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)

Family histories of male patients with histologically confirmed malignant gliomas were compared to family histories of controls (wives). Included were 77 case families with 892 relatives and 77 control families with 719 relatives. Cases had significantly more siblings than controls (P = 0.02), although cases were not preferentially the oldest or the youngest sibs. Odds ratios of two or more were found for mental retardation, Parkinson's disease, and meningitis for the relatives of cases versus controls, but none were statistically significant. The excesses of Parkinson's disease and meningitis were explained by the family of one particularly interesting case containing three relatives with meningitis and two relatives with Parkinson's disease. Noteworthy age-adjusted odds ratios for cancer among relatives of cases compared to relatives of controls were 1.6 (95% confidence interval (CI) = 1.0-2.3) for cancer of any site, 2.4 (95% CI = 0.8-6.1) for breast cancer, and 4.0 (95% CI = 0.6-10.7) for lung cancer. Only the odds ratio for cancer of any site was statistically significant. Overall, 6 of 77 (8%) of cases came from families that included two or more relatives with breast or lung cancer in addition to the proband with malignant glioma. These three cancer sites may form familial clusters worthy of further evaluation in future studies by pedigree and genetic linkage analyses.
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PMID:Familial factors associated with malignant gliomas. 222 74

The influence of memantine on several properties of a neuronal cell line was tested. The aim was to get some insight into possible mechanisms of action of this drug which is therapeutically applicable in treatment of spasticity, Parkinson's disease, and cerebral coma. In neuroblastoma X glioma hybrid cells, memantine, at micromolar concentrations, blocked the depolarization induced by iontophoretically applied serotonin (5-hydroxytryptamine, 5-HT). In the hybrid cells, receptors of the 5-HT3 type mediated the depolarization, which was frequently accompanied by a series of action potentials. The inhibition by memantine of the serotonin response occurred fast and was completely reversible, irrespective of whether the cell showed a stable membrane potential or spontaneous action potentials. However, memantine did not alter spontaneous or electrically evoked action potential activity in the hybrid cells, and apparently did not block the underlying ionic conductances. Furthermore memantine did not affect either the cation permeability activated by substance P in the hybrid cells or the K+ channel triggered by bradykinin in a glioma cell line. Thus, memantine appears specifically to suppress the ion channel opened by serotonin in the hybrid cells. The interaction of memantine with serotonin receptors and the associated ion channels reported here, might give an important clue, as to a site of action of memantine in the nervous system.
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PMID:Memantine (1-amino-3,5-dimethyladamantane) blocks the serotonin-induced depolarization response in a neuronal cell line. 335 74

1. Although glial cells in culture are known to secrete growth factors and are also known to be responsive to some of them, detailed comparisons are difficult because the bulk of information was based on various animals of origin, developmental stages, growth properties, culture age, and culture conditions. 2. To present a unified picture of the growth factors and their receptors found in glial cells, we surveyed the expression of messenger RNAs of a panel of growth factors and receptors, using reverse transcription-polymerase chain reaction (RT-PCR), in three common glial cell types: rat astrocytes in primary culture, rat glioma line C6, and human glioma line A172. 3. We observed that normal and neoplastic glial cells in culture express multiple growth factors and also possess most of the receptors to the factors, suggesting multiple autocrine functions. In addition, glia produce growth factors known to be capable of acting on neurons, implicating paracrine function involving glia-neuron interaction. Glial cells also produce growth factors and receptors that are capable of communicating with hematopoietic cells, suggesting neuroimmunologic interaction. What is most interesting is that glial cells express receptors for growth factors previously thought to be acting on neurons only. 4. The current study demonstrates the feasibility of screening from a small sample a large number of growth factors and receptors. The method portends future clinical application to biopsy or necropsy samples from brain tumors or pathologic brains suffering from degenerative diseases such as Alzheimer's or Parkinson's disease.
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PMID:Expression of mRNAs of multiple growth factors and receptors by astrocytes and glioma cells: detection with reverse transcription-polymerase chain reaction. 859 Apr 53

