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)

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

Parkinson's disease (PD) is thought to be caused by environmental and genetic factors. Mutations in four genes, alpha-synuclein, parkin, DJ-1, and UCH-L1, have been identified in autosomal inherited forms of PD. The pathogenetic cause for the loss of neuronal cells in PD patients, however, remains to be determined. Due to the rarity of mutations in humans with PD, the analysis of animal models might help to further gain insights into the pathogenesis of familial PD. For UCH-L1, deficiency has been described in gad mice leading to axonal degeneration and formation of spheroid bodies in nerve terminals. Here, we investigated the gene expression pattern of the brain of 3-month-old Uch-l1-deficient gracile axonal dystrophy (gad) mice by microarray analysis. A total of 146 genes were differentially regulated by at least a 1.4-fold change with 103 being up-regulated and 43 being down-regulated compared with age and sex matched wildtype littermate mice. The gene products with altered expression are involved in protein degradation, cell cycle, vesicle transport, cellular structure, signal transduction, and transcription regulation. Most of the genes were modestly regulated, which is in agreement that severe alteration of these pathways might be lethal. Among the genes most significantly down-regulated is the brain-derived neurotrophic factor which might be one aspect of the pathogenesis in gad mice. Interestingly, several subunits of the transcription factor CCAAT/enhancer binding protein are up-regulated, which plays a central role in most altered pathways.
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PMID:Microarray expression analysis of gad mice implicates involvement of Parkinson's disease associated UCH-L1 in multiple metabolic pathways. 1520 21

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

Exogenous administration of various neurotrophic factors has been shown to protect neurons in animal model of Parkinson's disease (PD). Several attempts are being made to search a tissue source simultaneously expressing many of these neurotrophic factors. Carotid body (CB) contains oxygen-sensitive glomus cells rich in dopamine (DA) and expresses glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor and neurotrophin-3. We have attempted to study the functional restoration following co-transplantation of CB cells and ventral mesencephalic cells (VMC) in a 6-hydroxydopamine-lesioned rat model of PD. A significant recovery (p < 0.001) in d-amphetamine-induced circling behavior (80%) and spontaneous locomotor activity (85%) was evident in co-transplanted animals at 12 weeks post-transplantation as compared to lesioned animals. Similarly, a significant (p < 0.001) restoration was observed in DA-D(2) receptor binding (77%), striatal DA (87%) and 3,4-dihydroxyphenylacetic acid (DOPAC) (85%) levels and nigral DA (75%) and DOPAC (74%) levels. Functional recovery was accompanied by tyrosine hydroxylase (TH) expression and quantification of TH-positive cells by image analysis revealed a significant restoration in TH-immunoreactive (IR) fiber density in striatum, as well as TH-IR neurons in substantia nigra pars compacta in co-transplanted animals over VMC-transplanted animals. The result suggests that co-transplantation of CB cells along with VMC provides better and long-term functional restoration in the rat model of PD, possibly by supporting the survival of newly grafted cells as well as remaining host DA neurons.
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PMID:Co-transplantation of carotid body and ventral mesencephalic cells as an alternative approach towards functional restoration in 6-hydroxydopamine-lesioned rats: implications for Parkinson's disease. 1544 61

