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)

Patients with Parkinson's disease have received intracerebral transplants of autologous adrenal medulla in the attempt to counteract their severe motor dysfunctions. Unfortunately, in the majority of cases, clinical improvement has not persisted and there has been extremely poor survival of the grafts. Based on the recent observations of long-term viability of adrenal medulla grafts in the interior of transected peripheral nerves, adrenal medulla/peripheral nerve complexes were constructed in the brain to promote extended viability of chromaffin cells. A three-step, time-dependent transplantation procedure is described that results in a 100% survival rate of the adrenal medulla graft. The grafts consist of a stable population of approximately 2.0 x 10(3) chromaffin cells that survive for at least 6 months (longest time point studied): Immunoreactivity to catecholamine-related enzymes (tyrosine hydroxylase, dopamine beta-hydroxylase) and the low-affinity NGF receptor (192-IgG) are expressed by the chromaffin cells. The ultrastructural characteristics of the cells are normal and comparable to their in vivo counterparts. Construction of these peripheral nerve/adrenal medulla complexes evidently improves local conditions in and around the grafts, enabling the chromaffin cells to remain viable. This new methodology achieves the goal of reliable and extended survival of the adrenal medulla graft after intracerebral transplantation. The enhanced longevity now provides an opportunity to reevaluate the efficacy of the adrenal medulla transplant to ameliorate the functional disorders associated with striatal dopamine depletion, especially over long time periods.
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PMID:Peripheral nerve segments promote consistent long-term survival of adrenal medulla transplants in the brain. 136 82

Intracerebral adrenal medulla grafts have been used in human patients as an experimental treatment for Parkinson's disease, based on studies in animal models of this disorder. However, alterations in chromaffin cell properties after transplantation and the factors controlling graft survival are poorly understood. Since cell adhesion molecules (CAMs) are involved in regeneration and development of neural tissue in vivo and in vitro, the present study was undertaken to determine the expression of CAMs in adrenal medulla isografts. Fragments of rat adrenal medulla were implanted into the right lateral ventricle. The majority of grafts survived quite well, for up to 2 months (the longest studied period). The implanted chromaffin cells did not develop extensive processes. The cells retained tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH) immunoreactivity, while phenylethanolamine N-methyltransferase (PNMT) expression was decreased. Surviving transplanted chromaffin cells showed enhancement and spreading of surface L1/Ng-CAM expression as compared to normal chromaffin cells in adrenal medulla. The implanted chromaffin cells demonstrated only partial conversion to neuronal phenotypes. These chromaffin cells did not develop extensive processes, but showed an enhancement of L1/Ng-CAM expression. Surviving chromaffin cells were accompanied by reorganization of their closely associated extracellular matrix (ECM). As compared to normal in situ adrenal medulla, graft ECM demonstrated a substantial increase of L1/Ng-CAM and laminin immunoreactivities and a distinct decrease in J1/tenascin expression. Some adrenal medulla grafts degenerated, particularly when misplaced within the host brain parenchyma. In these cases the grafts showed fragmentation of ECM and gradual disappearance of CAMs. These results suggest that surviving adrenal medulla grafts exhibit increased synthesis of certain CAMs by chromaffin cells, which may be involved in interactions between chromaffin cells and the surrounding ECM. It is speculated that both surviving and degenerating adrenal medulla grafts could provide CAMs and ECM components including laminin to host brain and this way contribute to functional effects of grafts.
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PMID:Cell adhesion molecules in adrenal medulla grafts: enhancement of chromaffin cell L1/Ng-CAM expression and reorganization of extracellular matrix following transplantation. 220 83

A sandwich enzyme immunoassay (EIA) was established by using purified beta 2-microglobulin (beta 2-MG) as a standard protein and a polyclonal antibody raised against human beta 2-MG. The EIA was applied for the measurement of beta 2-MG levels in human cerebrospinal fluid (CSF) from parkinsonian patients and control patients devoid of neurological diseases. beta 2-MG contents in CSF of the control group and the parkinsonian group were 1.81 +/- 0.11 micrograms/ml CSF and 0.63 +/- 0.09 microgram/ml CSF, respectively. Thus, beta 2-MG content in CSF was reduced in parkinsonian patients to less than 35% of the control value (P less than 0.005). We had previously reported that the activity and content of dopamine beta-hydroxylase (DBH) were decreased in CSF from parkinsonian patients. A significant positive correlation (r = 0.87) was observed between the beta 2-MG content and DBH activity for CSF from 45 patients. These results suggest a probable link between an immunological change and the changes in catecholaminergic neurons in Parkinson's disease.
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PMID:Beta 2-microglobulin decrease in cerebrospinal fluid from parkinsonian patients. 268 94

