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)

Astrocytes secreting a large amount of 3,4-dihydroxyphenylalanine (dopa) were generated by adenoviral transduction of the human tyrosine hydroxylase (TH) gene. After characterizing in vitro, the effect of transplantation of these astrocytes to the striatum of hemiparkinsonian model rats was investigated. Subconfluent cortical astrocytes were infected by replication-defect adenovirus type 5 carrying the human TH-1 gene or the LacZ reporter gene under the promoter of the glial fibrillary acidic protein (AdexGFAP-HTH-1, AdexGFAP-NL-LacZ). Dopa secretion was not evident at 3 days after the transduction of the HTH-1 gene but it increased from 7 days up to at least 4 months. The secretion was substrate (tyrosine)-dependent, and was enhanced by loading tetrahydrobioputerin (BH4) concentration-dependently. One-third of the hemiparkinsonian model rats, that were transplanted the HTH-1 gene-transduced astrocytes or introduced the direct injection of the viral vector to the striatum, showed a reduction of methamphetamine-induced rotations for at least 6 weeks. Apomorphine-induced rotation was decreased to the 50% level of the control's, but the reduction was obtained equally by the transplantation of HTH-1 gene-transduced or LacZ reporter gene-transduced astrocytes, or by the introduction of HTH-1 or LacZ gene carrying adenovirus. Treatment with FK506 for 3 weeks improved the late-phase apomorphine-induced rotations following the introduction of the HTH-1 gene carrying adenovirus. Histological examination revealed that, in animals that showed a reduction of methamphetamine-rotation, the TH positive astrocytes-like cells were distributed widely in the host striatum for at least 4 weeks. The number of TH positive astrocytes-like cells and their immunoreactivity decreased after 6 weeks when OX-41 positive microglias/macrophages were infiltrated. Data indicate that the adenoviral transduction of the human TH gene to astrocytes and its introduction to the striatum is a promising approach for the treatment of Parkinson's disease. However, the further technical improvements are required to optimize the adenoviral gene delivery, such as the control of viral toxicity and the regulation of the immune response.
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PMID:Dopa-producing astrocytes generated by adenoviral transduction of human tyrosine hydroxylase gene: in vitro study and transplantation to hemiparkinsonian model rats. 1061 14

We used a retroviral-mediated gene transfer system to transduce primary rat astrocytes with a transgene in which the activity of a tyrosine hydroxylase (TH) cDNA is under the transcriptional control of a human promoter of the glial fibrillary acidic protein (GFAP). The engineered cells were tested for their therapeutic efficacy in a rodent model of Parkinson's disease (PD). The method is based both on the properties of astrocytes, as well as on those of the promoter. Astrocytes are an integral part of the neural tissue, have a long life span, are more resistant to oxidative stress than neurons, and possess an efficient secretory system. The GFAP promoter is active throughout postnatal life, and its activity is up-regulated by many insults to the brain, including PD. Transduced astrocytes were implanted into the striata of rats lesioned with 6-hydroxydopamine (6-OHDA), and the efficacy of grafted cells tested. Implanted astrocytes induced a significant reduction in the turning behavior that occurs in response to apomorphine for at least 4 weeks after grafting, and transgenic mRNA and protein could be detected in implanted brains. These results indicate that the gFa2-TH construct can be readily adapted to be used with a retroviral gene transfer system to obtain nontumorigenic cells that sustain a sufficient level of transgene activity to enable therapeutic effectiveness for prolonged periods. These results further endorse the use of astrocytes for gene therapy in the central nervous system.
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PMID:Primary astrocytes retrovirally transduced with a tyrosine hydroxylase transgene driven by a glial-specific promoter elicit behavioral recovery in experimental parkinsonism. 1065 84

