Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is continued interest in the assessment and potential use of antioxidants as neuroprotective agents in diseases associated with increased oxidative stress, such as Parkinson's disease. The neuroprotective effect of a natural antioxidant drink, EM-X (a ferment derivative of unpolished rice, papaya and seaweeds with effective microorganisms), was investigated using the 6-hydroxydopamine (6-OHDA)-lesion rat model of Parkinson's disease. The nigrostriatal dopaminergic neurons were unilaterally lesioned with 6-OHDA (8 microg) in rats that were treated with a 10-times diluted EM-X drink (dilEM-X), standard EM-X drink (stdEM-X) or tap water for 4 days. Seven days post lesion, the integrity (no. of tyrosine hydroxylase positive cells (TH+ cells) in the substantia nigra pars compacta (SNpc)) and functionality (dopamine and its metabolites DOPAC and HVA content in the striata) of nigrostriatal dopaminergic neurons were assessed. In the vehicle-treated rats, infusion of 8 microg of 6-OHDA significantly reduced the number of TH+ cells in the SNpc as well as the levels of dopamine, DOPAC and HVA in the striata on the lesion side. The loss of TH+ cells, dopamine and HVA, but not the DOPAC levels, was significantly attenuated by stdEM-X pretreatment, but not by the dilEM-X pretreatment. There were no significant changes in the TH+ cells, or in the monoamine levels with the EM-X pretreatment per se, except for a small but significant fall in the levels of dopamine with the stdEM-X. The evidence presented supports the potential neuroprotective effects of stdEM-X drink, although its effect on dopamine levels needs further investigation.
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PMID:The antioxidant drink effective microorganism-X (EM-X) pre-treatment attenuates the loss of nigrostriatal dopaminergic neurons in 6-hydroxydopamine-lesion rat model of Parkinson's disease. 1514 43

1-methyl-4-phenyl-1,2,4,6,-tetrahydropyridine (MPTP) is a selective neurotoxin that produces striatal dopamine depletion resulting in parkinsonism like symptoms in humans and is, therefore, used to generate animal models for Parkinson's disease (PD). In this study, C57BL/6N mice were treated with MPTP acutely (3x20 mg/kg, 2-hour interval, one day injection). Mice were then sacrificed 24 hours after the last injection and brain tissue was collected for analysis. Significant decrease of striatal dopamine (DA) and the metabolites (DOPAC, HVA) was observed after MPTP treatment. MPTP also reduced protein expression of tyrosine hydroxylase (TH) in the striatum. Real time RT-PCR was used to examine selective genes of the dopaminergic system in the substantia nigra. Our data demonstrated that MPTP significantly decreased gene expression of TH, dopamine transporter (DAT), and vesicle monoamine transporter (VMAT), coinciding with the pattern of dopamine concentration changes and protein expression after MPTP treatment. Although a significant decrease of DA metabolites was observed in striatum, there was no change in the expression of monoamine oxidases (MAO-A, MAO-B) or catechol O-methyltransferase (COMT), indicating that these changes might be simply a consequence of reduced monoamine levels. In addition, gene expression of alpha-synuclein was also decreased with MPTP treatment, but there was no change in beta-synuclein and parkin. This is the first study using real-time PCR to indicate that MPTP selectively alters gene expression and provides information for clinical studies in PD. Future studies will focus on gene expression of other pathways that may be affected by MPTP treatment and investigation of gene expression in specific cell types in vivo using LCM technology.
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PMID:Selective alterations of gene expression in mice induced by MPTP. 1549 5

