochemical analyses have in general failed to detect altered activity of other protease types in AD tissues. However, this relatively selective reduction in proline endopeptidase activity in AD tissue (in terms of protease types investigated) is not specific for disease type, since activity was also reduced (65%-70% of control) in tissue samples from LBD, PD and HD cases. The data suggest that reduction in proline endopeptidase activity may be a characteristic of a generalized process of neurodegeneration. Although the precise cellular function of this enzyme in normal/ pathological tissues remains to be determined, the question arises as to whether pharmacological strategies designed to enhance proline endopeptidase activity in brain tissue may improve patient outcome in the above disorders.
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PMID:Comparison of proline endopeptidase activity in brain tissue from normal cases and cases with Alzheimer's disease, Lewy body dementia, Parkinson's disease and Huntington's disease. 873 97

Several diseases related to brain aging seem to be due to neuronal loss and decreased synaptic functions. Therefore it is important to clarify the cellular and molecular mechanism of age-related-neuronal death and -reduction in synaptic activities in the brain. I here review recent advances in cellular and molecular studies on neuronal death and the decrease in synaptic functions. Neuronal death is caused not only with physiological aging but also by several pathological states such as 1) results from abnormal metabolism of beta APP (Alzheimer's disease), 2) increased level of extraneuronal glutamate and intracellular Ca2+/NO (cerebral ischemia), and 3) appearance of neurotoxic MPP+ (1-methyl-4-phenyl-pyridinium ion) (Parkinson's disease) etc. From neurotoxicological aspect of neuro-glial interaction, I introduce recent findings on signaling pathways of NO synthase induction in glial cells and cytotoxic action of NO in neurons. Furthermore I also describe and discuss our findings obtained in the brain of old rats as well as in senescence accelerated mice (accelerated aging substrain of AKR/J-mouse) regarding age-related changes in synaptic activity and neurotransmittor receptor-mediated signaling system.
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PMID:[Neurochemical aspect of brain aging--neuronal death and decreased synaptic functions]. 875 25

This review focuses on two restorative strategies against Parkinson's disease: (1) intrastriatal implantation of fetal dopamine producing cells and (2) application of neurotrophic factors. (1) Neuronal transplantation of dopaminergic embryonic ventral mesencephalic cells aims at compensating the striatal dopamine deficit in Parkinson's disease. Clinically, dopaminergic ventral mesencephalic grafts have been demonstrated to ameliorate rigidity, bradykinesia, and efficacy of L-DOPA therapy, for instance reduction of L-DOPA-induced dyskinesias and ON-OFF-fluctuations. Future experimental refinements predominantly concern the improvement of survival of the transplanted fetal dopaminergic neurons and the use of genetically modified cells. (2) Neurotrophic factor therapy relates to the prevention and/or restoration of the progressing nigral cell loss in Parkinson's disease. In this regard special emphasis is put on the newly characterized glial cell line-derived neurotrophic factor (GDNF). More recent results and perspectives of this concept are discussed.
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PMID:Neuronal transplantation and neurotrophic factors in the treatment of Parkinson's disease--update February 1995. 882 Oct 56

Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor which has been purified on the basis of its ability to promote the survival of dopaminergic neurons in vitro. GDNF has subsequently been cloned and its sequence shown to be distantly related to transforming growth factor-beta (TGF-beta). To identify GDNF expressing cells in the adult rat brain, in situ hybridization using a digoxygenin (DIG)-labelled riboprobe has been performed. Our results show that GDNF mRNA is mainly expressed in neurons and that its synthesis is not restricted to dopaminergic areas. It is widely expressed in the cortex, the hippocampus, the striatum, the substantia nigra, the thalamus, the cerebellum and the spinal cord. Neuronal GDNF expression varies among brain regions as determined by the intensity of the in situ signal. Double labelling of the substantia nigra using tyrosine hydroxylase immunohistochemistry, associated with GDNF in situ hybridization, show that the majority of dopaminergic neurons express GDNF. The widespread expression of GDNF throughout the adult brain suggests that its administration in Parkinson's disease should be restricted to the altered structures, in order to avoid possible deleterious side effects.
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PMID:Neuronal GDNF expression in the adult rat nervous system identified by in situ hybridization. 910 88

The qualitative changes in substantia nigra were analysed in the material of 25 cases of Parkinson's disease. A morphometric quantitative study of depletion of pigmented dopaminergic cells of substantia nigra was performed in six long-term cases of the disease. In addition, the number of melanin nodules was assessed as a marker of cell disintegration. The results obtained were compared with the morphometric evaluation of neuronal depletion in the mesocorticolimbic system (ventral tegmental area-VTA). The qualitative study indicated that melanin depletion in dopaminergic cells of substantia nigra in Parkinson's disease is diffuse and it is located mainly in the lateral alfa layer. Neuronal depletion with concomitant numerous extracellular neuromelanin nodules and granules was observed. A slight astrocytic gliosis free of macrophages accompanied cellular changes. The qualitative changes in substantia nigra are similar to those observed in VTA. The morphometric evaluation revealed that depletion of dopaminergic neurons in substantia nigra in Parkinson's disease is 73%, on average, while in VTA it remains under 5%. Hence, depletion in substantia nigra is much more intense. The analysis of the relationship between the number of neurons in substantia nigra and the age of subjects in the control group indicated that the number of neurons decreased proportionally to the age. In the group under study no significant relationship between neurons depletion and duration of disease or patients age was found. In the studied group of patients with Parkinson's disease, the number of melanin nodules in substantia nigra was significantly higher than in controls.
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PMID:[Morphometric assessment of lesions in the dopaminergic nigrostriatal system in Parkinson disease]. 914 73


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