Virtually any neurological disorder leads to activation of resident microglia and invasion of blood-borne macrophages, which are accompanied by an increase in number and change in phenotype of astrocytes, a phenomenon generally termed reactive astrocytosis. One of the functions attributed to activation of astrocytes is thought to involve restoration of tissue damage. Hitherto, the role of astrocytes in the inflammatory reaction occurring in Parkinson's disease has not received much attention. In the present study, we examined the inflammatory events in autopsies of the substantia nigra and putamen from Parkinson's disease patients using age-matched autopsies from normal patients as controls. In the substantia nigra, activation of microglia was consistently observed in all Parkinson's disease autopsies as verified from immunohistochemical detection of CR3/43 and ferritin. Activation of resident microglia was not observed in the putamen. No differences were observed between controls and Parkinson's disease autopsies from the substantia nigra and putamen, in terms of distribution, cellular density or cellular morphology of astrocytes stained for glial fibrillary acidic protein or metallothioneins I and II, the latter sharing high affinity for metal ions and known to be induced in reactive astrocytes, possibly to exert anti-oxidative effects. Together, these findings indicate that the inflammatory process in Parkinson's disease is characterized by activation of resident microglia without reactive astrocytosis, suggesting that the progressive loss of dopaminergic neurons in Parkinson's disease is an ongoing neurodegenerative process with a minimum of involvement of the surrounding nervous tissue. The absence of reactive astrocytosis in Parkinson's disease contrasts what follows in virtually any other neurological disorder and may indicate that the inflammatory process in Parkinson's disease is a unique phenomenon.
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PMID:The absence of reactive astrocytosis is indicative of a unique inflammatory process in Parkinson's disease. 1065 22

The present study examines N-myc and c-myc protein expression with Western blotting and single and double-labeling immunohistochemistry in the hippocampus in Alzheimer disease (AD), the striatum in Huntington disease (HD) and the substantia nigra in Parkinson disease (PD). No modifications in the N-myc and c-myc expression are found in hippocampal neurons in AD, striatal neurons in HD, and pigmented neurons of the substantia nigra in PD. Yet punctate synaptic-like N-myc immunoreactivity, matching enhanced synaptophysin expression, occurs in diffuse plaques, but not in dystrophic neurites of neuritic plaques. In contrast, c-myc immunoreactivity is found in dystrophic neurites, but not in aberrant sproutings of neuritic plaques, as shown by double-labeling immunohistochemistry to c-myc and phosphorylated tau or phosphorylated neurofilament epitopes, and to c-myc and GAP-43, respectively. Strong N-myc and c-myc are observed in reactive astrocytes in AD, HD and PD, as revealed by double-labeling with N-myc or c-myc and GFAP. Finally, no relationship is found between nuclear DNA fragmentation and increased N-myc or c-myc expression in individual cells. These results demonstrate that neuron death in AD, HD and PD is not associated with modifications in the steady-state expression of N-myc and c-myc in individual neurons, and that neurofibrillary degeneration and Lewy body formation are not accompanied by increased immunoreactivity to these transcription factors. Increased N-myc and c-myc expression in reactive astrocytes probably plays a role in reactive astrocytosis in human neurodegenerative disorders.
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PMID:N-myc and c-myc expression in Alzheimer disease, Huntington disease and Parkinson disease. 1083 22

A mutation in the parkin gene has been identified as the cause for an autosomal recessively inherited form of early onset Parkinson's disease. We have recently isolated the mRNA coding for the rat homologue of parkin and showed its widespread expression in the central nervous system (CNS) by in situ hybridization. In the present study we investigated the distribution of parkin in the rat cerebral cortex with a polyclonal antibody that reacts with a single approximately 52-kDa protein, corresponding to the predicted molecular mass of parkin. Conventional light microscopic studies revealed intense parkin immunoreactivity (IR) throughout the cortex. Examination of mixed cortical neuro-glial cultures by indirect immunofluorescence technique coupled to traditional epifluorescence and confocal microscopy analysis demonstrated the expression of parkin in the cytoplasm and neurites of neurons, and its absence in glial fibrillary acidic protein (GFAP)-positive astrocytes. The predominant neuronal parkin-IR and -mRNA expression was confirmed by Western blot analysis and reverse transcription-polymerase chain reaction (RT-PCR), respectively, performed on highly enriched neuronal and type I astrocytes cultures. The information gathered in our study about the cellular and subcellular distribution of parkin should facilitate further research on its physiological role in the nervous system.
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PMID:Regional and cellular expression of the parkin gene in the rat cerebral cortex. 1102 28