We previously demonstrated that treating gravid female rats with the bacteriotoxin lipopolysaccharide (LPS) led to the birth of offspring with fewer than normal dopamine (DA) neurons. This DA neuron loss was long-lived and associated with permanent increases in the pro-inflammatory cytokine tumor necrosis factor alpha (TNFalpha). Because of this pro-inflammatory state, we hypothesized that these animals would be more susceptible to subsequent exposure of DA neurotoxins. We tested this hypothesis by treating female Sprague-Dawley rats exposed to LPS or saline prenatally with a subtoxic dose of the DA neurotoxin rotenone (1.25 mg/kg per day) or vehicle for 14 days when they were 16 months old. After another 14 days, the animals were sacrificed. Tyrosine hydroxylase-immunoreactive (THir) cell counts were used as an index of DA neuron survival. Animals exposed to LPS prenatally or rotenone postnatally exhibited a 22% and 3%, respectively, decrease in THir cell counts relative to controls. The combined effects of prenatal LPS and postnatal rotenone exposure produced a synergistic 39% THir cell loss relative to controls. This loss was associated with decreased striatal DA and increased striatal DA activity ([HVA]/[DA]) and TNFalpha. Animals exposed to LPS prenatally exhibited a marked increase in the number of reactive microglia that was further increased by rotenone exposure. Prenatal LPS exposure also led to increased levels of oxidized proteins and the formation of alpha-Synuclein and eosin positive inclusions resembling Lewy bodies. These results suggest that exposure to low doses of an environmental neurotoxin like rotenone can produce synergistic DA neuron losses in animals with a preexisting pro-inflammatory state. This supports the notion that Parkinson's disease (PD) may be caused by multiple factors and the result of "multiple hits" from environmental toxins.
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PMID:Rotenone potentiates dopamine neuron loss in animals exposed to lipopolysaccharide prenatally. 1553 Aug 76

Several multifunctional iron chelators have been synthesized from hydroxyquinoline pharmacophore of the iron chelator, VK-28, possessing the monoamine oxidase (MAO) and neuroprotective N-propargylamine moiety. They have iron chelating potency similar to desferal. M30 is a potent irreversible rat brain mitochondrial MAO-A and -B inhibitor in vitro (IC50, MAO-A, 0.037 +/- 0.02; MAO-B, 0.057 +/- 0.01). Acute (1-5 mg/kg) and chronic [5-10 mg/kg intraperitoneally (i.p.) or orally (p.o.) once daily for 14 days]in vivo studies have shown M30 to be a potent brain selective (striatum, hippocampus and cerebellum) MAO-A and -B inhibitor. It has little effects on the enzyme activities of the liver and small intestine. Its N-desmethylated derivative, M30A is significantly less active. Acute and chronic treatment with M30 results in increased levels of dopamine (DA), serotonin(5-HT), noradrenaline (NA) and decreases in DOPAC (dihydroxyphenylacetic acid), HVA (homovanillic acid) and 5-HIAA (5-hydroxyindole acetic acid) as determined in striatum and hypothalamus. In the mouse MPTP (N-methy-4-phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson's disease (PD) it attenuates the DA depleting action of the neurotoxin and increases striatal levels of DA, 5-HT and NA, while decreasing their metabolites. As DA is equally well metabolized by MAO-A and -B, it is expected that M30 would have a greater DA neurotransmission potentiation in PD than selective MAO-B inhibitors, for which it is being developed, as MAO-B inhibitors do not alter brain dopamine.
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PMID:Novel multifunctional neuroprotective iron chelator-monoamine oxidase inhibitor drugs for neurodegenerative diseases. In vivo selective brain monoamine oxidase inhibition and prevention of MPTP-induced striatal dopamine depletion. 1618 14

