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)

Positron emission tomography (PET) can detect the presence of striatal, pallidal, midbrain, and cortical dopamine terminal dysfunction in vivo in Parkinson's disease (PD). In addition, dopamine release during motor tasks can be assessed as reflected by changes in receptor availability to PET ligands. Furthermore, the functional effects of focal dopamine replacement via implantation of fetal cells or glia-derived neurotrophic factor (GDNF) infusion into putamen can be monitored. In this review, the insight that PET has given us concerning the role of dopamine in motor control is presented, and the functional substrates underlying PD symptomatologies are discussed.
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PMID:PET studies on the function of dopamine in health and Parkinson's disease. 1284 71

Oxidative stress is thought to be a major contributor to the progress of the Parkinson's Disease (PD) because of the high vulnerability of dopaminergic cells against oxidative stress. The present work demonstrates that with the expression of the baculovirus p35 gene, PC12 cells could gain a high resistance against oxidative toxicants, hydrogen peroxide (H(2)O(2)) and 6-hydroxydopamine (6-OHDA). The DNA fragmentation analysis showed that PC12 cells underwent apoptosis after exposure to H(2)O(2) or 6-OHDA, while PP35 cells, a p35-expressing PC12 cell line, did not. Flow cytometric analysis showed that treatment with 150 microM H(2)O(2) or 120 microM 6-OHDA for 24 h caused 52.86% or 66.36% apoptotic cell, respectively, in PC 12 cells, but only 4.26% or 5.80% in PP35 cells. The cell viability measured by 3-(4,5-dimethylthiazal-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay indicated that H(2)O(2) and 6-OHDA induced a dose-dependent cell death on PC12 cells that were greatly remitted on PP35 cells. The viability of PP35 cells was even stronger than that of PC12 cells protected by glial cell line deprived neurotrophic factor (GDNF). The surviving PP35 cells remained normal cell morphology and showed positive with tyrosine hydroxylase (TH) immunocytochemical staining. These results indicate that baculovirus p35 gene possesses remarkable ability to rescue PC12 cells from death in experimental paradigms associated with oxidative stress.
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PMID:Baculovirus p35 gene greatly enhances PC12 cell's resistance against oxidative stress. 1460 15

The recent identification of neurotrophic factors, such as the glial cell line derived neurotrophic factor (GDNF), acting on mesencephalic dopaminergic neurons, offers the possibility to stimulate the axonal regeneration of these cells which are affected in Parkinson's disease. Nevertheless, a safe and efficient GDNF delivery system that may be used in clinical trials is still lacking. We have developed GDNF-releasing microspheres capable of releasing the neurotrophic factor for at least 2 months in vivo. In this study we demonstrate that these microspheres, when implanted in the brains of 'Parkinsonian' rats, were well tolerated, and were able to induce sprouting of the preserved dopaminergic fibers with synaptogenesis. Moreover, this neural regeneration was accompanied by functional improvement. The implantation of GDNF-releasing microspheres could be a promising strategy in the treatment of Parkinson's disease.
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PMID:Striatal implantation of GDNF releasing biodegradable microspheres promotes recovery of motor function in a partial model of Parkinson's disease. 1460 82

Glial cell line-derived neurotrophic factor (GDNF) offers the possibility to stimulate axonal regeneration of mesencephalic dopaminergic neurons, which are affected in Parkinson's disease. Nevertheless, a safe and efficient GDNF delivery system that may be used in clinical trials is still lacking. In a previous study, we showed that GDNF-releasing microspheres can deliver the neurotrophic factor for 2 months, allowing in a partial rat model of Parkinson's disease a sprouting of the preserved dopaminergic fibers and functional improvement 8 weeks after the treatment. The present study confirms these previous observations and shows that the amphetamine-induced rotation score is still decreased 24 weeks after the end of GDNF delivery. Nevertheless, the improvement was not statistically significant at the latest time point due to the spontaneous reinnervation observed in the model used.
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PMID:Long-term effect of intra-striatal glial cell line-derived neurotrophic factor-releasing microspheres in a partial rat model of Parkinson's disease. 1503 31