The utility of transgenes for both basic and applied studies has been augmented by the recent advent of versions that can be regulated by the addition of suitable activators. However, still more convenient would be transgenes whose expression responded appropriately to endogenous signals. The promoter of the glial fibrillary acidic protein (GFAP) gene is a candidate for this role in the central nervous system (CNS) since the GFAP gene is specifically expressed in astrocytes in the CNS and its activity is upregulated in response to almost any CNS injury. As a feasibility study, we isolated a C6 rat glioma cell line stably transfected with a lacZ reporter gene driven by the gfa2 human GFAP promoter fragment. We find that the activity of the transgene indeed responds to an environmental signal, forskolin, that induces astrocyte-like differentiation of C6 cells. We also isolated a C6 line carrying a transgene in which the gfa2 promoter directs expression of a cDNA for tyrosine hydroxylase (TH), the rate-limiting enzyme for catecholamine synthesis. This transgene should be of considerable interest for gene therapy for Parkinson's disease. We show that in this cell line both TH mRNA and protein are upregulated by forskolin. Finally, we note that the growth rate of C6 cells is severely depressed by forskolin, suggesting that predifferentiation of these cells prior to implant may retard their tumor forming capacity, prolonging the time that they can be used in animal models in vivo.
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PMID:Differentiation-dependent expression of transgenes in engineered astrocyte cell lines. 953 Sep 33

We have studied the effects of unilateral ventral medial pallidotomy in 26 patients with medically intractable Parkinson's disease with marked drug-induced dyskinesias. Preoperatively, all patients were assessed during one 5-day admission according to the Core Assessment Programme for Intracerebral Transplantation (CAPIT) protocol, including rating in the 'practically defined off' and 'best on' states before and during a single-dose levodopa challenge. Motor performance was assessed with subset categories of the Unified Parkinson's Disease Rating Scale (UPDRS), timed motor tests and a standard dyskinesia rating scale. Pallidotomy was performed under stereotaxic CT guidance with intra-operative extracellular microelectrode recording made from the basal ganglia. All patients were re-assessed 3 months postoperatively and a subgroup (n = 9) have so far also been re-assessed after 1 year. Pre- and postoperative performance scores were compared in order to determine which categories of performance improved postoperatively. Significance was accepted at P < 0.005 in order to take into account the multiple number of comparisons performed. Patient medication was compared pre- and postoperatively and the morbidity associated with surgery was also recorded. The most significant improvement postoperatively was the diminution of 'on' dyskinesias contralaterally (67%, P = 0.0001); however, ipsilateral (45%, P = 0.0006) and axial (50%, P = 0.0008) dyskinesias also improved. Contralateral to pallidotomy, the median 'off' motor UPDRS score improved by 27% (P = 0.001) and a significant improvement was also observed in contralateral rigidity by 25% (P = 0.001). There were trends towards improvement in contralateral tremor (33%, P = 0.016) and bradykinesia (24%, P = 0.013) scores. Ipsilateral rigidity improved by 22% (P = 0.005), but other ipsilateral motor scores did not alter significantly. The 'off' gait/postural instability score and 'off' walking time showed marginally significant improvements by 7% (P = 0.007) and 29% (P = 0.014), respectively. On medication, no significant postoperative improvements in parkinsonism were detected. Anti-parkinsonian medication increased by 11% postoperatively. In the subgroup who were available for assessment 1 year postoperatively, responses were generally maintained. Two (7.7%) of the 26 patients had fatal complications (one cerebral haemorrhage and one haemorrhagic infarct) directly related to surgery. Among the remaining 24 patients, four (15.4% of the total 26) had major complications (two persisting and two transient). Ten patients (38.5%) had minor complications. The majority of the complications (major and minor) occurred in the earlier operated patients and the complication rate subsequently declined with increasing operative experience. The remaining 10 patients (38.5%) had no significant side-effects. One of these 10 patients died from an incidental malignant glioma 6 months postoperatively. These findings confirm that levodopa-induced dyskinesias are dramatically reduced following ventral medial pallidotomy and constitute the principal indication for pallidotomy. Improvements in underlying parkinsonism were of smaller magnitude. Pallidotomy may also offer some patients an opportunity to increase antiparkinsonian medication. Patient selection for medial pallidotomy should, therefore, be based largely on anticipated improvements in levodopa-induced dyskinesias, but this must be balanced against the associated morbidity and mortality.
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PMID:A study of medial pallidotomy for Parkinson's disease: clinical outcome, MRI location and complications. 954 88

