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)

Interleukin (IL)-1 beta, IL-6, epidermal growth factor (EGF), and transforming growth factor-alpha (TGF-alpha) were measured for the first time in the brain (caudate nucleus, putamen and cerebral cortex) from control and parkinsonian patients by highly sensitive sandwich enzyme immunoassays. The concentrations of IL-1 beta, IL-6, EGF, and TGF-alpha in the dopaminergic, striatal regions were significantly higher in parkinsonian patients than those in controls, whereas those in the cerebral cortex did not show significant differences between parkinsonian and control subjects. Since these cytokines and growth factors may play important roles as neurotrophic factors in the brain, the present results suggest that they may be produced as compensatory responses in the nigrostriatal dopaminergic regions in Parkinson's disease, and may be related, at least in part, to the process of neurodegeneration in Parkinson's disease.
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PMID:Interleukin-1 beta, interleukin-6, epidermal growth factor and transforming growth factor-alpha are elevated in the brain from parkinsonian patients. 770 May 68

The etiology of Parkinson's disease, one of the most frequent neurodegenerative disorders in human, is unknown. New hopes concerning satisfactory therapies include transplants of autologous adrenal medullary chromaffin tissue, fetal mesencephalic dopaminergic neurons, and local application of growth factors with a neurotrophic capacity. A large body of evidence supports the notion that neurons require trophic support not only during a limited period of ontogenesis, but during their whole lifespan. Relevant molecules promote survival, transmitter synthesis and other differentiated properties, and become crucially important when a neuron is metabolically or toxically impaired. Several molecules, most of which occur in the striatum and the substantia nigra, have been identified that protect lesioned dopaminergic nigrostriatal neurons in culture or in animal models of Parkinson's disease. These include members of the neurotrophin, fibroblast growth factor, and insulin-like growth factor families as well as epidermal growth factor/transforming growth factor alpha, interleukins and ciliary neurotrophic factor. Whether their effects are merely pharmacological, or reflect a physiological role in the nigrostriatal system, is unclear as yet. This article reviews experiments that document the trophic effects of these factors on dopaminergic neurons and discusses their possible physiological and therapeutic relevance.
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PMID:Growth factors in Parkinson's disease. 819 55

Among the pathogenetic phenomena of Parkinson's disease, the character of the selective degeneration of nigrostriatal system with severe gliosis is not fully understood. Here, we have shown that dopaminergic neurons may be exclusively sensitive to elevated acidity elicited after the addition of glial mitogenic factors such as epidermal growth factor and basic fibroblast growth factor or after the direct treatment with hydrochloric acid. The acid sensitivity was specific to dopaminergic neurons. The neurons other than dopaminergic neurons in culture from the ventral mesencephalon were not sensitive to acidity and the neurons from several brain areas were the same as above, except for the hippocampal neurons which had slight acid vulnerability. Choline acetyltransferase assay studies demonstrated that the cholinergic neuronal population in the septum and corpus striatum had no acid sensitivity. The vulnerability of dopaminergic neurons either elicited by glial mitogenic factor or derived from the direct acid exposure was inhibited by the addition of brain-derived neurotrophic factor (BDNF), but not by neurotrophin-3 or nerve growth factor. These findings suggest that dopaminergic neurons have selective acid vulnerability on which BDNF has a pronounced protective effect.
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PMID:Selective acid vulnerability of dopaminergic neurons and its recovery by brain-derived neurotrophic factor. 878 12

Interleukin (IL)-1 beta , IL-2, IL-4, IL-6, epidermal growth factor (EGF), and transforming growth factor (TGF)-alpha were measured for the first time in ventricular cerebrospinal fluid (VCSF) from control non-parkinsonian patients, patients with juvenile parkinsonism (JP) and patients with Parkinson's disease (PD) by highly sensitive sandwich enzyme immunoassays. All cytokines were detectable in VCSF from control and parkinsonian patients, and the concentrations were much higher than those in lumbar CFS. The concentrations of IL-1 beta, IL-2, IL-4 and TGF-alpha in VCSF were higher in JP than those in controls (P < 0.05). In contrast, the concentrations of IL-2 and IL-6 in VCSF from patients with PD were higher than those from control patients (P < 0.05). These results agree with our previous reports, in which the cytokine levels were elevated in the striatal dopaminergic region of the brain from patients with PD. Since VCSF is produced in the ventricles, the alteration of cytokines in VCSF may reflect the changes of cytokines in the brain. Because cytokines play an important role as mitogens and neurotrophic factors in the brain, the increases in cytokines as a compensatory response may occur in the brain of patients of JP or PD during the progress of neurodegeneration. Increase in cytokines may contribute not only as a compensatory response but as a primary initiating trigger for the neurodegeneration.
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PMID:Interleukin (IL)-1 beta, IL-2, IL-4, IL-6 and transforming growth factor-alpha levels are elevated in ventricular cerebrospinal fluid in juvenile parkinsonism and Parkinson's disease. 880 36