Previously, this laboratory has shown that human foetal progenitor cells derived from ventral mesencephalon (VM) can be developmentally directed towards a dopaminergic lineage. In the present study, the effects are reported of several as yet untested differentiation/survival factors on the controlled conversion of neural progenitor cells to dopaminergic neurons. Positive immunoreactivity to tyrosine hydroxylase (TH) and raised levels of dopamine (DA) and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), secreted into culture medium, were used to indicate the presence of the dopaminergic neuronal phenotype, i.e., active TH. Incubation with retinoic acid (RA) (0.5 microM) lead to an increase in the number of cultured cells showing positive immunoreactivity for the neuronal marker, microtubule-associated protein (MAP)-2ab. A concomitant increase in TH-positive immunoreactivity was also demonstrated. The brain-derived neurotrophic factor (BDNF) (50 ng/ml), glial-derived neurotrophic factor (GDNF) (10 ng/ml) and interleukin-1 beta (IL-1 beta) (10 ng/ml) also had positive effects in promoting neural progenitor cell differentiation towards the dopaminergic phenotype in the presence of dopamine (10 microM) and forskolin (Fsk) (10 microM). There was no synergy in this effect when progenitor cells were incubated with all of these agents simultaneously. The trans-differentiation potential of the progenitor cells to be directed towards other neurotransmitter phenotypic lineages was also investigated. It was found that, with the right cocktails of agents, serotonin (Ser) (75 microM), acidic fibroblast growth factor (aFGF) (10 ng/ml), BDNF (50 ng/ml) and forskolin (10 microM), these same cells could be directed down the serotonergic cell lineage pathway (as judged by the appearance of tryptophan hydroxylase (TPH) positive immunoreactivity, and synthesis of 5-HT and its metabolites, secreted into the culture medium). However, no cocktail containing noradrenaline (10 nM-500 microM), BDNF (50 ng/ml) and forskolin (10 microM) was found which promoted differentiation towards the noradrenergic cell phenotype as judged by the absence of any TH or D beta H positive immunoreactivity, and no formation of 3,4-dihydroxyphenylethyleneglycol (DOPEG), the principal metabolite of noradrenaline. The controlled trans-differentiation potential of these cell could pave the way for development and harvesting of large numbers of neurons of the appropriate neurotransmitter phenotype for future transplantation therapies for the treatment of neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease.
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PMID:The differentiation potential of human foetal neuronal progenitor cells in vitro. 1546 16

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

Striatal trophic activity was assessed in female rhesus monkeys of advancing age rendered hemiparkinsonian by unilateral intracarotid administration of MPTP. Three age groups were analyzed: young adults (8-9.5 years) n=4, middle-aged adults (15-17 years) n=4, and aged adults (21-31 years) n=7. Fresh frozen tissue punches of caudate nucleus and putamen were collected 3 months after MPTP treatment and assayed for combined soluble striatal trophic activity, brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF). This time point was chosen in an effort to assess a relatively stable phase of the dopamine (DA)-depleted state that may model the condition of Parkinson's disease (PD) patients at the time of therapeutic intervention. Analyses were conducted on striatal tissue both contralateral (aging effects) and ipsilateral to the DA-depleting lesion (lesion x aging effects). We found that combined striatal trophic activity in the contralateral hemisphere increased significantly with aging. Activity from both middle-aged and aged animals was significantly elevated as compared to young adults. Following DA depletion, young animals significantly increased combined striatal trophic activity, but middle-aged and aged animals did not exhibit further increases in activity over their elevated baselines. BDNF levels in the contralateral hemisphere were significantly reduced in aged animals as compared to young and middle-aged subjects. With DA depletion, BDNF levels declined in young and middle-aged animals but did not change from the decreased baseline level in old animals. GDNF levels were unchanged with aging and at 3 months after DA depletion. The results are consistent with several conclusions. First, by middle age combined striatal trophic activity is elevated, potentially reflecting a compensatory reaction to ongoing degenerative changes in substantia nigra DA neurons. Second, in response to DA depletion, young animals were capable of generating a significant increase in trophic activity that was sustained for at least 3 months. This capacity was either saturated or was not sustained in middle-aged and aged animals. Third, the aging-related chronic increase in combined striatal trophic activity was not attributable to BDNF or GDNF as these molecules either decreased or did not change with aging.
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PMID:Striatal trophic factor activity in aging monkeys with unilateral MPTP-induced parkinsonism. 1562 62

