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)

Different strategies have been worked out to promote survival of transplanted fetal ventral mesencephalic cells (VMCs) using trophic and nontrophic support. Olfactory ensheathing cells (OECs) express high level of growth factors including NGF, bFGF, GDNF, and NT3, which are known to play important role in functional restoration or neurodegeneration. In the present investigation, an attempt has been made to study functional restoration in 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease (PD) following cotransplantation of VMC and OECs (cultured from olfactory bulb, OB) in striatal region. The functional restoration was assessed using neurobehavioral, neurochemical, and immunohistochemical approach. At 12 weeks, post-transplantation, a significant recovery (P < 0.001) in D-amphetamine induced circling behavior (73%), and spontaneous locomotor activity (SLA, 81%) was evident in cotransplanted animals when compared with 6-OHDA-lesioned animals. A significant restoration (P < 0.001) in [3H]-spiperone binding (77%), dopamine (DA) (82%) and 3,4-dihydroxy phenyl acetic acid (DOPAC) level (75%) was observed in animals cotransplanted with OECs and VMC in comparison to lesioned animals. A significantly high expression and quantification of tyrosine hydroxylase (TH)-positive cells in cotransplanted animals further confirmed the supportive role of OECs in viability of transplanted dopaminergic cells, which in turn may be helping in functional restoration. This was further substantiated by our observation of enhanced TH immunoreactivity and differentiation in VMC cocultured with OECs under in vitro conditions as compared to VMC alone cultures. The results suggest that cotransplantation of OECs and VMC may be a better approach for functional restoration in 6-OHDA-induced rat model of Parkinson's disease.
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PMID:Olfactory ensheathing cell transplantation restores functional deficits in rat model of Parkinson's disease: a cotransplantation approach with fetal ventral mesencephalic cells. 1526 63

The transplantation of dopaminergic (DA) neurons is used for treating Parkinson's disease. However, their actual application is restricted by a limited source of DA cells. Here we report that DA cells can be increased 5- to 10-fold in vitro by the soluble factors from cortex in early developmental stages, which is much more than any previously identified growth factors such as BDNF, GDNF and NT3. We also show that the effect of the soluble factors from cortex is stronger than those of midbrain at embryonic early developmental ages. In contrast, at middle ages the soluble factors from midbrain present a much stronger effect. These findings suggest that the development of DA cells may be regulated by growth factors in a complex spatial and temporal network.
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PMID:Survival and differentiation of dopaminergic neurons can be regulated by soluble factors from cortex in vitro. 1530 22

We have used cDNA array analysis to examine the expression of genes in reactive astrocytes of dopamine-depleted striatum of rats in vivo, an animal model for Parkinson disease, compared to those from control striatum. The striatum of both normal adult rats and rats whose substantia nigra had been lesioned with 6-hydroxydopamine was removed one week following lesion. After fixing the tissue in RNAlater, individual astrocytes, isolated directly from dissociated striatum and confirmed to be astocytes by expression of glial fibrillary acidic protein (GFAP) mRNA using single cell RT-PCR, were used as the source of mRNA. Co-localization of GFAP with either of 2 antibodies known to label only reactive astrocytes in vivo confirmed that virtually all astrocytes in the lesioned striatum were reactive. The analysis has identified 29 genes whose expression is turned on or enhanced in dopamine-depleted striatal astrocytes and 2 whose expression is decreased. In situ hybridization was used to confirm the localization of 8 of these genes to astrocytes: these included GDNF, NGF, bFGF, TNF-alpha, MIP-1alpha, c-jun, Fra-1 and Fra-2. Understanding these gene differences that occur in astrocytes in response to dopamine depletion should enhance our ability to promote recovery from the injury.
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PMID:Gene expression profiles of reactive astrocytes in dopamine-depleted striatum. 1544 82