One of the drawbacks with fetal ventral mesencephalic (VM) grafts in Parkinson's disease is the limited outgrowth into the host striatum. In order to enhance graft outgrowth, epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) were administered by implantation of bioactive rods to the lateral part of the striatum to support grafted fetal VM implanted to the medial portion of the striatum. The polymer-based bioactive rods allow for a local secretion of neurotrophic factors over a time period of approximately 2 weeks. Moreover, glial cell line-derived neurotrophic factor (GDNF) and transforming growth factor-beta1 (TGFbeta1) were administered using the same technique. Concomitant administration of GDNF and TGFbeta1 was achieved by insertion of one GDNF and one TGFbeta1 rod. This was performed to investigate possible additive effects between GDNF and TGFbeta1. Rotational behavior, outgrowth from and nerve fiber density within the VM graft, and the number of TH-positive cells were studied. Functional compensation by reduction of rotational behavior was significantly enhanced in animals carrying bFGF and GDNF rods in comparison with animals carrying only VM graft. EGF and bFGF significantly increased the innervation density. Moreover, the nerve fiber density within the grafts was significantly enhanced by bFGF. Cell counts showed that a significantly higher number of TH-positive neurons was found in grafts treated with bFGF than that found in GDNF-treated grafts. An additive effect of TGFbeta1 and GDNF was not detectable. These results suggest that bioactive rods is a useful tool to deliver neurotrophic factors into the brain, and since bFGF was a potent factor concerning both functional, immunohistochemical and cell survival results, it might be of interest to use bFGF-secreting rods for enhancing the overall outcome of VM grafts into patients suffering from Parkinson's disease.
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PMID:Implantation of bioactive growth factor-secreting rods enhances fetal dopaminergic graft survival, outgrowth density, and functional recovery in a rat model of Parkinson's disease. 1087 23

We found that in Parkinson's disease (PD) the levels of various cytokines [tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-2, IL-4, IL-6, epidermal growth factor (EGF), transforming growth factor (TGF)-alpha, TGF-beta1] were significantly increased in the striatum (caudate and putamen) of the postmortem brain and in ventricular or spinal cerebrospinal fluid (VCSF, LCSF). Furthermore, the levels of the apoptosis-related proteins such as bcl-2 and soluble Fas (sFas) in the striatum were also elevated in PD. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated parkinsonism mice, the levels of IL-1beta in the striatum were significantly increased, but those of nerve growth factor (NGF) were significantly decreased, compared with control mice. In hemiparkinsonism rats produced by injection of 6-hydroxydopamine (6-OHDA) into one side of the median forebrain bundle, the levels of TNF-alpha in the 6-OHDA-treated side were increased in the striatum and substantia nigra, but not in the cerebral cortex, compared with those in the control side. Repeated administration of L-DOPA in the 6-OHDA-treated rats did not change the TNF-alpha levels in the control side and in the 6-OHDA-treated side in the substantia nigra, striatum, and cerebral cortex. Our results suggest that the changes in the levels of cytokines, neurotrophins, and apoptosis-related proteins in the nigrostriatal regions of PD may be involved in apoptosis and degeneration of the nigrostriatal DA neurons.
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PMID:Cytokines in Parkinson's disease. 1112 4

We report on generation of dopamine neurons from long-term cultures of human fetal mesencephalic precursor cells. These CNS precursor cells were successfully expanded in vitro using the mitogens epidermal growth factor (EGF) and fibroblast growth factor-2 (FGF-2). Incubation of these cultures in 3% atmospheric oxygen resulted in higher cellular yields than room air. Following incubation in differentiation media containing interleukin (IL)-1b (IL-1b), IL-11, leukemia inhibitory factor (LIF), and glial cell line-derived neurotrophic factor (GDNF), up to 1% of the precursor cells converted into cells immunoreactive for tyrosine hydroxylase (TH), a marker for dopamine neurons. The TH immunoreactive cells exhibited morphological and functional properties characteristic of dopamine neurons in culture. These precursor cells might serve as a useful source of human dopamine neurons for studying the development and degeneration of human dopamine neurons and may further serve as a continuous, on-demand source of cells for therapeutic transplantation in patients with Parkinson's disease.
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PMID:Long-term proliferation and dopaminergic differentiation of human mesencephalic neural precursor cells. 1147 98

