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)

Increasing evidence has indicated that proinflammatory cytokines such as TNF-alpha and IL-1beta, produced by activated microglia and astrocytes, play a key role in progressive degeneration of the nigrostriatal dopaminergic neurons in Parkinson's disease (PD). Since alpha-synuclein is a major component of Lewy bodies in PD brains, we studied the constitutive and cytokine/neurotrophic factor-regulated expression of alpha-synuclein in cultured human neurons by Northern blot and Western blot analyses. The constitutive expression of alpha-synuclein mRNA was identified in a variety of human neural and non-neural cell lines. The levels of alpha-synuclein expression were elevated markedly in NTera2 teratocarcinoma cells following retinoic acid-induced neuronal differentiation, accompanied with an increased expression of synphilin-1, while they were unaltered in NTera2-derived differentiated neurons by exposure to TNF-alpha, IL-1beta, BDNF or GDNF. These results indicate that alpha-synuclein expression in human neurons is up-regulated during differentiation, but is unaffected by a panel of cytokines and neurotrophic factors which are supposed to be involved in the nigral neuronal death and survival.
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PMID:Alpha-synuclein expression is up-regulated in NTera2 cells during neuronal differentiation but unaffected by exposure to cytokines and neurotrophic factors. 1147 75

Fibroblast growth factor (FGF) 8 has been well established to play a critical role in the early development of the central nervous system (CNS). We report here extensive neuronal localization and neurotrophic function of FGF8 in the nervous system. In sections of mouse embryos at E10.5, FGF8 was immunohistochemically found in neurons at the marginal zones of the CNS and in the dorsal root ganglia (DRG). Neuronal localization of FGF8 was marked at later embryonic stages and in adults, involving most of the central and peripheral neurons, including intermuscular enteric neurons, DRGs, and paraaortic sympathetic ganglia. Functionally, FGF8 promoted neurite outgrowth in human neuroblastoma SK-N-MC cells as well as in rat pheochromocytoma PC12 cells, suggesting that FGF8 acts as a neurotrophic factor. FGF8 also supported neuronal survival and differentiation in cultured human neural progenitor cells. In a cell growth assay, treatment with 50 ng/ml FGF8 on human cultured neuroblastoma SK-N-MC and IMR32 cells attenuated the growth of both. In accordance with these in vitro findings, the immunohistochemical analysis on human neurological diseases showed that FGF8 expression is evident in differentiating histological types of neuroblastoma and ganglioneuroblastoma, and that the levels of FGF8 immunoreactivity in the substantia nigra from Parkinson's disease are significantly lower than those in age-matched controls. Taken together, the present findings strongly suggest that FGF8 acts as a more generalized neurotrophic factor than previously reported.
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PMID:Extensive neuronal localization and neurotrophic function of fibroblast growth factor 8 in the nervous system. 1153 26

1. The long-term delivery of neurotrophic factors to specific regions of the central nervous system via gene therapy offers a new strategy for the treatment of neurodegenerative disorders. 2. The neurotrophic factor glial cell line-derived neurotrophic factor (GDNF) is a potent dopaminergic (DA) trophic factor that ameliorates the behavioural and histological consequences of lesioning DA neurons in rodent and primate models of Parkinson's disease. 3. Glial cell line-derived neurotrophic factor gene therapy may have a potential use in the clinical treatment of Parkinson's disease. 4. We examined whether injection of an adenoviral vector encoding human GDNF preproprotein (Ad GDNF) could protect the rat nigrostriatal DA system from progressive neuronal degeneration. Because Parkinson's disease occurs primarily in the elderly population, we studied the effect of GDNF gene delivery in an aged rat model of Parkinson's disease. 5. In the aged (20 month) Fischer 344 rat, Ad GDNF was injected either near DA cell bodies in the substantia nigra (SN) or at the DA terminals in the striatum. One week following gene delivery, the neurotoxin 6-hydroxydopamine (6-OHDA) was injected unilaterally into the striatum to cause progressive degeneration of the DA neurons. 6. Injection of GDNF vector into either the striatum or the SN provided significant cell protection against 6-OHDA. However, only striatal injection of Ad GDNF protected against the development of behavioural and neurochemical changes that occur in the DA-depleted brain. 7. The results of this study are reviewed here and the behavioural and cellular effects of GDNF gene delivery into striatal versus mesencephalic sites are discussed.
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PMID:Adenoviral vector-mediated delivery of glial cell line-derived neurotrophic factor provides neuroprotection in the aged parkinsonian rat. 1170 92

