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)

It has been reported recently that the immunosuppressant FK506 produced neurotrophic and neuroprotective effects on dopaminergic neurons in vitro and in vivo. We investigated whether tripchlorolide, an immunosuppressive extract of Chinese herb Tripterygium wilfordii Hook F, could exert similar neurotrophic and neuroprotective effects similar to those of FK506. It was found that tripchlorolide promoted axonal elongation and protected dopaminergic neurons from a neurotoxic lesion induced by 1-methyl-4-phenylpyridinium ion (MPP+) at concentrations of as low as 10(-12) to 10(-8) M. In situ hybridization study revealed that tripchlorolide stimulated brain-derived neurotrophic factor (BDNF) mRNA expression. In vivo administration of tripchlorolide (1 microg/kg, ip) for 28 days effectively attenuated the rotational behavior challenged by D-amphetamine in the model rats by transection of the medial forebrain bundle. In addition, tripchlorolide treatment (0.5 or 1 microg/kg/day for 28 days) increased the survival of dopaminergic neurons in substantia nigra pars compacta by 50 and 67%, respectively. Moreover, tripchlorolide markedly prevented the decrease in amount of dopamine in the striatum of model rats. Taken together, our data provide the first evidence that tripchlorolide acts as a neuroprotective molecule that rescues MPP+ or axotomy-induced degeneration of dopaminergic neurons, which may imply its therapeutic potential for Parkinson's disease. The underlying mechanism may be relevant to its neurotrophic effect and its efficacy in stimulating the expression of BDNF.
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PMID:Neurotrophic and neuroprotective effects of tripchlorolide, an extract of Chinese herb Tripterygium wilfordii Hook F, on dopaminergic neurons. 1250 65

Nerve growth factor was the first identified protein with anti-apoptotic activity on neurons. This prototypic neurotrophic factor, together with the three structurally and functionally related growth factors brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3) and neurotrophin-4/5 (NT4/5), forms the neurotrophin protein family. Target T cells for neurotrophins include many neurons affected by neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and peripheral polyneuropathies. In addition, the neurotrophins act on neurons affected by other neurological and psychiatric pathologies including ischemia, epilepsy, depression and eating disorders. Work with cell cultures and animal models provided solid support for the hypothesis that neurotrophins prevent neuronal death. While no evidence exists that a lack of neurotrophins underlies the etiology of any neurodegenerative disease, these studies have spurred on hopes that neurotrophins might be useful symptomatic-therapeutic agents. However first clinical trials led to variable results and severe side effects were observed. For future therapeutic use of the neurotrophins it is therefore crucial to expand our knowledge about their physiological functions as well as their pharmacokinetic properties. A major challenge is to develop methods for their application in effective doses and in a precisely timed and localized fashion.
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PMID:Neurotrophins. 1257 26

Parkinson's disease (PD) is a chronic neurodegenerative disorder, and it has been suggested that treatments promoting survival and functional recovery of affected dopaminergic neurons could have a significant and long-term therapeutic value. In the present study, we investigated the neuroprotective effects of acupuncture on the nigrostriatal system in rat unilaterally lesioned with 6-hydroxydopamine (6-OHDA, 4 microg/microl, intrastriatal injection) using tyrosine hydroxylase (TH) and receptor for brain-derived neurotrophic factor, trkB, immunohistochemistries. Two weeks after the lesions were made, rats presented with asymmetry in rotational behavior (118.3 +/- 17.5 turns/h) following injection with apomorphine, a dopamine receptor agonist (0.5 mg/kg, sc). In contrast, acupunctural treatment at acupoints GB34 and LI3 was shown to significantly reduce this motor deficit (14.6 +/- 13.4 turns/h). Analysis via TH immunohistochemistry revealed a substantial loss of cell bodies in the substantia nigra (SN) (45.7% loss) and their terminals in the dorsolateral striatum ipsilateral to the 6-OHDA-induced lesion. However, acupunctural treatment resulted in the enhanced survival of dopaminergic neurons in the SN (21.4% loss) and their terminals in the dorsolateral striatum. Acupuncture also increased the expression of trkB significantly (35.6% increase) in the ipsilateral SN. In conclusion, we observed that only acupuncturing without the use of any drug has the neuroprotective effects against neuronal death in the rat PD model and these protective properties of acupuncture could be mediated by trkB.
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PMID:Acupuncture prevents 6-hydroxydopamine-induced neuronal death in the nigrostriatal dopaminergic system in the rat Parkinson's disease model. 1266 52