Major depression, opioid addiction, neurodegenerative diseases, and glial tumors are associated with disturbances of imidazoline receptors (IR) in the human brain. In depression, the level of a 45-kD IR protein (putative I1-IR) is increased in the brain of suicide victims (51%) and in platelets of depressed patients (40%). The density of platelet I1-IR ([125I]-p-iodoclonidine binding) is also increased in depression (135%). The 29/30-kD IR protein (putative I2B-IR) is downregulated (19%) in suicide victims in parallel with a reduction (40%) in the density of I2B-IR ([3H]idazoxan binding). Antidepressant drugs induce downregulation of 45-kD IR protein and I1-sites in platelets of depressed patients and upregulation of I2-sites in rat brain. The densities of I2B-IR and the related 29/30-kD IR protein are decreased (39% and 28%) in the brain of heroin addicts. The density of I2B-IR is increased in Alzheimer's disease (63%) and decreased in Huntington's disease (56%). Brain I2B-IR is not altered in Parkinson's disease. The level of I2-IR in glial tumors is increased (two-fivefold) in parallel with the abundance of the related 29/30-kD IR protein (39%), whereas the level of 45-kD IR protein is decreased (39%). The possible functional relevance of these findings in the context of the pathogenesis of these disorders remains to be elucidated.
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PMID:Imidazoline receptors and human brain disorders. 1041 44

Cells expressing a tyrosine hydroxylase (TH) cDNA under control of the promoter of the human glial fibrillary acidic protein (GFAP) gene were tested for therapeutic efficacy in a rat model of Parkinson's disease. The GFAP gene encodes an intermediate filament protein found almost exclusively in astrocytes. Its promoter is of interest for gene therapy as it is expressed in astrocytes throughout postnatal life and is upregulated in response to almost any damage to the central nervous system, including Parkinson's disease. We previously showed that a line of C6 rat glioma cells that expresses a GFAP-TH transgene, C6-THA, displays increased transgene activity when differentiated by forskolin treatment. Accordingly, the effects were investigated of implantation of both undifferentiated and differentiated C6-THA cells into the striatum of rats that had been lesioned with 6-hydroxydopamine. Implantation of either cell type produced significant behavioral recovery one week after transplantation, as judged by the turning response to apomorphine. At two and three weeks after transplantation, the behavioral effect of the undifferentiated cells was no longer statistically significant, whereas that for the forskolin-differentiated cells remained robust. Transgenic TH mRNA and protein could be detected in implants of both cell types, and in agreement with the behavioral results, levels were higher for the differentiated C6-THA cells than for the undifferentiated cells. These results indicate that the GFAP promoter is sufficiently active to enable production of therapeutic levels of dopamine from a GFAP-TH transgene, and suggest the use of astrocytes for gene therapy for Parkinson's disease. They also show that beneficial modifications of cells produced by treatment while in culture may be maintained following implantation.
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PMID:Gene therapy in a rodent model of Parkinson's disease using differentiated C6 cells expressing a GFAP-tyrosine hydroxylase transgene. 1046 75