The concentration of neuropeptide Y has been determined in the cortex and hippocampus of subjects with Parkinson's disease and compared to changes of activity of dopamine beta-hydroxylase and concentration of somatostatin. Despite a marked reduction in the concentration of somatostatin in the severely demented subject, in both cortex and hippocampus, no significant change in concentration of NPY was found in either region. This finding therefore suggests that the majority of NPY within the cortex is independent of somatostatin. This study provides some further evidence of neurochemical similarities between the dementia of Parkinson's disease and Alzheimer's disease.
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PMID:Dissociation of neuropeptide Y and somatostatin in Parkinson's disease. 286 Sep 55

Recent reports of adrenal medullary autografts in patients with Parkinson's disease raise several important questions with respect to the cell types actually being transplanted as well as the potential for chromaffin cell banking prior to neural transplantation. In this study, we determined the general morphological characteristics of the human adrenal medulla and assessed factors important for the maintenance of cultured chromaffin cells for later use as transplants. The human adrenal medulla contained islands of cortical cells scattered throughout the gland as well as Schwann cells, nerve endings, endothelial cells, pericytes, isolated ganglionic neurons, and connective tissue elements such as fibroblasts and smooth muscle cells. Because many of these cell types are mitotically active, transplantation of medullary fragments that contain these cells could have far-reaching consequences. One approach that could circumvent the problems arising from multiple cell types in the medulla is differential plating of chromaffin cells prior to transplantation. Differential plating yielded relatively pure populations of chromaffin cells that demonstrated excellent viability if processed within 2 hours after cessation of the gland's circulation. Chromaffin cells cultured in the presence of nerve growth factor exhibited a neuronal phenotype, possessed catecholamine histofluorescence, and displayed tyrosine hydroxylase- and dopamine beta-hydroxylase-like immunoreactivity. The sex and age of the donor did not affect cell viability or morphological characteristics.
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PMID:Organization, fine structure, and viability of the human adrenal medulla: considerations for neural transplantation. 320 12

1. Dopamine beta-hydroxylase is stored and released with catecholamines by exocytosis from secretory vesicles in noradrenergic neurons and chromaffin cells. Although dopamine beta-hydroxylase enzymic activity is measurable in cerebrospinal fluid, such activity is unstable, and its relationship to central noradrenergic neuronal activity in humans is not clearly established. To explore the significance of cerebrospinal fluid dopamine beta-hydroxylase, we applied a homologous human dopamine beta-hydroxylase radioimmunoassay to cerebrospinal fluid, in order to characterize the properties and stability of cerebrospinal fluid dopamine beta-hydroxylase, as well as its relationship to central noradrenergic neuronal activity and its variation in disease states such as hypertension, renal failure, Parkinsonism and congenital dopamine beta-hydroxylase deficiency. 2. Authentic, physically stable dopamine beta-hydroxylase immunoreactivity was present in normal human cerebrospinal fluid at a concentration of 31.3 +/- 1.4 ng/ml (range: 18.5-52.5 ng/ml), but at a 283 +/- 27-fold lower concentration than that found in plasma. Cerebrospinal fluid and plasma dopamine beta-hydroxylase concentrations were correlated (r = 0.67, P = 0.001). Some degree of local central nervous system control of cerebrospinal fluid dopamine beta-hydroxylase was suggested by incomplete correlation with plasma dopamine beta-hydroxylase (with an especially marked dissociation in renal disease) as well as the lack of a ventricular/lumbar cerebrospinal dopamine beta-hydroxylase concentration gradient. 3. Cerebrospinal fluid dopamine beta-hydroxylase was not changed by the central alpha 2-agonist clonidine at a dose that diminished cerebrospinal fluid noradrenaline, nor did cerebrospinal fluid dopamine beta-hydroxylase correspond between subjects to cerebrospinal fluid concentrations of noradrenaline or methoxyhydroxyphenylglycol; thus, cerebrospinal fluid dopamine beta-hydroxylase concentration was not closely linked either pharmacologically or biochemically to central noradrenergic neuronal activity. 4. Cerebrospinal fluid dopamine beta-hydroxylase was not changed in essential hypertension. In Parkinson's disease, cerebrospinal fluid dopamine beta-hydroxylase was markedly diminished (16.3 +/- 2.9 versus 31.3 +/- 1.4 ng/ml, P < 0.001) and rose by 58 +/- 21% (P = 0.02) after adrenal-to-caudate chromaffin cell autografts. In congenital dopamine beta-hydroxylase deficiency, lack of detectable dopamine beta-hydroxylase immunoreactivity in cerebrospinal fluid or plasma suggests absent enzyme (rather than a catalytically defective enzyme) as the origin of the disorder. 5. We conclude that cerebrospinal fluid dopamine beta-hydroxylase immunoreactivity, while not closely linked to central noradrenergic neuronal activity, is at least in part derived from the central nervous system, and that its measurement may be useful in both the diagnosis and treatment of neurological disease.
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PMID:Dopamine beta-hydroxylase immunoreactivity in human cerebrospinal fluid: properties, relationship to central noradrenergic neuronal activity and variation in Parkinson's disease and congenital dopamine beta-hydroxylase deficiency. 814 25