Dementia is a frequent complication of Parkinson's disease (PD) and usually occurs late in the protracted course of the illness. We have already reported numerous MHC class II-positive microglia in the hippocampus in PD patients, and that this phenomenon may be responsible for functional changes in the neurons and the cognitive decline in PD patients. In this study, we have investigated the distribution of activated microglia and the immunohistochemical and the mRNA expression of several cytokines and neurotrophic factors of the hippocampus in PD and dementia with Lewy bodies (DLB). The brains from five cases of PD and five cases of DLB that were clinically and neuropathologically diagnosed, and those from four normal controls (NC) were evaluated by immunohistochemistry using anti-HLA-DP, -DQ, -DR (CR3/43), anti-alpha-synuclein, anti-brain-derived neurotrophic factor (BDNF), and anti-glial fibrillary acidic protein antibodies. In addition, the mRNA expressions of cytokines (IL-1alpha, IL-1beta, TNF-alpha, IL-6, TGF-beta) and neurotrophic factors (BDNF, GDNF, NGF, NT-3) of these brains were evaluated by the reverse transcription-PCR method. MHC class II-positive microglia were distributed diffusely in the hippocampus of PD and DLB brains. Although the cytoplasm of pyramidal and granular cells of the hippocampus in NC brains was strongly stained by anti-BDNF antibodies, it was only weakly stained in PD and DLB brains. The mRNA expression of IL-6 was significantly increased in the hippocampus of PD and DLB brains, and that of BDNF was significantly decreased in the hippocampus of DLB brains. The increased number of activated microglia and the production of neurotrophic cytokines such as IL-6, together with the decreased expression of the neurotrophic factors of neurons in the hippocampus of PD and DLB brains, may be related to functional cellular changes associated with dementia.
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PMID:Cytokine production of activated microglia and decrease in neurotrophic factors of neurons in the hippocampus of Lewy body disease brains. 1561 28

Cell microencapsulation represents a promising tool for the treatment of many central nervous system (CNS) diseases such as Parkinson's disease. In this technology, cells are surrounded by a semipermeable membrane which protects them from mechanical stress and isolates them from host's immune response. However, if the future clinical application of this strategy is wanted, many challenges remain including the improvement of the mechanical resistance of the microcapsules and the optimization of the intracapsular microenvironment conditions. In this way, the selection of the matrix is essential because the morphological and the physiological behavior of the cells depend on the interactions between the matrix and the enclosed cells. Assuming these considerations, three types of microcapsules elaborated with four different polymers: alginate, cellulose sulfate, agarose and pectin have been fabricated and compared in order to evaluate some key properties such as morphology, size and mechanical stability. Furthermore, GDNF secreting Fischer rat 3T3 fibroblasts were immobilized in each type of capsule and the viability and neurotrophic factor release was determinated. Results showed that the alginate and pectin microcapsules were the most resistant devices, maintaining an adequate microenvironment for the enclosed cells. In contrast, cells entrapped in alginate-cellulose sulfate matrices presented the lowest mechanical resistance, cell viability and GDNF production.
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PMID:Microcapsules prepared with different biomaterials to immobilize GDNF secreting 3T3 fibroblasts. 1577 39

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

There is considerable evidence that pharmacological doses of the pineal hormone, melatonin, are neuroprotective in diverse models of neurodegeneration including Parkinson's disease. However, there is limited information about the effects of physiological doses of this hormone in similar models. In this study, rats were chronically treated with melatonin via drinking water following partial 6-hydroxydopamine lesioning in the striatum. The two doses of melatonin (0.4 microg/ml and 4.0 microg/ml) were within the reported physiological concentrations present in the serum and cerebrospinal fluid respectively. At 2 weeks after surgery, the higher dose of melatonin significantly attenuated rotational behavior in hemi-parkinsonian rats compared to similarly lesioned animals receiving either vehicle (P < 0.001) or the lower dose of melatonin (P < 0.01). Animals were perfused or sacrificed 10 weeks after commencing melatonin treatment for immunohistochemical or mRNA studies. Animals treated with 4.0 microg/ml melatonin exhibited normal tyrosine hydroxylase (TH) immunoreactivity in the lesioned striatum, whereas little or no TH immunofluorescence was visible in similarly lesioned animals receiving vehicle. In contrast, semiquantitative RT-PCR analysis revealed no group differences in TH mRNA, suggesting spontaneous recovery of this transcript as observed previously in partially lesioned animals. There were no significant differences in striatal GDNF mRNA levels between sham and lesioned animals. However, there was a significant (P < 0.01) increase in GDNF mRNA expression in the intact contralateral striata of lesioned animals treated with vehicle. Interestingly, melatonin treatment attenuated this novel compensatory contralateral increase in striatal GDNF expression, presumably due to its neuroprotective effect. These findings support a physiological role for melatonin in protecting against parkinsonian neurodegeneration in the nigrostriatal system.
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PMID:Physiological neuroprotection by melatonin in a 6-hydroxydopamine model of Parkinson's disease. 1637 67