We investigated neurochemically and neuropathologically the utility of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice as a model of Parkinson's disease. The changes in dopamine D1 and D2 receptors and dopamine uptake sites were determined by quantitative autoradiography using [3H]SCH23390, [3H]raclopride and [3H]mazindol, respectively. Dopamine and 3,4-dihydroxyphenyl acetic acid (DOPAC) contents in the striatum were measured by high-performance liquid chromatography. The distribution of nigral neurons and reactive astrocytes was determined by immunohistochemical staining with antibody against tyrosine hydroxylase (TH) and glial fibrillary acidic protein (GFAP). The mice received four intraperitoneal injections of MPTP (10 mg/kg) at 1-h intervals and then the brains were analyzed at 3 and 7 days after the treatments. No significant change in dopamine D1 receptors was observed in the striatum and substantia nigra after acute treatment with MPTP. Dopamine D2 receptors were reduced significantly in the substantia nigra only 7 days after the MPTP treatment, whereas striatum showed no significant change in the binding throughout the experiments. In contrast, dopamine uptake sites were reduced markedly in the striatum and substantia nigra 3 and 7 days after the MPTP treatment. Dopamine and DOPAC content were also reduced in the striatum 3 and 7 days after the MPTP treatment. An immunohistochemical study indicated a loss of the number of TH-positive neurons in the substantia nigra 7 days after the MPTP treatment. In contrast, numerous GFAP-positive astrocytes were evident in the striatum 7 days after the MPTP treatment. These results provide valuable information for the pathogenesis of acute stage of Parkinson's disease.
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PMID:Biochemical and immunohistological changes in the brain of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse. 1111 42

The protective effects of 2-amino-6-trifluoromethoxy benzothiazole (riluzole), a Na(+) channel blocker with antiglutamatergic activity were investigated in the model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced depletion of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels in mice. The mice were injected intraperitoneally (i.p.) with four administrations of MPTP (10 mg/kg) at 1 h intervals and then the brains were analyzed at 3 and 7 days after the treatments. Dopamine, DOPAC and HVA levels were significantly decreased in the striatum 3 days after MPTP treatments. Riluzole dose-dependently antagonized the MPTP-induced decrease in dopamine, DOPAC and HVA levels in the striatum. MPTP treatment also caused a severe decrease in the amount of nigral tyrosine hydroxylase protein (TH) and microtuble-associated protein 2 (MAP 2) and produced a marked increase in the striatal glial fibrillary acidic protein (GFAP). Our immunohistochemical study with TH and MAP 2 staining showed that riluzole can protect against MPTP-induced neuronal damage in the substantia nigra. Furthermore, riluzole markedly increased the striatal GFAP-positive astrocytes 3 days after MPTP treatments. These results suggest that riluzole is effective against MPTP-induced neurodegeneration of the nigrostriatal dopaminergic neuronal pathway. Our findings also may provide a rationale for the identification of astrocytes as a prominent target for the development of new therapies of Parkinson's disease.
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PMID:Riluzole (2-amino-6-trifluoromethoxy benzothiazole) attenuates MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neurotoxicity in mice. 1157 43

Astrocytes, with their many functions in producing and controlling the environment in the brain, are of great interest when it comes to studying regeneration after injury and neurodegenerative diseases such as in grafting in Parkinson's disease. This study was performed to investigate astrocytic guidance of growth derived from dopaminergic neurons using organotypic cultures of rat fetal ventral mesencephalon. Primary cultures were studied at different time points starting from 3 days up to 28 days. Cultures were treated with either interleukin-1 beta (IL-1 beta), which has stimulating effects on astrocytic proliferation, or the astrocytic inhibitor cytosine arabinoside (Ara-C). Tyrosine hydroxylase (TH)-immunohistochemistry was used to visualize dopaminergic neurons, and antibodies against glial fibrillary acidic protein (GFAP) and S100 beta were used to label astrocytes. The results revealed that a robust TH-positive nerve fiber production was seen already at 3 days in vitro. These neurites had disappeared by 5 days. This early nerve fiber outgrowth was not guided by direct interactions with glial cells. Later, at 7 days in vitro, a second wave of TH-positive neuritic outgrowth was clearly observed. GFAP-positive astrocytic processes guided these neurites. TH-positive neurites arborized overlying S100 beta-positive astrocytes in an area distal to the GFAP-positive astrocytic processes. Treatment with IL-1 beta resulted in an increased area of TH-positive nerve fiber network. In cultures treated with Ara-C, neither astrocytes nor outgrowth of dopaminergic neurites were observed. In conclusion, this study shows that astrocytes play a major role in long-term dopaminergic outgrowth, both in axonal elongation and branching of neurites. The long-term nerve fiber growth is preceded by an early transient outgrowth of dopamine neurites.
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PMID:Guidance of dopaminergic neuritic growth by immature astrocytes in organotypic cultures of rat fetal ventral mesencephalon. 1180 34