Vectors based on lentiviruses are opening up new approaches for the treatment of neurodegenerative diseases. Currently, the equine infectious anaemia virus (EIAV) vector is one of the most attractive gene delivery systems with respect to neuronal tropism. The aim was to validate EIAV-lentiviral vectors as a gene delivery system for neurotrophic factor genes in an animal model of Parkinson's disease. EIAV carrying the glial cell line-derived neurotrophic factor (GDNF) gene was unilaterally injected into rat striatum and above the substantia nigra (SN). One week later, the rats received a 6-OHDA lesion into the ipsilateral striatum. GDNF delivery led to extensive expression of GDNF protein within the striatum. In addition, near complete protection against dopaminergic cell death was observed in the GDNF-treated group.
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PMID:Neuroprotection in a rat Parkinson model by GDNF gene therapy using EIAV vector. 1507 20

The pathogenic process responsible for the loss of dopaminergic neurons within the substantia nigra of patients with Parkinson disease (PD) is poorly understood. Current research supports the involvement of fibroblast growth factor (FGF20) in the survival of dopaminergic cells. FGF20 is a neurotrophic factor that is preferentially expressed within the substantia nigra of rat brain. The human homologue has been mapped to 8p21.3-8p22, which is within an area of PD linkage revealed through our published genomic screen. To test whether FGF20 influences risk of PD, we genotyped five single-nucleotide polymorphisms (SNPs) lying within the FGF20 gene, in a large family study. We analyzed our sample (644 families) through use of the pedigree disequilibrium test (PDT), the genotype PDT, the multilocus-genotype PDT, and the family-based association test to assess association between risk of PD and alleles, genotypes, multilocus genotypes, and haplotypes. We discovered a highly significant association of PD with one intronic SNP, rs1989754 (P=.0006), and two SNPs, rs1721100 (P=.02) and ss20399075 (P=.0008), located in the 3' regulatory region in our overall sample. Furthermore, we detected a haplotype (A-G-C-C-T) that is positively associated with risk of PD (P=.0003), whereas a second haplotype (A-G-G-G-C) was found to be negatively associated with risk of PD (P=.0009). Our results strongly support FGF20 as a risk factor for PD.
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PMID:Fibroblast growth factor 20 polymorphisms and haplotypes strongly influence risk of Parkinson disease. 1512 13

Pramipexole hydrochloride (pramipexole) is a nonergot dopamine D(2) agonist, and the S(-)enantiomer is used for the treatment of Parkinson's disease (PD). Pramipexole possessed the highest affinity with the D(3) subtype among the D(2) receptor subfamily members (D(2), D(3), D(4)), lacking affinity with the D(1) and D(5) subtype. Pramipexole ameliorated the motor disturbances in PD animal models, induced contralateral rotational behavior reflecting post-synaptic D(2) receptor stimulation in the striatum, and showed a variety of neuroprotective effects in vitro and in vivo experimental systems. The neuroprotective effects of pramipexole seemed to be derived from several mechanisms: stimulation of D(2) autoreceptor, stimulation of D(3) receptor, inhibition of oxidative reaction and following radical production, increase of Bcl-2 protein and inhibition of apoptotic cell death, and production of neurotrophic factor. Clinical efficacy of pramipexole both in monotherapy and combined use with L-DOPA were confirmed evaluating by UPDRS (Unified Parkinson's Disease Rating Scale) II (Activities of daily living) and III (Motor), in the results of clinical studies mainly performed in USA and European countries and partly in Japan. In addition, patients initially treated with pramipexole demonstrated reduction in problematic symptoms and in loss of striatal [(123)I]2beta-carboxymethoxy-3beta-(4-idodophenyl)tropan uptake, a marker of dopamine neuron degeneration, compared with those initially treated with L-DOPA.
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PMID:[Pharmacological profiles and clinical effects of antiparkinsonian agent, pramipexole]. 1517 83

