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)

Impaired neuronal survival is a key event in the development of degenerative diseases, such as Parkinson's disease (PD). Here we show that transforming growth factor beta (TGF-beta) acts directly on rat E14 midbrain dopaminergic neurons in vitro, its survival-promoting effect being not mediated by BDNF, NT-3, or GDNF. Treatment with TGF-beta, sonic hedgehog (Shh), or fibroblast growth factor-8 (FGF8) significantly increased number of tyrosine hydroxylase (TH)-immunoreactive neurons after 7 days, whereas application of these factors added together further increased number of TH-positive neurons, compared to single-factor treatments. Neutralization of endogenous TGF-beta, Shh, or FGF8 significantly reduced number of dopaminergic neurons. TGF-beta treatment decreased number of apoptotic cells, having no effect on cell proliferation. Neutralization of TGF-beta in vivo during chick E6-10 resulted in reduced number of midbrain dopaminergic neurons. The results suggest that TGF-beta is required for survival of mesencephalic dopaminergic neurons acting in cooperation with Shh and FGF8.
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PMID:TGF-beta promotes survival on mesencephalic dopaminergic neurons in cooperation with Shh and FGF-8. 1519 87

The success of transplantation of human fetal mesencephalic tissue into the putamen of patients with Parkinson's disease (PD) is still limited by the poor survival of the graft. In animal models of fetal transplantation for PD, antiapoptotic agents, such as growth factors or caspase inhibitors, or agents counteracting oxidative stress enhance the survival and reinnervation potential of the graft. Genetic modification of the transplant could allow a local and continuous delivery of these factors at physiologically relevant doses. The major challenge remains the development of strategies to achieve both early and sustained gene delivery in the absence of vector-mediated toxicity. We recently reported that E14 rat fetal mesencephalon could be efficiently tranduced by adeno-associated virus type 2 (AAV2) vectors and that gene expression was maintained until at least 3 months after transplantation in the adult rat striatum. Here we report that an AAV2 vector can mediate the expression of the EGFP reporter gene under the control of a CMV promoter in organotypic cultures of freshly explanted solid fragments of human fetal mesencephalic tissue as early as 3 days to at least 6 weeks postinfection. These results suggest that AAV2 vectors could be used to genetically modify the human fetal tissue prior to transplantation to Parkinson's patients to promote graft survival and integration.
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PMID:Efficient early and sustained transduction of human fetal mesencephalon using adeno-associated virus type 2 vectors. 1556 68

Parkinson's disease is a disabling neurodegenerative disorder of unknown etiology characterized by a predominant and progressive loss of dopaminergic neurons in the substantia nigra. Recent findings suggest that impaired energy metabolism plays an important role in the pathogenesis of this disorder. The endogenously occurring guanidino compound creatine is a substrate for mitochondrial and cytosolic creatine kinases. Creatine supplementation improves the function of the creatine kinase/phosphocreatine system by increasing cellular creatine and phosphocreatine levels and the rate of ATP resynthesis. In addition, mitochondrial creatine kinase together with high cytoplasmic creatine levels inhibit mitochondrial permeability transition, a major step in early apoptosis. In the present study, we analyzed the effects of externally added creatine on the survival and morphology of dopaminergic neurons and also addressed its neuroprotective properties in primary cultures of E14 rat ventral mesencephalon. Chronic administration of creatine [5 mM] for 7 days significantly increased survival (by 1.32-fold) and soma size (by 1.12-fold) of dopaminergic neurons, while having no effect on other investigated morphological parameters. Most importantly, concurrent creatine exerted significant neuroprotection for dopaminergic neurons against neurotoxic insults induced by serum and glucose deprivation (P < 0.01), 1-methyl-4-phenyl pyridinium ion (MPP+) [15 microM] and 6-hydroxydopamine (6-OHDA) [90 microM] exposure (P < 0.01). In addition, creatine treatment significantly protected dopaminergic cells facing MPP+-induced deterioration of neuronal morphology including overall process length/neuron (by 60%), number of branching points/neuron (by 80%) and area of influence per individual neuron (by 60%). Less pronounced effects on overall process length/neuron and number of branching points/neuron were also found after 6-OHDA exposure (P < 0.05) and serum/glucose deprivation (P < 0.05). In conclusion, our findings identify creatine as a rather potent natural survival- and neuroprotective factor for developing nigral dopaminergic neurons, which is of relevance for therapeutic approaches in Parkinson's disease and for the improvement of cell replacement strategies.
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PMID:Effects of creatine treatment on the survival of dopaminergic neurons in cultured fetal ventral mesencephalic tissue. 1589 Apr 57