The finding that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) elicits parkinsonism in human beings suggests that endogenous or xenobiotic neurotoxic compounds may be involved in the etiology of Parkinson's disease (PD). We have shown that cerebrospinal fluid (CSF) of newly diagnosed and drug untreated patients with PD contains a low molecular weight substance(s) which inhibits the growth and function of dopaminergic neurons in culture. In addition, selegiline in a dosage below the level that inhibits monoamine oxidase B (MAO-B), protects dopaminergic neurons in culture against toxic factor(s) present in the CSF of patients with PD, and the said effect is mediated via elaboration of brain-derived neurotrophic factor (BDNF). In view of the fact that 6-hydroxydopamine (6-OHDA) or MPTP causes parkinsonism by generating free radicals, and inducers of metallothionein (MT) isoforms avert the said neurotoxicity, we intended to learn whether MT isoforms were capable of scavenging free radicals. By employing electron spin resonance spectroscopy (ESR), we examined for the first time the free radical scavenging effects of MT-I and MT-II isoforms on four types of free radicals. Solutions of 0.15 mM of MT-I and 0.3 mM of MT-II scavenged the 1,1-diphenyl-2-picrylhydrazyl radicals completely. Furthermore, they were able to scavenge hydroxyl radicals generated in a Fenton reaction. Moreover, MT-I scavenged almost 90% of the superoxide generated by the hypoxanthine and xanthine oxidase system, while MT-II could only scavenge 40%. By using 2,2,6,6-tetramethyl-4-piperidone as a "spin-trap" for the reactive oxygen species (containing singlet oxygen, superoxide and hydroxyl radicals) generated by photosensitized oxidation of riboflavin, and measuring the relative signal intensities of the resulting stable nitroxide adduct, 2,2,6,6-tetramethyl-4-piperidone-1-oxyl, we observed that MT-II could scavenge 92%, while MT-I could completely scavenge all the reactive species generated. The results of this investigation are interpreted to suggest that selegiline by preventing the generation of free radicals, MT isoforms by scavenging free radicals, and neurotrophins by rescuing dopaminergic neurons are capable of attenuating oxidative stress and of providing neuro-protection in PD.
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PMID:Metallothionein, neurotrophins and selegiline in providing neuroprotection in Parkinson's disease. 1267 4

Glutamate is the major excitatory transmitter in the brain. Recent developments in the molecular biology and pharmacology of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) subtype of glutamate receptors have led to the discovery of selective, potent, and systemically active AMPA receptor potentiators. These molecules enhance synaptic transmission and play important roles in plasticity and cognitive processes. In the present study, we first characterized a novel AMPA receptor potentiator, (R)-4'-[1-fluoro-1-methyl-2-(propane-2-sulfonylamino)-ethyl]-biphenyl-4-carboxylic acid methylamide (LY503430), on recombinant human GLUA1-4 and native preparations in vitro and then evaluated the potential neuroprotective effects of the molecule in rodent models of Parkinson's disease. Results indicated that submicromolar concentrations of LY503430 selectively enhanced glutamate-induced calcium influx into human embryonic kidney 293 cells transfected with human GLUA1, GLUA2, GLUA3, or GLUA4 AMPA receptors. The molecule also potentiated AMPA-mediated responses in native cortical, hippocampal, and substantia nigra neurons. We also report here that LY503430 provided dose-dependent functional and histological protection in animal models of Parkinson's disease. The neurotoxicity after unilateral infusion of 6-hydroxydopamine into either the substantia nigra or the striatum of rats and that after systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice were reduced. Interestingly, LY503430 also had neurotrophic actions on functional and histological outcomes when treatment was delayed until well after (6 or 14 days) the lesion was established. LY503430 also produced some increase in brain-derived neurotrophic factor in the substantia nigra and a dose-dependent increases in growth associated protein-43 (GAP-43) expression in the striatum. Therefore, we propose that AMPA receptor potentiators offer the potential of a new disease modifying therapy for Parkinson's disease.
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PMID:LY503430, a novel alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor potentiator with functional, neuroprotective and neurotrophic effects in rodent models of Parkinson's disease. 1273 Mar 50

Epidemiologic studies revealed that the prevalence of Parkinson disease is higher in males than in females and that the progression of the disease might be rapid in males compared with females. The reason for the gender difference is unknown; however, estrogens may be involved. Many studies have revealed that estrogens provide neuroprotective effects and that the protective mechanisms include antioxidant property and upregulation of Bcl-2, brain-derived neurotrophic factor, and glial cell-derived neurotrophic factor (GDNF). Upregulation of Bcl-2 or GDNF is mediated by nonnuclear estrogen receptor (ER) in addition to transcription regulation by ER. To avoid undesirable effect of estrogens, several selective ER modulators, raloxifene and genistein are considered.
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PMID:Estrogens and Parkinson disease: novel approach for neuroprotection. 1277 6

We describe the discovery of a novel, 20 kDa, secreted human protein named mesencephalic astrocyte-derived neurotrophic factor, or MANF. The homologous, native molecule was initially derived from a rat mesencephalic type-1 astrocyte cell line and recombinant MANF subcloned from a cDNA encoding human arginine-rich protein. MANF selectively protects nigral dopaminergic neurons, versus GABAergic or serotonergic neurons. The discovery of MANF marks a more systematic approach in the search for astrocyte-derived, secreted proteins that selectively protect specific neuronal phenotypes. Compared to glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), MANF was more selective in the protection of dopaminergic neurons at lower (0.05-0.25 ng/mL) and middle (0.5-2.5 ng/mL) concentrations: MANF>GDNF>BDNF. GDNF was more selective at higher concentrations (25-50 ng/ml): GDNF>MANF>BDNF. Two domains in MANF of 39-AA and 109-AA respectively, and eight cysteines are conserved from C. elegans to man. MANF is encoded by a 4.3 Kb gene with 4 exons, and is located on the short arm of human chromosome 3. The secondary structure is dominated by alpha-helices (47%) and random coils (37%). Studies to determine the localization of MANF in the brains of rat, monkey, and man, as well as the receptor, signaling pathways, and biologically active peptide mimetics are in progress. The selective, neuroprotective effect of MANF for dopaminergic neurons suggests that it may be indicated for the treatment of Parkinson's disease.
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PMID:MANF: a new mesencephalic, astrocyte-derived neurotrophic factor with selectivity for dopaminergic neurons. 1279 11