Parkinson's disease (PD) is a common neurodegenerative disorder that produces progressive disability despite symptomatic treatment. Several strategies, including stereotaxic brain lesions, deep brain stimulation, transplants of dopamine cells and administration of neurotrophic factors, have been proposed to improve efficacy and to counteract the progression of the disease. We here report the effects of repetitive intracerebral infusion of basic fibroblast growth factor (bFGF) and glial-derived neurotrophic factor, up to 1 year, in Cynomolgus monkeys with long standing asymmetric parkinsonism produced by unilateral intracarotid injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The treatment with neurotrophic factors was initiated when the parkinsonian deficits were stable, 6 months after the administration of MPTP. The evaluation of the response to the neurotrophic factors was performed by blind observers using: clinical scales that measured global motor deficit, motor ability in both hands, apomorphine-induced rotation, determination of the levels of monoamine metabolites in cerebrospinal fluid, and 6-F18-fluoro-l-DOPA (F-DOPA) uptake in the striatum and histology. Both factors, but bFGF more so, improve motor behavior, dopamine metabolism, striatal F-DOPA uptake, and the number of dopamine neurons. The procedure is well tolerated and provides a strong background for efficacy and safety of this treatment in patients with PD.
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PMID:Effects of fibroblast growth factor and glial-derived neurotrophic factor on akinesia, F-DOPA uptake and dopamine cells in parkinsonian primates. 1517 60

Glial cell line-derived neurotrophic factor (GDNF), a potent neurotrophic factor with restorative effects in a variety of rodent and primate models of Parkinson's disease (PD), could be of therapeutic value to PD. In this study, we show that intraventricular chronic infusion of low doses of GDNF using encapsulated genetically engineered C2C12 cells can exert: (1) transient recovery of motor deficits (hypokinesia); (2) significant protection of intrinsic striatal dopaminergic function in the immediate vicinity of the site of implantation of the capsule in the caudate nucleus, and (3) significant-long-lasting-neurotrophic properties at the nigral level with an increase volume of the cell bodies. These observations confirm the potent neurorestorative potential of GDNF in PD and the safety/efficacy of the encapsulation technology as a means to deliver in situ this neurotrophic cytokine even using an intraventricular approach.
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PMID:Encapsulated GDNF-producing C2C12 cells for Parkinson's disease: a pre-clinical study in chronic MPTP-treated baboons. 1519 99

Up-regulation of nestin expression was significantly induced in the caudate-putamen of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice in our previous observation [Brain Res 925 (2002) 9]. We hypothesized that the nestin-expressing cells might play an important role in the pathogenesis of parkinsonian model, and characterization of these nestin-expressing cells was studied by RT-PCR, immunohistochemistry and semi-quantitative analysis for various markers of glial fibrillary acid protein (GFAP), S-100, neuronal nuclear specific protein (NeuN), beta-tubulin, Ki-67 and brain-derived neurotrophic factor (BDNF) expression in MPTP-treated C57/BL mice. Firstly, significant increasing in both nestin protein and mRNA was found in MPTP-treated mice. Up-regulation of nestin expression started at day 1, peaked at day 3, and gradually went down at days 7-21 in the neostriatum after MPTP treatment. Secondly, double immunofluorescence indicated that almost all of nestin-positive cells exhibited GFAP (98%) or S-100 (96%)-immunoreactivity, whereas NeuN or beta-tubulin was hardly detected in these nestin-positive cells. Thirdly, a minor population (7.0%) of nestin-positive cells showed Ki-67 (cell proliferation marker)-immunoreactivity, showing some of them went into cell mitotic state. Finally but more interestingly, a major population (86%) of nestin-expressing cells also exhibited immunoreactivity for BDNF, one neurotrophic factor. These results present time-dependent up-regulation of nestin expression in neostriatum, the proliferative and neurotrophic properties of nestin-expressing astroglial cells in MPTP-treated C57/BL mice. Taken together with previous observations, this study suggests that nestin-expressing activated astroglial cells, possibly partially through synthesizing and releasing neurotrophic factors such as BDNF in the basal ganglia, may play important roles in protection of nigrostriatal dopamine neurons and in the pathogenesis of Parkinson's disease in mammals.
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PMID:Identification of brain-derived neurotrophic factor in nestin-expressing astroglial cells in the neostriatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice. 1520 28


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