Heme oxygenase-1 (HO-1) is an inducible enzyme involved in heme catabolism, tissue iron homeostasis and the cellular response to oxidative stress. Elevated HO-1 expression in astrocytes has been observed in association with abnormal iron deposition and increased oxidative stress in Parkinson's disease (PD). Since HO-1 could contribute to these aspects of PD pathobiology we have investigated its regulation in cultured astrocytes and C6 glioma cells. Here we report that dopamine is a potent inducer of HO-1. This induction is not mediated by a classical dopamine receptor and is not mimicked by a range of catecholamines and dopamine metabolites. When the time-course of HO-1 expression was compared between dopamine and hemin, the latter induced the gene immediately while the former did so with a lag. This suggested two distinct signal transduction pathways. However, cycloheximide blocked both hemin- and dopamine-induced HO-1 expression, suggesting that both pathways may involve proteins with short half-lives. Ascorbic acid blocked dopamine induction of HO-1 but had no effect on hemin-induced expression. This suggested that dopamine may signal upstream of the unstable protein by producing pro-oxidant metabolites or byproducts. Inhibition of monoamine oxidases A or B or catechol-O-methyl transferase did not block HO-1 induction by dopamine, indicating that these enzymes were not converting dopamine to an active metabolite. These results suggest that dopamine, released or secreted from affected neurons, may trigger HO-1 expression in neighboring astrocytes. HO-1 and its metabolites could then contribute to the oxidative stress and iron deposition associated with PD.
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PMID:Regulation of heme oxygenase-1 expression by dopamine in cultured C6 glioma and primary astrocytes. 1058 97

Many properties of HSV-1 are especially suitable for using this virus as a vector to treat diseases affecting the central nervous system (CNS), such as Parkinson's disease or malignant gliomas. These advantageous properties include natural neurotropism, high transduction efficiency, large transgene capacity, and the ability of entering a latent state in neurons. Selective oncolysis in combination with modulation of the immune response mediated by replication-conditional HSV-1 vectors appears to be a highly promising approach in the battle against malignant glioma. Helper virus-free HSV/AAV hybrid amplicon vectors have great promise in mediating long-term gene expression in the PNS and CNS for the treatment of various neurodegenerative disorders or chronic pain. Current research focuses on the design of HSV-1-derived vectors which are targeted to certain cell types and support transcriptionally regulatable transgene expression. Here, we review the recent developments on HSV-1-based vector systems and their applications in experimental and clinical gene therapy protocols.
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PMID:HSV-1-based vectors for gene therapy of neurological diseases and brain tumors: part II. Vector systems and applications. 1093 55

The Fas/Fas-L signalling system plays a role in the control of cell death and the survival of lymphocytes, in the regulation of the immune system, and in the progression of autoimmune diseases. Studies in the nervous system have shown Fas/Fas-L activation in multiple sclerosis and in various paradigms leading to neuronal death. Enhanced Fas and Fas-L expression has also been documented in astrocytomas and glioma cell lines. However, little is known about the possible implication of Fas/Fas-L signals in primary human neurodegenerative diseases. In an attempt to gain understanding of the mechanisms commanding cell death and neurone loss in Huntington's disease (HD) and Parkinson's disease (PD), Fas and Fas-L expression has been examined in the brains of patients with HD and PD with Western blotting and immunohistochemistry. Fas and Fas-L expression levels are reduced in the caudate and putamen, but not in the parietal cortex, in HD, as revealed in Western blots. Moreover, Fas and Fas-L immunoreactivity is reduced in striatal neurones in HD. Fas and Fas-L immunoreactivity is also decreased in neurones of the substantia nigra pars compacta in PD. Reduced Fas and Fas-L expression is observed equally in Lewy body-bearing and non-Lewy body-bearing neurones. Yet increased Fas and Fas-L immunoreactivity occurs in normal astrocytes in control brains and in reactive astrocytes in diseased brains. The meaning of increased Fas and Fas-L expression in astrocytes is still unclear. However, the present results suggest that Fas/Fas-L signals are minimized in sensitive neurones in HD and PD.
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PMID:Fas and Fas-L expression in Huntington's disease and Parkinson's disease. 1105 82


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