Four different forms of primary autonomic failure (multiple system atrophy, pure autonomic failure, Parkinson's disease and dopamine beta-hydroxylase deficiency) have been described. The first part of the article will focus on the interest to pharmacology of elucidating pathophysiological mechanisms underlying autonomic involvement at the central level (growth hormone response to clonidine acute challenge), presynaptic level (plasma catecholamine levels after yohimbine administration) and on post-synaptic receptors (binding studies, pressor responses to noradrenaline). The second part will discuss efficacy and side-effects of some of the many drugs which are currently proposed for the treatment of one of the most disabling symptoms related to autonomic failure, orthostatic hypotension. Special attention will be paid to drugs acting on blood composition (fludrocortisone, erythropoietin), on post-synaptic alpha-adrenoceptors (midodrine and clonidine) and on noradrenaline spill-over (yohimbine and L-Threo-DOPS).
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PMID:[Pharmacologic approach to autonomic failure]. 977 98

Neuronal injury has been consistently found in A10 midbrain dopamine neurons in Parkinson's disease (PD). To assess changes in neurotransmitter-related gene transcription, in these neurons in PD, tyrosine hydroxylase (TH) mRNA expression was examined in the ventral tegmental area (VTA) of seven PD cases and seven control subjects, using in situ hybridization histochemistry (ISHH). In controls, TH mRNA expression was found in both melanised and non-melanised neurons in the VTA. Neither population expressed dopamine beta-hydroxylase (DBH). Of the melanised neurons, 99% were TH mRNA positive. The level of the TH mRNA signal (expressed as grain density per cell) was similar in the two populations (melanised: 0.129+/-0.004 (mean+/-S.E.M.), n=142 vs. non-melanised: 0.138+/-0.006, n=89, P>0.05, Student's t-Test). In PD cases there was no significant change in TH mRNA expression in melanised neurons (0.138+/-0.003, n=196), and the proportion of positively labeled melanised neurons was 98%. However, non-melanised neurons showed significantly higher TH mRNA (0.163+/-0.006, n=87) than non-melanised neurons in control subjects (P<0.005) and melanised neurons in the PD cases (P<0.0005). This up-regulation of TH mRNA expression in non-melanised neurons may suggest the existence of a compensatory mechanism at presynaptic level.
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PMID:Up-regulation of tyrosine hydroxylase mRNA in a sub-population of A10 dopamine neurons in Parkinson's disease. 1092 42

Dopamine (DA) neurons degenerate in Parkinson's disease and dopamine neurotransmission may be affected in psychotic states seen in schizophrenia. Understanding the regulation of enzymes involved in DA metabolism may therefore lead to new treatment strategies for these severe conditions. We investigated mRNA expression of the cytosolic aldehyde dehydrogenase (ALDH1), presumably involved in DA degradation, by in situ hybridization in DA neurons of human postmortem material. Parallel labeling for GAPDH, neuron-specific enolase, tyrosine hydroxylase, dopamine transporter, and dopamine beta-hydroxylase was used to ensure suitability of tissue specimen and to identify all dopamine neurons. ALDH1 was found to be expressed highly and specifically in DA cells of both substantia nigra (SN) and the ventral tegmental area (VTA) of controls. A marked reduction of ALDH1 expression was seen in surviving neurons of SN pars compacta but not of those in the VTA in Parkinson's disease. In patients suffering from schizophrenia we found ALDH1 expression at normal levels in DA cells of SN but at significantly reduced levels in those of the VTA. We conclude that ALDH1 is strongly and specifically expressed in human mesencephalic dopamine neurons and that low levels of ALDH1 expression correlate with DA neuron dysfunction in the two investigated human conditions.
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PMID:ALDH1 mRNA: presence in human dopamine neurons and decreases in substantia nigra in Parkinson's disease and in the ventral tegmental area in schizophrenia. 1467 78

A functional --1021C --> T polymorphism in the dopamine beta-hydroxylase gene has been demonstrated to regulate plasma DBH activity. We report that individuals with genetically determined low serum DBH activity (genotype T/T) have protection against Parkinson's disease (p = 0.01). In particular, we observed an underrepresentation of the T/T genotype odds ratio = 0.46 (CI = 0.27-0.8). Rather than identifying a haplotype, or a marker in linkage disequilibrium with the risk variant, this to our knowledge is the first report directly linking PD susceptibility with a proven functional variant.
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PMID:A functional polymorphism regulating dopamine beta-hydroxylase influences against Parkinson's disease. 1499 26


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