Growth/differentiation factor 5 (GDF5) is a member of the transforming growth factor-beta superfamily that is expressed in the developing CNS, including the ventral mesencephalon (VM). GDF5 has been shown to increase the survival of dopaminergic neurones in animal models of Parkinson's disease. This study was aimed at characterising the effects of GDF5 on dopaminergic neurones in vitro. Treatment with GDF5 induced a three-fold increase in the number of dopaminergic neurones in embryonic day 14 rat VM cultures after six days in vitro. A significant increase was also observed in the numbers of astrocytes in GDF5-treated cultures. GDF5 treatment also had significant effects on the morphology of dopaminergic neurones in these cultures; total neurite length, number of branch points and somal area were all significantly increased after six days in vitro. Analysis of neurite length and numbers of branch points at each level of the neuritic field revealed that the most pronounced effects of GDF5 were on the secondary and tertiary levels of the neuritic field. The specific type I receptor for GDF5, bone morphogenetic protein receptor (BMPR)-Ib, was found to be strongly expressed in freshly-dissected E14 VM tissue, but its expression was lost with increasing time in culture. Accordingly, treatment with GDF5 for 24 h from the time of plating induced increases in the numbers of dopaminergic neurones, while treatment with GDF5 for 24 h after six days in vitro did not. This study shows that GDF5 can promote both the survival and morphological differentiation of VM dopaminergic neurones in vitro, lending support to its potential as a candidate dopaminergic neurotrophin for use in the treatment of Parkinson's disease.
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PMID:Effects of growth/differentiation factor 5 on the survival and morphology of embryonic rat midbrain dopaminergic neurones in vitro. 1590 56

Semaphorin3A (Sema3A) is known to cause neuronal apoptosis and serves as a chemorepellent factor for axonal growth. In our previous report, we found that Sema3A was up-regulated in the 6-OHDA-injected striatum of rats, suggesting that Sema3A was likely involved in dopaminergic (DA) depletion. In this study, we investigated whether Sema3A directly worked as a neurotoxin to DA neurons both in vitro and in vivo. First, effects of various dosages of Sema3A administration on the DA neurons of the E14 murine ventral mesencephalon were examined in vitro. Sema3A at a dose over 500 ng/ml induced apoptosis to DA neurons. Next, we examined whether the continuous infusion of Sema3A exerted degeneration of DA neurons in rats. We established a Sema3A-secreting cell line (BHK-Sema3A), confirming the secreting functions by immunocytochemical and Western blot assays. Adult Sprague-Dawley rats were unilaterally implanted into the striatum with BHK-Sema3A or BHK non-Sema3A control cells, and subsequently underwent behavioral and immunohistochemical evaluations. Rats that received BHK-Sema3A did not show significant differences in the number of amphetamine- and apomorphine-induced rotations and TH-positive neurons in the substantia nigra pars compacta compared to the control group. Our results revealed that Sema3A was toxic to cultured DA neurons at very high dosages, but the continuous secretion of Sema3A at modest dosage in vivo did not produce Parkinsonian pathophysiologic symptoms. Optimizing the dosage and infusion location (i.e., nigra) and timing (more than 1 week post-transplantation) might further reveal the contribution of Sema3A to the pathogenesis of Parkinson's disease.
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PMID:Toxicity of semaphorin3A for dopaminergic neurons. 1591 Nov 22