Although the mammalian brain has long been thought to be entirely postmitotic, the recent discovery has confirmed an existence of neural stem or progenitor cells in various regions of the adult mammalian brain. Like embryonic stem cells, adult neural progenitor cells possess the capacity of self-renewal and differentiation potential for neurogenesis or gliogenesis. In addition to the subventricular zone and hippocampus where active cell division naturally occurs, adult neural progenitors with neurogenic potential exist in the striatum and the vicinity of dopaminergic neurons in the substantia nigra. Normally, progenitors in those regions proliferate at a low level, and most proliferated cells remain uncommitted. In response to the selective lesion of nigrostriatal dopaminergic pathway by the neurotoxins, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 6-hydroxydopamine, progenitors in the injured areas markedly increase their proliferation rate. Depending upon the magnitude and kinetics of the lesion, neurogenesis and gliogenesis were induced in the lesion sites at varying extents. A large number of growth and neurotrophic factors influence proliferation and/or differentiation of progenitor cells under normal and lesioned conditions. Some factors (epidermal and basic fibroblast growth factors and brain-derived neurotrophic factor) are facilitatory, while others (usually bone morphogenetic proteins) are inhibitory, for controlling division and fate of neuronal or glial progenitors. Expression of endogenous factors and their respective receptors in existing and newborn cells are also subject to be altered by the lesion. These genomic responses are considered to be important elements for the formation of a local molecular niche for a given phenotypic cell regeneration. Taken together, adult neural progenitor cells in the nigrostriatal dopaminergic system have the ability to respond to the lesion to repopulate missing cells. The regenerative neuro- or gliogenesis in situ can, at least in part, endogenously compensate injured neural elements, and achieve a self-repair of neurodegenerative disorders such as Parkinson's disease.
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PMID:Adult neural stem/progenitor cells in neurodegenerative repair. 1281 87

We recently found that human amniotic epithelial (HAE) cells secrete biologically active neurotrophins such as brain-derived neurotrophic factor and neurotrophin-3, both of which exhibit trophic activities on dopamine (DA) neurons. The present study explored whether implantation of HAE cells can be a possible means to deliver trophic factors into the brain to prevent the death of DA neurons in a rat model of Parkinson's disease. We first investigated the ability of HAE cells to produce factors capable of promoting DA cell survival in vitro, and then tested whether HAE cell grafts survive and prevent the death of nigral DA neurons in rats with 6-hydroxydopamine lesions. A treatment with conditioned medium derived from HAE cell cultures enhanced the survival of tyrosine hydroxylase (TH)-immunopositive DA cells in serum-free cultures. The conditioned medium also protected the morphological integrity of TH-positive neurons against toxic insult with 6-hydroxydopamine. HAE cells were grafted into the midbrain of immunosuppressed rats. The rats were then subjected to a unilateral nigrostriatal lesion induced by intrastriatal infusions of 6-hydroxydopamine. HAE cell transplants were found to survive without evidence for overgrowth 2 weeks postgrafting. The number of nigral DA cells, detected with either TH-immunohistochemistry or retrograde labelling with fluorogold, was significantly increased in rats given the grafts as compared to that in control animals without the grafts. The results indicate that HAE cells produce diffusible molecules that can enhance the survival of DA neurons. Although the factors that contribute to the currently observed effects remain to be fully determined, implantation of HAE cells could be a viable strategy to counteract the loss of DA neurons in Parkinson's disease.
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PMID:Implantation of human amniotic epithelial cells prevents the degeneration of nigral dopamine neurons in rats with 6-hydroxydopamine lesions. 1286 58

To identify susceptibility genes for Parkinson's disease (PD) and to establish tailor-made medicine for PD, we studied 20 single nucleotide polymorphisms (SNPs) in 18 candidate genes for association with PD. We found that homozygosity for the V66M polymorphism of the BDNF gene occurs more frequently in PD patients than in unaffected controls and confirmed an association with the S18Y polymorphism of the UCHL1 gene. We further started microsatellite marker-based genome-wide association studies by using the pooled DNA method. We have finished checking approximately 6800 markers and found some significant associations (p=3.9 x 10(-6)) on chromosome 1 where other studies showed a linkage. Genes in linkage disequilibrium with these markers may be associated with pathogenesis of PD.
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PMID:Toward identification of susceptibility genes for sporadic Parkinson's disease. 1457 23


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