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)

Rat pheochromocytoma PC12 cells were genetically modified in vitro to express recombinant beta-nerve growth factor (beta-NGF) using a replication-deficient retroviral vector carrying the mouse beta-NGF gene and subsequently implanted into the striatum of a mouse model of Parkinson's disease. The fate of the genetically modified PC12 cells (PC12N.8) was assessed at varying times postimplantation by studying immunoreactivity (IR) to tyrosine hydroxylase (TH) or the rat NGF receptor (NGFR). In vitro, the genetically modified PC12 cells displayed a neuronal morphology in the absence of exogenous NGF which was characterized by extensive neurite outgrowth. In addition, the genetically modified PC12 displayed a catecholaminergic phenotype in vitro as assessed by TH-IR. Following implantation into the striatum, the survival of PC12N.8 cells was limited. Surviving cells could be identified by NGFR-IR, but not by TH-IR. In addition, PC12N.8 cells with a neuronal morphology similar to that observed in vitro were only rarely observed in vivo. No tumors were observed in PC12N.8 graft recipients up to 30 days postimplantation. In contrast, intrastriatal tumors were observed in 50% of the PC12 cell recipients. These data demonstrate that PC12 cells genetically modified in vitro to synthesize beta-NGF do not revert to the mitotic phenotype of the parent PC12 cell line following implantation into the adult striatum, an observation that suggests that these cells may continue to express recombinant beta-NGF in vivo. The data further suggest that the genetically modified PC12 cells lose the catecholaminergic phenotype following implantation into the striatal parenchyma.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Survival and differentiation within the adult mouse striatum of grafted rat pheochromocytoma cells (PC12) genetically modified to express recombinant beta-NGF. 167 94

Transplantation of adrenal chromaffin cells into the striatum of Parkinson's disease patients is unlikely to become a reliable therapy unless techniques are devised to improve cell survival. To address this issue, we investigated the use of genetically altered astrocytes that constitutively secrete beta-nerve growth factor (NGF) to provide trophic support for adrenal chromaffin cells grafted into the dopamine-denervated striatum of the rat. Primary rat astrocytes were altered genetically in vitro by infection with a retroviral vector harboring a mouse beta-NGF transgene under constitutive long terminal repeat transcriptional control. Confluent cultures of these genetically altered astrocytes secrete NGF into their culture medium at a rate of approximately 9 pg/10(5) cells/h. This rate of NGF secretion is at least 10-fold higher than that of confluent sister cultures of uninfected astrocytes. The effects of the NGF-secreting astrocytes on the survival and neuronal transformation of dissociated adrenal chromaffin cells were assessed in vitro and following transplantation into the dopamine-denervated striatum of the adult rat. In vitro experiments demonstrated that neuritic outgrowth is stimulated when postnatal day 12 chromaffin cells are grown on a monolayer of the genetically altered astrocytes. When co-grafted with genetically altered astrocytes, young postnatal chromaffin cells displayed extensive neuritic outgrowth within the host brain 2 weeks postimplantation, whereas chromaffin cells grafted alone or with normal astrocytes retain an endocrine-like morphology. Survival of the chromaffin cells is also enhanced 3-6-fold when co-grafted with the genetically altered astrocytes. In addition, the neuronally transformed chromaffin cells appear to lose adrenergic properties as assessed by diminished immunoreactivity to the adrenergic marker, phenylethanolamine-N-methyltransferase. Although their survival is also enhanced approximately 4-fold relative to controls, adult chromaffin cells do not convert to a neuronal morphology when co-grafted with the genetically altered astrocytes. These studies demonstrate that rat astrocytes carrying a mouse NGF transgene provide trophic support for intrastriatal chromaffin cell grafts.
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PMID:The use of genetically altered astrocytes to provide nerve growth factor to adrenal chromaffin cells grafted into the striatum. 168 84

Adrenal gland involvement in Parkinson's disease was reported by different authors. Further studies became relevant after adrenal was proposed as dopaminergic donor for neurotransplantation. Chromaffin cells were grown in culture and the effects of nerve growth factor (NGF) tested: no differences were observed between parkinsonian and control cells. The expression of the beta-NGF mRNA in the parkinsonian adrenal was analyzed: a specific cDNA was synthesized and a 168 bp portion amplified using PCR. The products were identified and the identity of the fragment was confirmed by sequencing. Quantitative PCR demonstrated a beta-NGF mRNA concentration exceeding 5 fg/micrograms of total adrenal RNA. These findings demonstrate the retained functional capacity of the parkinsonian adrenal to respond to NGF and express the beta-NGF mRNA.
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PMID:Maintained cellular function of adrenal medullary cells in parkinsonian dysautonomia. 174 39