Vascular endothelial growth factor (VEGF) has been shown to display neuroprotective effects on dopaminergic (DA) neurons. Here, we investigated the neurorescue effects of VEGF on 6-hydroxydopamine (6-OHDA)-treated DA neurons in vitro and in vivo. Initially, we examined in vitro whether 1, 10, or 100 ng/ml of VEGF administration at 2 or 4 h after 6-OHDA treatment rescued DA neurons derived from E14 murine ventral mesencephalon. The earlier treatment of VEGF suppressed 6-OHDA-induced loss of DA neurons more than the delayed treatment. Next, we examined whether the continuous infusion of VEGF had neurorescue effects in a rat model of Parkinson's disease. We established a human VEGF secreting cell line (BHK-VEGF) and encapsulated the cells into hollow fibers. The encapsulated cells were unilaterally transplanted into the striatum of adult rats at 1 or 2 weeks after 6-OHDA lesions, and animals subsequently underwent behavioral and immunohistochemical evaluations. Compared to lesioned rats that received BHK-Control capsules, lesioned rats transplanted with BHK-VEGF capsules showed a significant reduction in the number of amphetamine-induced rotations, a significant preservation of TH-positive neurons in the substantia nigra pars compacta, and a remarkable glial proliferation in the striatum, with the earlier transplantation exerting much more benefits than the delayed transplantation. Parallel studies revealed that the observed in vitro and in vivo neurorescue effects were likely mediated by VEGF's angiogenic and glial proliferative effects, as well as its direct effects on the neurons. Our results suggest that VEGF is a highly potent neurorescue molecule for Parkinson's disease therapy.
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PMID:Neurorescue effects of VEGF on a rat model of Parkinson's disease. 1604 99

Increasing evidences suggest that activated microglia may contribute to neurodegeneration in Parkinson's disease (PD). In the present study, primary ventral mesencephalic (VM) cultures from E14 rats and PC12 cells were utilized as in vitro models to examine the mechanism underlying microglia activation mediated dopaminergic neurodegeneration. Using lipopolysaccharide (LPS) (1-100 ng/ml) as a tool, we observed that microglia activation-mediated a selective dopaminergic neurodegeneration in VM neuron-glia cultures, which was supported by the further study showing that conditioned medium (CM) from microglia-enriched cultures treated with LPS (10-100 ng/ml) decreased PC12 cell viability. The results from antibody neutralization, NO inhibition and superoxide neutralization suggested that the dopaminergic cell death was due to the production of microglia-derived proinflammatory factors (TNF-alpha, NO and superoxide), among which reactive oxygen species (ROS) might outweigh proinflammatory cytokines. Apoptosis assay on PC12 cells and primary dopaminergic neurons showed that apoptosis was a mechanism for both microglia activation-mediated dopaminergic cell death. Through Western blot and immunocytochemistry, we found that caspase-3 activation was involved in both dopaminergic cell injuries. Finally, the results from laser scanning confocal microscope demonstrated that PC12 cell intracellular free Ca(2+) ([Ca(2+)](i)) increased early after CM treatment. [Ca(2+)](i) increase involved influx of calcium from the extracellular milieu and release from intracellular stores and participated in the CM-induced PC12 cell apoptosis. Further investigations indicated that TNF-alpha, IL-1beta, NO and superoxide contributed at different degrees to CM-induced [Ca(2+)](i) increase and apoptosis in PC12 cells. Using primary VM cultures and PC12 cells, our study shows the roles of proinflammatory factors, apoptosis, caspase-3 activation and Ca(2+) disturbance in microglia activation-mediated dopaminergic cell degeneration. Understanding the mechanism for microglia activation-mediated dopaminergic neurodegeneration may contribute to the development of new neuroprotective strategies against PD.
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PMID:Involvement of proinflammatory factors, apoptosis, caspase-3 activation and Ca2+ disturbance in microglia activation-mediated dopaminergic cell degeneration. 1611 14

Generation of dopaminergic (DA) neurons from multipotent embryonic progenitors represents a promising therapeutical strategy for Parkinson's disease (PD). Aim of the present study was the establishment of enhanced cell culture conditions, which optimize the use of midbrain progenitor cells in animal models of PD. In addition, the progenitor cells were characterized during expansion and differentiation according to morphological and electrophysiological criteria and compared to primary tissue. Here, we report that CNS precursors can be expanded in vitro up to 40-fold and afterwards be efficiently differentiated into DA neurons. After 4-5 days under differentiation conditions, more than 70% of the neurons were TH+, equivalent to 30% of the total cell population. Calcium imaging revealed the presence of calcium-permeable AMPA receptors in the differentiated precursors which are capable to contribute to many developmental processes. The overall survival rate, degree of reinnervation and the behavioral performance after transplantation of 4 days in-vitro-differentiated cells were similar to results after direct grafting of E14 ventral mesencephalic cells, whereas after shorter or longer differentiation periods, respectively, less effects were achieved. Compared to the amount of in-vitro-generated DA neurons, the survival rate was only 0.8%, indicating that these cells are very vulnerable. Our results suggest that expanded and differentiated DA precursors from attached cultures can survive microtransplantation and integrate within the striatum in terms of behavioral recovery. However, there is only a short time window during in vitro differentiation, in which enough cells are already differentiated towards a DA phenotype and simultaneously not too mature for implantation. However, additional factors and/or genetical manipulation of these expanded progenitors will be required to increase their in vivo survival in order to improve both the ethical and the technical outlook for the use of fetal tissue in clinical transplantation.
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PMID:Dopaminergic properties and function after grafting of attached neural precursor cultures. 1625 57