Intracerebral neural xenografts elicit a host immune response that results in their rapid rejection. This forms a key barrier to the therapeutic use of xenogeneic tissue transplantation for conditions such as Parkinson's disease. The current study sought to provide insight into the cellular components of donor cell suspensions that are important in stimulating the host rejection response and thereby to suggest rational manipulations of xenogeneic donor tissue that might ultimately enhance its clinical utility. The neural stem cell mitogens, epidermal growth factor and fibroblast growth factor-2, have been used to isolate and expand populations of primordial neural precursor cells from the embryonic pig brain. The immune response elicited by these cells on transplantation into the non-immunosuppressed rat has been fully characterised. In the first experiments, expanded neural precursors were grafted into the hemi-parkinsonian, non-immunosuppressed Sprague-Dawley rat and graft status and host response examined 10, 21, 35 and 60 days post-transplantation. While equivalent primary tissue grafts were completely eliminated at 35 days, grafts of expanded neural precursors with healthy neurofilament-positive projections were present at all time-points, and two large grafts remained even at 60 days. Some grafts appeared to elicit minimal host immune responses at the time-points they were examined, although most did appear to be undergoing a rejection process since a co-ordinated response involving host cytotoxic T-lymphocytes, microglia/macrophages, immunoglobulin M and complement could be demonstrated to varying degrees. Subsequent experiments went on to demonstrate further that expanded precursor populations and primary tissue suspensions differed in their immunogenic profile. Firstly, when primary tissue was injected intraperitoneally into immunocompetent rats a vigorous primary humoral response was generated. No such response was detected following injection of expanded neural precursors. Secondly, flow cytometric analysis revealed small but significant levels of class II porcine major histocompatibility complex expression in primary cell suspensions but no such expression in expanded precursor populations.The results of this study therefore demonstrate that the immunogenicity of porcine neural cell suspensions used for intracerebral grafting is reduced when neural stem cell mitogens are used to expand precursor cells. The implications of these findings in the development of novel xenogeneic cellular therapies for neurodegenerative conditions such as Parkinson's disease are discussed.
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PMID:Porcine neural xenografts in the immunocompetent rat: immune response following grafting of expanded neural precursor cells. 1156 30

Transplantation of dopaminergic ventral mesencephalic (VM) tissue into the basal ganglia of patients with Parkinson's disease (PD) shows at best moderate symptomatic relief in some of the treated cases. Experimental animal studies and clinical trials with allogenic and xenogenic pig-derived VM tissue grafts to PD patients indicate that one reason for the poor outcome of neural transplantation is the low survival and differentiation of grafted dopaminergic neurons. To improve dopaminergic cell survival through a gene-therapeutic approach we have established and report here results of lipid-mediated transfer of the gene for human glial cell line-derived neurotrophic factor (GDNF) to embryonic (E27/28) porcine VM tissue kept as organotypic explant cultures. Treatment of the developing VM with two mitogens, basic fibroblast growth factor and epidermal growth factor, prior to transfection significantly increased transfection yields. Expression of human GDNF via an episomal vector could be detected by in situ hybridization and by the measuring of GDNF protein secreted into the culture medium. When compared to mock-transfected controls, VM tissue expressing recombinant GDNF contained significantly higher numbers of tyrosine hydroxylase-positive neurons in the cultured VM tissue. We conclude that lipid-mediated gene transfer employed on embryonic pig VM explant cultures is a safe and effective method to improve survival of dopaminergic neurons and may become a valuable tool to improve allo- and xenotransplantation treatment in Parkinson's disease.
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PMID:Lipid-mediated glial cell line-derived neurotrophic factor gene transfer to cultured porcine ventral mesencephalic tissue. 1242 9

The applications of neural progenitor cells in clinical therapy for neural degeneration, such as Parkinson's disease, Huntington's disease, and cerebral infarction, have long been explored widely. It had been suggested that these cells may block the apoptosis of ischemia-induced neuronal damage and may themselves resist neurotoxic factors. In the present study, neural progenitor cells derived from the cortex of rodent embryos were cultured with the mitogenic agent epidermal growth factor. It was observed that these progenitor cells could self-renew and differentiate into a number of types of neurons and glial cells. By using sodium nitroprusside, glutamate, and N-methyl-D-aspartate, these neural progenitor cells were shown to have a higher resistance to neurotoxicity induced by these drugs compared with primary neuronal cells. However, the release of nitric oxide in response to glutamate by these neural progenitor cells was similar to the released by primary neuronal cells. Also, when the glutamate-stimulated increase in intracellular free Ca(2+) concentration was measured, stimulation of the glutamate receptors could not induce a significant influx of Ca(2+) into these progenitor cells until they differentiated. Our results suggest that the resistance of neural progenitor cells to neurotoxicity may be partially due to a lack of response to glutamate. In addition, some progenitor-generated neurotrophic factors may contribute to the resistance of these cells to nitric oxide-induced neurotoxicity.
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PMID:Neural progenitor cells resist excitatory amino acid-induced neurotoxicity. 1250 90


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