Glial cell line-derived neurotrophic factor (GDNF) shows potent neuroprotective as well as neurorestorative actions on the adult neurons impacted in animal models of Parkinson's disease (PD). Long-term pharmaco-physiological effects of GDNF on developing dopaminergic (DA) neurons have not yet been explored because of technical difficulties in producing prolonged cell type-specific delivery of this neurotrophic factor in mammalian embryonic brain. The current studies used our previously characterized 9.0-kb tyrosine hydroxylase promoter to produce transgenic mice with neuronal cell type-specific expression of GDNF in substantia nigra pars compacta (SNc) and locus coeruleus (LC). These mice were used to test the parsimonious hypothesis that increased developmental expression of GDNF in SNc and LC would significantly enhance the number of postmitotic adult neurons. To our surprise, adult transgenic mice carrying the TH9.0kb-GDNF hybrid gene showed dramatic reductions in both the numbers and the volumes of SNc-DA and LC-noradrenergic (NA) neurons by quantitative morphometric analysis. The decrease in the number of DA neurons was apparent as early as postnatal day 2, the period before the major naturally occurring apoptotic cell death in midbrain. Aged transgenic mice exhibited no further significant deficits in motor behaviors. These data suggest that continuous, early developmental GDNF expression exerts physiological effects on newly differentiated, immature dopamine neurons that differ from those observed on more mature and adult DA neurons. Further elucidation of the mechanisms underlying differential GDNF actions will greatly improve the pharmacological efficacy of GDNF in fetal neural transplantation as well as adult neuronal gene therapy in PD patients.
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PMID:Marked dopaminergic cell loss subsequent to developmental, intranigral expression of glial cell line-derived neurotrophic factor. 1182 87

Parkinson's disease (PD) is a debilitating neurodegenerative condition that is characterised by a progressive loss of dopaminergic neurones of the substantia nigra pars compacta (SNpc) and the presence of alpha-synuclein cytoplasmic inclusions (Lewy bodies). Cardinal symptoms include tremor, bradykinesia, and rigidity, although cognitive and autonomic disturbances are not uncommon. Pharmacological treatment targeting the dopaminergic network is relatively effective at ameliorating these symptoms, especially in the early stages of the disease, but none of these therapies are curative and they generate their own problems. As dopaminergic neuronal death in PD occurs in a gradual manner, it is amenable to treatments that can either protect remaining dopaminergic neurones or prevent death of those neurones that have begun to die. Use of neurotrophic factors is a potential candidate, as various factors have been shown to increase dopaminergic neuronal survival in culture and promote survival and axonal growth in animal models of PD. Glial cell line-derived neurotrophic factor (GDNF) is currently the most effective substance that has been intensively studied and shown to have a specific 'dopaminotrophic' effect. This review will therefore focus on studies that have investigated GDNF and discuss the potential for neurotrophic factor treatment in PD.
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PMID:Prospects for the treatment of Parkinson's disease using neurotrophic factors. 1182 97

Stem cells have been suggested as candidate therapeutic tools for neurodegenerative disorders, given their ability to give rise to the appropriate cell types after grafting in vivo. In this review I summarize some of the evidence currently available concerning two approaches for the treatment of Parkinson's disease: (1) The generation of dopaminergic neurons from embryonic stem cells, multipotent stem cells, and neuronal progenitor cells for cell replacement therapy. (2) The engineering of multipotent stem cells to release glial cell-line derived neurotrophic factor, a potent neurotrophic factor for dopaminergic neurons, in a neuroprotective and neuroregenerative approach to the treatment of Parkinson's disease.
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PMID:Stem cells in the treatment of Parkinson's disease. 1203 Dec 76

Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor for dopamine neurons that has been proposed for use in the treatment of Parkinson's disease (PD). Previous studies using viral vectors to deliver GDNF in rodent models of PD have entailed administering the virus either prior to or immediately after neurotoxin-induced lesions, when the nigrostriatal pathway is largely intact, a paradigm that does not accurately reflect the clinical situation encountered with Parkinson's patients. In this study, recombinant adeno-associated virus carrying the gene encoding GDNF (rAAV-GDNF) was administered to animals bearing a maximal lesion in the nigrostriatal system, more closely resembling fully developed PD. Rats were treated with 6-hydroxydopamine into the medial forebrain bundle and assessed by apomorphine-induced rotational behavior for 5 weeks prior to virus administration. Within 4 weeks of a single intrastriatal injection of rAAV-GDNF, unilaterally lesioned animals exhibited significant behavioral recovery, which correlated with increased expression of dopaminergic markers in the substantia nigra, the medial forebrain bundle, and the striatum. Our findings demonstrate that rAAV-GDNF is capable of rescuing adult dopaminergic neurons from near complete phenotypic loss following a neurotoxic lesion, effectively restoring a functional dopaminergic pathway and diminishing motoric deficits. These data provide further support for the therapeutic potential of rAAV-GDNF-based gene therapy in the treatment of PD.
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PMID:Adeno-associated viral delivery of GDNF promotes recovery of dopaminergic phenotype following a unilateral 6-hydroxydopamine lesion. 1207 87