Although the etiology of Parkinson's disease (PD) is not fully understood, there are numerous studies that have linked the increased risk for developing PD to pesticides exposure including paraquat (PQ). Moreover, the exposure to a combination of compounds or chemical mixtures has been suggested to further increase this risk. In the current study, the effects of PQ on the nigrostriatal dopaminergic system in male C57BL6 mice exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were examined to assess the impact of toxic substance mixtures exposure on neurochemical and behavioral changes. In this study, a low non-toxic dose of MPTP (10mg/kg) was injected once a day for 5 days and was followed by PQ (7 mg/kg) once a day for 6 days (subacute protocol) or once a week for 10 weeks (chronic protocol). The results from the subacute protocol showed that PQ reduced the turnover of dopamine (DA) as indicated by a 21% and a 22.3% decrease in dihydroxyphenyl acetic acid (DOPAC), homovanillic acid and increased S-adenosyl methionine/S-adenosyl homocysteine index (SAM/SAH) by 100%. However, the administration of PQ to MPTP primed mice resulted in the decrease of DOPAC, HVA, DA, by 35.8%, 35.2% and 22.1%, respectively. In addition, PQ decreased the total number of movements (TM) by 28% but MPTP plus PQ decreased TM by 41%. The SAM/SAH index showed that MPTP increased methylation by 33.3%, but MPTP plus PQ increased methylation by 81%. In the chronic protocol, the data showed that MPTP administration did not affect DA, DOPAC, and HVA levels. The administration of PQ led to significant decrease in DOPAC, HVA, and TD by 31.6%, 19.9%, and 21.2% respectively with no effect on DA levels. The MPTP plus PQ group showed reduced DA, DOPAC, HVA, and total distance traveled by 58.4%, 82.8%, 55.8%, and 83.9%, respectively. Meanwhile, PQ administration caused a reduction in tyrosine hydroxylase immunoreactivity in the substantia nigra, and this effect was more pronounced in MPTP pretreated mice. It was concluded from this study that prior treatment with MPTP potentiated the effects of PQ in reducing DA, DOPAC, HVA, TH immunoreactivity, locomotor activity, and increasing the methylation index. The enhanced effects of PQ following MPTP administration further support the role of toxic substance mixtures in causing Parkinson's disease.
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PMID:The potentiating effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on paraquat-induced neurochemical and behavioral changes in mice. 1658 56

A possible link between Parkinson's disease and pesticide exposure has been suggested, and recently it was shown that the herbicide atrazine (ATR) modulates catecholamine metabolism in PC12 cells and affects basal ganglia function in vivo. Hence, the objectives of this study were to: (i) determine if ATR is capable of modulating dopamine (DA) metabolism in striatal tissue slices in vitro and (ii) explore possible mechanisms of its effects. Striatal tissues from adult male Sprague-Dawley rats were incubated with up to 500 microM ATR in a metabolic shaker bath at 37 degrees C and an atmosphere of 95% O(2) and 5% CO(2) for 4h. At the end of incubation, samples were collected for both tissue and media levels of DA and its metabolites (3,4-dihydroxyphenylacetic acid, DOPAC and homovanillic acid, HVA), which were determined by high-performance liquid chromatography with electrochemical detection (HPLC-ECD). To gain some mechanistic insight in to the way ATR affects DA metabolism, several pharmacological manipulations were performed. Striata exposed to ATR at concentrations of 100 microM and greater had a dose-dependent decrease of tissue levels of DA. At doses of ATR 50 microM and greater, the DOPAC+HVA/DA ratio was dose-dependently increased. Tyrosine hydroxylase (TH, the rate-limiting enzyme in DA synthesis) protein levels and activity were not affected by ATR treatment. However, high potassium-induced DA release into the medium was decreased, whereas the increase in media DA observed in the presence of the DA uptake inhibitor nomifensine was increased even further by ATR in a dose-dependent manner. All of these effects of ATR were observed at levels that were not toxic to the tissue, as LDH release into the medium (lactate dehydrogenase, an index of non-specific cytotoxicity) was not affected by ATR. Taken together, results from this study suggest that ATR decreases tissue DA levels not by affecting TH activity, but possibly by interfering with the vesicular storage and/or cellular uptake of DA.
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PMID:Dopaminergic toxicity of the herbicide atrazine in rat striatal slices. 1721 51