Experimental studies in rodents show that beta-nerve growth factor can increase the survival, neurite outgrowth, and functional effect of grafts of adrenal chromaffin cells to the basal ganglia. We, therefore, have begun to investigate whether treatment with nerve growth factor might also increase the functional effect of autografts of adrenal medullary tissue in patients with Parkinson's disease. Previous studies have shown that stereotactic implantation of adrenal tissue pieces produces a transient functional improvement that lasts for a few months. This report describes a trial of grafting of adrenal chromaffin tissue into the putamen, supported by infusion of nerve growth factor. The patient is a 63-year-old woman with a 19-year history of Parkinson's disease, now complicated by on-off phenomena and drug-induced hyperkinesia, despite optimized medical management. The left adrenal gland was removed, and the medulla was dissected into 1- to 2-mm3 pieces in a solution containing nerve growth factor purified from mouse submandibular gland. Pieces were implanted in six tracts 3 to 4 mm from a previously placed cannula in the left putamen. Through the cannula, nerve growth factor was infused for 23 days for a total dose of 3.3 mg. Clinical assessment consisted of global ratings for rigidity and/or hypokinesia and for drug-induced hyperkinesia. Measures of gait and fine-motor control were also made. The motor readiness potential and auditory evoked potentials were recorded.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Intraputaminal infusion of nerve growth factor to support adrenal medullary autografts in Parkinson's disease. One-year follow-up of first clinical trial. 201 10

Mouse 3T3 fibroblasts were genetically modified by transfection with a mammalian expression vector containing the rat beta-nerve growth factor (NGF) gene. The transfected cell line, designated 3E, contains several hundred copies of the rat NGF gene and secretes high levels of biologically active NGF. Pieces of collagen gel containing the NGF-secreting 3E cells were grafted to the brains of unilaterally fimbria-fornix-lesioned rats. Grafts of the genetically modified NGF-producing cells rescued axotomized basal forebrain cholinergic neurons and significantly reduced cholinergic cell death in the medial septum as compared with rats treated with grafts of the parental 3T3 cells. Grafted fibroblast cells were detected, and rescue effects were noted up to 6 weeks after grafting. Local effects of NGF secreted by grafted cells were also seen at the gel-brain border in the form of sprouting acetylcholinesterase immunoreactive host cortical fibers. We suggest that implantation of genetically modified cells producing NGF may have therapeutic applications in rescuing damaged central cholinergic neurons in senile dementia of the Alzheimer type as well as in providing trophic support for chromaffin tissue grafts in Parkinson's disease.
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PMID:Rescue of basal forebrain cholinergic neurons after implantation of genetically modified cells producing recombinant NGF. 232 66

The current study analyzed NGF protein levels in the brains of patients with Alzheimer's disease (AD) as compared with aged neurologically normal individuals. An established two-site ELISA was used to measure NGF-like immunoreactivity in the hippocampus, superior temporal gyrus, superior frontal gyrus, inferior parietal lobule, frontal and occipital cortical poles, cerebellum, amygdala, putamen, and nucleus basalis of Meynert (nbM). ChAT activity was assayed in adjacent tissue samples. NGF levels were also evaluated in Parkinson's disease for comparison with both AD and age-matched control cases. Regardless of the brain bank (University of Cincinnati, Rush Presbyterian St. Luke's Medical Center in Chicago, or University of Alabama at Birmingham), NGF-like activity was at least moderately increased with AD in virtually every brain region examined except for the nbM, in which significant declines were observed. NGF levels were also increased when compared with age-matched Parkinson's cases (frontal cortex). NGF-like activity was not related to age at onset or disease duration in AD cases, nor did NGF levels correlate with age at death in the control or AD groups. Correlations between ChAT and NGF-like activity across brains varied considerably and were generally not significant. The present findings indicate that AD is characterized by a widespread increase in cortical and subcortical NGF. Although a correlation with ChAT activity was not observed in cortex, the AD-related decline in NGF found in nbM is consistent with the possibility of impaired retrograde transport of NGF to this region.
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PMID:Nerve growth factor in Alzheimer's disease: increased levels throughout the brain coupled with declines in nucleus basalis. 766 3