Fetal rat kidney cells produce high levels of glial-derived neurotrophic factor (GDNF) and exert neuroprotective effects when transplanted into the brain in animal models of Parkinson's disease and stroke. The purpose of the present experiment was to produce kidney cell lines that secrete GDNF. Genes encoding two truncated N-terminal fragments of SV40 large T antigen, T155g and T155c, which does not code for small t antigen, were used. T155g was transduced into E17 cultured fetal Sprague-Dawley rat kidney cortex cells using a plasmid vector, and T155c was transduced with a plasmid and a retroviral vector. Sixteen clones were isolated from cultures transfected with the T155g-expressing plasmid. No cell lines were obtained with T155c. Four clones produced GDNF at physiological concentrations ranging from 55 to 93 pg/ml of medium. These four clones were transplanted into the ischemic core or penumbra of rats that had undergone middle cerebral artery occlusion (MCAO). Three of the four clones reduced the volume of infarction and the behavioral abnormalities normally resulting from MCAO. Blocking experiments with antibodies to GDNF and platelet-derived growth factor (PDGF) suggested that these growth factors contributed only minimally to the reduction in infarct volume and behavioral abnormality. These cell lines may be useful for intracerebral transplantation in animal models of brain injury, stroke, or Parkinson's disease.
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PMID:T155g-immortalized kidney cells produce growth factors and reduce sequelae of cerebral ischemia. 1207 90

In Parkinson's disease (PD), therapies to delay or suppress the progression of cell death in nigrostriatal dopamine neurons have been proposed by use of various agents. An inhibitor of type B monoamine oxidase (MAO-B), (-)deprenyl (selegiline), was reported to have neuroprotective activity, but clinical trials failed to confirm it. However, the animal and cellular models of PD proved that selegiline protects neurons from cell death. Among selegiline-related propargylamines, (R)(+)-N-propargyl-1-aminoindan (rasagiline) was the most effective to suppress the cell death in in vivo and in vitro experiments. In this paper, the mechanism of the neuroprotection by rasagiline was examined using human dopaminergic SH-SY5Y cells against cell death induced by an endogenous dopaminergic neurotoxin N-methyl(R)salsolinol (NM(R)Sal). NM(R)Sal induced apoptosis (but not necrosis) in SH-SY5Y cells, and the apoptotic cascade was initiated by mitochondrial permeability transition (PT) and activated by stepwise reactions. Rasagiline prevented the PT in mitochondria directly and also indirectly through induction of antiapoptotic Bcl-2 and a neurotrophic factor, glial cell line-derived neurotrophic factor (GDNF). Long-term administration of propargylamines to rats increased the activities of antioxidative enzymes superoxide dismutase (SOD) and catalase in the brain regions containing dopamine neurons. Rasagiline and related propargylamines may rescue degenerating dopamine neurons through inhibiting death signal transduction initiated by mitochondria PT.
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PMID:Neuroprotection by propargylamines in Parkinson's disease: suppression of apoptosis and induction of prosurvival genes. 1220 Jan 98

Glial cell-line derived neurotrophic factor (GDNF) gene therapy might offer new strategies for the treatment of Parkinson's disease (PD). GDNF is a potent dopaminergic (DA) neurotrophic factor. The effect of GDNF gene therapy was assessed using anatomical, behavioral, and neurochemical approaches. We examined the protective effect of increased striatal GDNF levels achieved by delivery of an adenoviral vector (Ad-) encoding human GDNF (Ad-GDNF). Animals were injected with Ad-GDNF prior to striatal lesion. Striatal DA concentration was measured by microdialysis. Animals receiving 6-hydroxydopamine (6-OHDA) only showed a significant decrease in rotation when compared to those receiving Ad-GDNF prior to the 6-OHDA neurotoxin. Under basal conditions, the Ad-GDNF group showed a significant (P < or = 0.05) increase (1880%) in DA concentration when compared to the 6-OHDA group. Amphetamine challenge induced a significantly (P < or = 0.05) higher release of DA in the Ad-GDNF group than in the 6-OHDA group. These findings show that long-term delivery of GDNF protein in the striatum provides significant cell, behavioral, and neurochemical protection.
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PMID:Behavioral improvement and dopamine release in a Parkinsonian rat model. 1221 21


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