The loss of dopaminergic neurones in the substantia nigra with Parkinson's disease may result from inflammation-induced proliferation of microglia and reactive macrophages expressing inducible nitric oxide synthase (iNOS). We have investigated the effects of the supranigral administration of lipopolysaccharide on iNOS-immunoreactivity, 3-nitrotyrosine formation and tyrosine hydroxylase-immunoreactive neuronal number, and retrogradely labelled fluorogold-positive neurones in the ventral mesencephalon in male Wistar rats. Following supranigral lipopolysaccharide injection, 16-18 h previously, there was intense expression of NADPH-diaphorase and iNOS-immunoreactivity in non-neuronal, macrophage-like cells. This was accompanied by intense expression of glial fibrillary acidic protein-immunoreactive astrocytosis in the substantia nigra. There were also significant reductions in the number of tyrosine hydroxylase(50-60%)- and fluorogold (65-75%)-positive neurones in the substantia nigra. In contrast, tyrosine hydroxylase-immunoreactivity in the ventral tegmental area was not altered. Pre-treatment of animals with the iNOS inhibitor, S-methylisothiourea (10 mg kg(-1), i.p.), led to a significant reduction of lipopolysaccharide-induced cell death. Similar reduction of tyrosine hydroxylase-immunoreactivity and fluorogold-labelled neurones in the substantia nigra following lipopolysaccharide administration suggests dopaminergic cell death rather than down-regulation of tyrosine hydroxylase. We conclude that the expression of iNOS- and 3-nitrotyrosine-immunoreactivity and reduction of cell death by S-methylisothiourea suggest the effects of lipopolysaccharide may be nitric oxide-mediated, although other actions of lipopolysaccharide (independent of iNOS induction) cannot be ruled out.
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PMID:Involvement of inducible nitric oxide synthase in inflammation-induced dopaminergic neurodegeneration. 1188 72

Recent studies have implicated chronic elevated exposures to environmental agents, such as metals (e.g. manganese, Mn) and pesticides, as contributors to neurological disease. Eighteen-month-old rats received intraperitoneal injections of manganese chloride (6 mg Mn/kg/day) or equal volume of saline for 30 days in order to study the effect of manganese on the dopamine- and GABA-neurons. The structures studied were substantia nigra, striatum, ventral tegmental area, nucleus accumbens and globus pallidus. First, we studied the enzymatic activity of mitochondrial complex II succinate dehydrogenase (SDH). We found an overall decrease of SDH in the different brain areas analyzed. We then studied the mRNA levels for tyrosine hydroxylase (TH) and the dopamine transporter (DAT) by in situ hybridization. TH mRNA but not DAT mRNA was significantly induced in substantia nigra and ventral tegmental area following Mn treatment. Correspondingly, TH immunoreactivity was increased in substantia nigra and ventral tegmental area. Manganese treatment significantly decreased GAD mRNA levels in individual GABAergic neurons in globus pallidus but not in striatum. We also quantified the density of glial fibrillary acidic protein (GFAP)-labeled astrocytes and OX-42 positive cells. Reactive gliosis in response to Mn treatment occurred only in striatum and substantia nigra and the morphology of the astrocytes was different than in control animals. These results suggest that the nigrostriatal system could be specifically damaged by manganese toxicity. Thus, changes produced by manganese treatment on 18-month-old rats could play a role in the etiology of Parkinson's disease.
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PMID:Differential regulation of glutamic acid decarboxylase mRNA and tyrosine hydroxylase mRNA expression in the aged manganese-treated rats. 1210 97


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