Previous studies have demonstrated that astrocytes genetically modified to express recombinant nerve growth factor (NGF) support the survival and neuronal transdifferentiation of intrastriatal adrenal chromaffin cell grafts at 2 weeks post-transplantation [15]. The present study was performed to determine whether these effects would be maintained at longer times post-transplantation and, if so, whether the co-grafts would reduce rotational behavior in the unilateral 6-hydroxydopamine-lesioned rat. In the present study, we have demonstrated that primary type I rat astrocytes infected with a replication-defective retrovirus conferring expression of a mouse beta-NGF cDNA sequence secrete NGF at a rate that is approximately 40-fold higher than that of controls (i.e., 8.0 vs. 0.2 pg NGF/h/10(5) cells, respectively). The genetically modified astrocytes were also found to express recombinant NGF following intrastriatal transplantation, as indicated by a 23% increase in striatal NGF content compared with controls, measured at 4 weeks post-transplantation. When NGF-producing astrocytes and adrenal chromaffin cells were co-grafted into the dopamine-denervated striatum of the unilateral 6-hydroxydopamine-lesioned rat, the chromaffin cells displayed extensive neurite outgrowth and a 5-12-fold increase in survival compared to controls at 10 weeks post-grafting. These effects were paralleled by a 60% reduction of apomorphine-induced rotational behavior, suggesting a partial normalization of striatal function. These results suggest that genetically modified astrocytes promote the prolonged survival and function of adrenal chromaffin cell grafts in a rat model of Parkinson's disease.
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PMID:Nerve growth factor released by transgenic astrocytes enhances the function of adrenal chromaffin cell grafts in a rat model of Parkinson's disease. 783 45

Nerve growth factor (NGF) is well established for its ability to promote growth and survival for specific neuronal populations. However, its participation in the pathogenesis of human nervous system disorders such as Parkinson's disease (PD) remains to be resolved. This study examined NGF levels in the serum of healthy persons, in patients with PD and in parkinsonian rats using a double site immune-enzymatic assay (EIA) with the murine 27/21 anti-beta-NGF monoclonal antibody. PD patients were divided in two groups according to the stages of the disease (Grade: I-II and Grade: III-IV of Hoenh and Yahr scale). NGF levels in parkinsonian rats showed significant (P<0.01) reductions when compared with serum from normal animals. The NGF levels in early states of the disease (Grade I-II) showed greater reductions (P<0.01) in comparison to those with advanced stages (Grade III-IV). We consider that alterations in NGF levels may reflect ongoing neurodegenerative processes in PD.
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PMID:Nerve growth factor levels in Parkinson disease and experimental parkinsonian rats. 1236 11

This study determined the effects of pcDNA3-beta-nerve growth factor (NGF) gene-modified bone marrow stromal cells (BMSC) on the rat model of Parkinson's disease (PD). The recombinant plasmid pcDNA3-beta-NGF was transfected into BMSC, and NGF expression and its biological activity in vitro were detected. BMSC modified by the NGF gene were then grafted into the corpus striatum of PD rats, and the rotation behavior was evaluated at 1, 2, 4, and 6 weeks post-transplantation. A significant improvement in rotation behavior was observed in PD rats subjected to cell transplantation, especially in PD rats receiving NGF-modified BMSC. The genetically modified BMSC survived and expressed beta-NGF but did not differentiate into tyrosine hydroxylase-positive cells in vivo. The present findings suggested that genetically modified BMSC could be effective for PD treatment, and the mechanisms might involve the neuroprotective effects of beta-NGF.
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PMID:Effects of pcDNA3-beta-NGF gene-modified BMSC on the rat model of Parkinson's disease. 1827 10

Parkinson's disease has been the object of several therapeutic strategies based upon replacement of the degenerating dopaminergic neurons. Adrenal medullary transplants were tried initially, because of the biochemical relationship between chromaffin cells of the medulla and dopaminergic neurons of the substantia nigra. Compared to transplant of fetal neurons, autologous grafts of adrenal medullary tissue has the advantage of using a readily available source of tissue without the problems of immunosuppression. However, these cells have not proven to be as effective as fetal neurons, probably because they do not fully differentiate into neurons. In animal models, brief treatment with nerve growth factor can facilitate such differentiation. This study is a clinical evaluation of the efficacy of adrenal medullary cell transplantation, combined with nerve growth factor infusion. Two patients were selected who were moderately to severely affected (Hoehn-Yahr stage 2 in on-phase and stage 4 in off-phase). After adrenalectomy, small pieces of medulla were prepared and implanted stereotactically into the dorsal putamen on one side of the brain. A catheter filled with mouse beta-nerve growth factor (NGF) was placed close to the grafts. Infusion of NGF was continued for one month. Despite a progressively deteriorating course prior to surgery, both patients showed improvement on the rating scales postoperatively. There was also significant improvement in timed motor tests. Motor readiness evoked potentials showed increased voltage over the operated hemisphere. The study points to methods and feasibility of supplying nerve growth factor intraparenchymally to the human brain. Possible implications with respect to other growth factors, particularly Glial cell-line Derived Neurotrophic factor (GDNF) are discussed.
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PMID:Long-term beneficial effects of adrenal medullary autografts supported by nerve growth factor in Parkinson's disease. 2428 25


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