An intensive search is underway to identify candidates to replace the cells that degenerate in Parkinson's disease (PD). To date, no suitable substitute has been found. We have recently found that adult rat bone marrow stromal cells (MSCs) can be induced to assume a neuronal phenotype in vitro. These findings may have particular relevance to the treatment of PD. We now report that adult MSCs express multiple dopaminergic genes, suggesting that they are potential candidates for cell therapy. Using RT-PCR, we have examined families of genes that are associated with the development and/or survival of dopaminergic neurons. MSCs transcribe a variety of dopaminergic genes including patched and smoothened (components of the Shh receptor), Gli-1 (downstream mediator of Shh), and Otx-1, a gene associated with formation of the mesencephalon during development. Furthermore, Shh treatment elicits a 1.5-fold increase in DNA synthesis in cultured MSCs, suggesting the presence of a functional Shh receptor complex. We have also found that MSCs transcribe and translate Nurr-1, a nuclear receptor essential for the development of dopamine neurons. In addition, MSCs express a variety of growth factor receptors including the glycosyl-phosphatidylinositol-anchored ligand-binding subunit of the GDNF receptor, GFRalpha1, as well as fibroblast growth factor receptors one and four. The expression of genes that are associated with the development and survival of dopamine neurons suggests a potential role for these cells in the treatment of Parkinson's disease.
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PMID:Adult rat bone marrow stromal cells express genes associated with dopamine neurons. 1657 67

Type II errors may be having a significant impact on drug discovery. This is of particular importance in the clinical neurosciences, where endpoints are often subjective scores of disability rather than unequivocal events such as survival. Here we examine a recently published study [Lang AE, Gill S, Patel NK, et al. Randomized controlled study of intraputamenal glial cell-derived neurotrophic factor infusion in Parkinson disease. Ann Neurol 2006;59:459-66] in an area of immense importance to neuroscience. This small study found no detectable clinical benefit from infused intraputamenal GDNF as a treatment for Parkinson disease. However the standard deviation of the accrued data turned out to be considerably higher than had been anticipated in the power analysis performed prior to the study. In order to determine what impact, if any, this had on the conclusions that could be drawn, the actual data were analyzed by means of both the t-test and the rank-based Somers'D. The study was found to be underpowered and thus incapable of ruling out a large effect of GDNF on Parkinson disease. It therefore does not contradict the large effects seen in previous open-label studies.
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PMID:GDNF in Parkinson disease: an object lesson in the tyranny of type II. 1687 72

GDNF is a potent neurotrophic factor for nigrostriatal dopaminergic neurons in vitro and in animal models of Parkinson's disease (PD), but has largely failed when tested in therapeutic applications in human PD. We report here that GDNF requires transforming growth factor-beta (TGF-beta) to elicit its neurotrophic activity. Lesioning the mouse nigrostriatal system with MPTP significantly upregulates striatal TGF-beta2 mRNA levels. As expected, GDNF protects against the destructive effects of MPTP, including losses of TH-ir nigral neurons, striatal dopamine and TH-ir fibers. Application of antibodies neutralizing all three TGF-beta isoforms to the MPTP-lesioned striatum abolishes the neurotrophic effect of GDNF. We show that TGF-beta antibodies are not toxic and do not interfere with retrograde transport of iodinated GDNF, suggesting that TGF-beta antibodies do not impair internalization and retrograde trafficking of GDNF. We conclude that striatal TGF-beta may be essential for permitting exogenous GDNF to act as a neuroprotective factor.
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PMID:GDNF applied to the MPTP-lesioned nigrostriatal system requires TGF-beta for its neuroprotective action. 1714 11


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