Potential roles for variants in the human BDNF gene in human brain disorders are supported by findings that include: (a) influences that this trophic factor can exert on important neurons, brain regions, and neurotransmitter systems, (b) changes in BDNF expression that follow altered neuronal activity and drug treatments, and (c) linkages or associations between genetic markers in or near BDNF and human traits and disorders that include depression, schizophrenia, addictions, and Parkinson's disease. We now report assembly of more than 70 kb of BDNF genomic sequence, delineation of 7 noncoding and 1 coding human BDNF exons, elucidation of BDNF transcripts that are initiated at several alternative promoters, identification of BDNF mRNA splicing patterns, elucidation of novel sequences that could contribute to activity-dependent BDNF mRNA transcription, targeting and/or translation, elucidation of tissue-specific and brain-region-specific use of the alternative human BDNF promoters and splicing patterns, identification of single nucleotide polymorphism (SNP), and simple sequence length polymorphism (SSLP) BDNF genomic variants and identification of patterns of restricted haplotype diversity at the BDNF locus. We also identified type 2 BDNF-locus transcripts that are coded by a novel gene that is overlapped with type 1 BDNF gene and transcribed in reverse orientation with several alternative splicing isoforms. Association studies of BDNF variants reveal no associations with Parkinson's disease. Comparisons between substance abusers and controls reveal modest associations. These findings increase interest in this diverse human gene.
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PMID:Human brain derived neurotrophic factor (BDNF) genes, splicing patterns, and assessments of associations with substance abuse and Parkinson's Disease. 1566 11

L-Dihydroxyphenylalanine (L: -DOPA), the anti-parkinsonian drug affording the greatest symptomatic relief of parkinsonian symptoms, is still misunderstood in terms of its neurotoxic potential and the mechanism by which generated dopamine (DA) is able to exert an effect despite the absence of DA innervation of target sites in basal ganglia. This review summaries important aspects and new developments on these themes. On the basis of L: -DOPA therapy in animal models of Parkinson's disease, it appears that L: -DOPA is actually neuroprotective, not neurotoxic, as indicated by L: -DOPA's reducing striatal tissue content of the reactive oxygen species, hydroxyl radical (HO(*)), and by leaving unaltered the extraneuronal in vivo microdialysate level of HO(*). In addition, the potential beneficial anti-parkinsonian effect of L: -DOPA is actually increased because of the fact that the basal ganglia are largely DA-denervated. That is, from in vivo microdialysis studies it can be clearly demonstrated that extraneuronal in vivo microdialysate DA levels are actually higher in the DA-denervated vs. the intact striatum of rats - owing to the absence of DA transporter (i.e., uptake sites) on the absent DA nerve terminal fibers in parkinsonian brain. In essence, there are fewer pumps removing DA from the extraneuronal pool. Finally, the undesired motor dyskinesias that commonly accompany long-term L: -DOPA therapy, can be viewed as an outcome of L: -DOPA's sensitizing DA receptors (D(1)-D(5)), an effect easily replicated by repeated DA agonist treatments (especially agonist of the D(2) class) in animals, even if the brain is not DA-denervated. The newest findings demonstrate that L: -DOPA induces BDNF release from corticostriatal fibers, which in-turn enhances the expression of D(3) receptors; and that this effect is associated with motor dyskinesias (and it is blocked by D(3) antagonists). The recent evidence on mechanisms and effects of L: -DOPA increases our understanding of this beneficial anti-parkinsonian drug, and can lead to improvements in L: -DOPA effects while providing avenues for reducing or eliminating L: -DOPA's deleterious effects.
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PMID:Peculiarities of L: -DOPA treatment of Parkinson's disease. 1575 Aug 45

Parkinson's disease (PD) is a movement disorder caused by degeneration of the nigrostriatal dopamine (DA) neurons in the substantia nigra pars compacta and the resultant deficiency in the neurotransmitter DA at the nerve terminals in the striatum. We and other investigators found increased levels of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6, and decreased levels of neurotrophins such as brain-derived neurotrophic factor (BDNF) in the nigrostriatal region of postmortem brains and/or in the ventricular or lumbar cerebrospinal fluid (CSF) from patients with sporadic PD, and in animal models, such as 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)- and 6-hydroxydopamine (6-OHDA)-induced PD. These changes in cytokine and neurotrophin levels may be initiated by activated microglia, which may then promote apoptotic cell death and subsequent phagocytosis of DA neurons. Cytokines as pleiotropic factors, promote signals that either lead to cell death or exert neuroprotective effects. The discovery of toxic changes in trophic microglia by M. Sawada and co-workers is important to this point. Ultimately, microglial cells may regulate cellular changes that cause either harm or benefit by producing cytokines or neurotrophins depending upon the primary cause and the circumstances during the inflammatory process of PD.
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PMID:Inflammatory process in Parkinson's disease: role for cytokines. 1577 50


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