The poor survival of dopamine grafts in Parkinson's disease is one of the main obstacles to the widespread application of this therapy. One hypothesis is that implanted neurons, once removed from the embryonic environment, lack the differentiation factors needed to develop the dopaminergic phenotype. In an effort to improve the numbers of dopamine neurons surviving in the grafts, we have investigated the potential of adenoviral vectors to deliver the differentiation factor sonic hedgehog or the glial cell line-derived neurotrophic factor GDNF to dopamine-rich grafts in a rat model of Parkinson's disease. Adenoviral vectors containing sonic hedgehog, GDNF, or the marker gene LacZ were injected into the dopamine depleted striatum of hemiparkinsonian rats. Two weeks later, ventral mesencephalic cell suspensions were prepared from embryos of donor ages E12, E13, E14 or E15 and implanted into the vector-transduced striatum. Pre-treatment with the sonic hedgehog vector produced a three-fold increase in the numbers of tyrosine hydroxylase-positive (presumed dopaminergic) cells in grafts derived from E12 donors, but had no effect on E13-E15 grafts. By contrast, pre-treatment with the GDNF vector increased yields of dopamine cells in grafts derived from E14 and E15 donors but had no effect on grafts from younger donors. The results indicate that provision of both trophic and differentiation factors can enhance the yields of dopamine neurons in ventral mesencephalic grafts, but that the two factors differ in the age and stage of embryonic development at which they have maximal effects.
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PMID:Delivery of sonic hedgehog or glial derived neurotrophic factor to dopamine-rich grafts in a rat model of Parkinson's disease using adenoviral vectors Increased yield of dopamine cells is dependent on embryonic donor age. 1632 2

Glial-cell-line-derived neurotrophic factor (GDNF), neurturin (NRTN), artemin (ARTN) and persephin (PSPN), known as the GDNF family ligands (GFLs), influence the development, survival and differentiation of cultured dopaminergic neurons from ventral mesencephalon (VM). Detailed knowledge about the effects of GFLs on other neuronal populations in the VM is essential for their potential application as therapeutic molecules for Parkinson's disease. Hence, in a comparative study, we investigated the effects of GFLs on cell densities and morphological differentiation of gamma-aminobutyric acid-immunoreactive (GABA-ir) and serotonin-ir (5-HT-ir) neurons in primary cultures of E14 rat VM. We observed that all GFLs [10 ng/ml] significantly increased GABA-ir cell densities (1.6-fold) as well as neurite length/neuron. However, only GDNF significantly increased the number of primary neurites/neuron, and none of the GFLs affected soma size of GABA-ir neurons. In contrast, only NRTN treatment significantly increased 5-HT-ir cells densities at 10 ng/ml (1.3-fold), while an augmentation was seen for GDNF and PSPN at 100 ng/ml (2.4-fold and 1.7-fold, respectively). ARTN had no effect on 5-HT-ir cell densities. Morphological analysis of 5-HT-ir neurons revealed a significant increase of soma size, number of primary neurites/neuron and neurite length/neuron after GDNF exposure, while PSPN only affected soma size, and NRTN and ARTN failed to exert any effect. In conclusion, we identified GFLs as effective neurotrophic factors for VM GABAergic and serotonergic neurons, demonstrating characteristic individual action profiles emphasizing their important and distinct roles during brain development.
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PMID:GDNF family ligands display distinct action profiles on cultured GABAergic and serotonergic neurons of rat ventral mesencephalon. 1638 Jan


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