Numerous epidemiological studies have shown an association between pesticide exposure and an increased risk of developing Parkinson's disease (PD). Here, we provide evidence that the insecticide dieldrin causes specific oxidative damage in the nigrostriatal dopamine (DA) system. We report that exposure of mice to low levels of dieldrin for 30 days resulted in alterations in dopamine-handling as evidenced by a decrease in dopamine metabolites, DOPAC (31.7% decrease) and HVA (29.2% decrease) and significantly increased cysteinyl-catechol levels in the striatum. Furthermore, dieldrin resulted in a 53% decrease in total glutathione, an increase in the redox potential of glutathione, and a 90% increase in protein carbonyls. Alpha-synuclein protein expression was also significantly increased in the striatum (25% increase). Finally, dieldrin caused a significant decrease in striatal expression of the dopamine transporter as measured by (3)H-WIN 35,428 binding and (3)H-dopamine uptake. These alterations occurred in the absence of dopamine neuron loss in the substantia nigra pars compacta. These effects represent the ability of low doses of dieldrin to increase the vulnerability of nigrostriatal dopamine neurons by inducing oxidative stress and suggest that pesticide exposure may act as a promoter of PD.
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PMID:Dieldrin exposure induces oxidative damage in the mouse nigrostriatal dopamine system. 1729

Paraquat is a toxin suggested to contribute to pathogenesis of Parkinson's disease. The aim of the present study was to examine toxic influence of subchronic treatment with this pesticide (5 days, one injection per day, 2-3 days of withdrawal) on dopaminergic, serotonergic, noradrenergic and GABAergic neurons. Paraquat decreased the number of tyrosine hydroxylase-immunoreactive (TH-ir) neurons in the substantia nigra by 22% (measured 3 days after withdrawal). Two days after withdrawal the levels of the dopamine metabolites and dopamine turnover in the caudate-putamen, substantia nigra and prefrontal cortex were reduced by ca. 20-60%, and the binding of [(3)H]GBR 12,935 to dopamine transporter dropped by 25-40% in the caudate-putamen. Three days after paraquat withdrawal, the level of dopamine in the caudate-putamen was significantly increased, and earlier decreases in DOPAC and HVA in the substantia nigra, as well as [(3)H]GBR 12,935 binding in the caudate-putamen were reversed. Moreover, an increase in serotonin turnover in the caudate-putamen and prefrontal cortex, and noradrenaline level in the former structure was observed 2-3 days after paraquat withdrawal. Three days after the last paraquat injection 24-35% decreases in the proenkephalin mRNA levels and 5-7% reduction in glutamic acid decarboxylase (GAD)67 mRNA were found in the caudate-putamen. The present study suggests that subchronic paraquat administration triggers processes characteristic of early stages of dopaminergic neuron degeneration, and activates compensatory mechanisms involving dopaminergic, noradrenergic, serotonergic and GABAergic transmissions.
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PMID:Toxic influence of subchronic paraquat administration on dopaminergic neurons in rats. 1749 92

To explore a recently established association between histaminergic and dopaminergic neuronal phenotypic systems in brain, we determined the effect of the respective histaminergic H(3) receptor agonist and antagonist/inverse agonist, imetit and thioperamide, on L-DOPA - derived tissue and extracellular DA and metabolite levels in the striatum of 6-hydroxydopamine (6-OHDA) - lesioned rats (i.e., parkinsonian rats). We also examined the influence of histamine H(3) ligands on L-DOPA evoked behavioral responses (locomotor activity, number of rearings, stereotyped behavior and motor coordination). Using HPLC/ED and in vivo microdialysis technique imetit (5 mg/kg, i.p.) but not thioperamide (5 mg/kg, i.p.) was shown to attenuate an L-DOPA-evoked (15 mg/kg, i.p.; carbidopa, 30 min pretreatment) increase in extracellular DA in the neostriatum of 6-OHDA-lesioned rats. However, both imetit and thioperamide increased microdialysate levels of DOPAC and HVA, probably by enhancing intraneuronal DA utilization. As indicated by neurochemical analysis of the striatum imetit produced a decrease in tissue DA content. These findings support the hypothesis that central H(3) histaminergic receptors have a modulatory role in the storage, metabolism and release of DA derived from exogenous L-DOPA challenge. Furthermore, evidence from behavioral studies indicate that histamine H3 receptor blockade markedly improved motor coordination. Conversely, histamine H(3) receptor stimulation, being without effect on motor coordination, enhanced vertical activity in rats. From the above we conclude that the histamine H(3) agonism may augment motor dyskinesia in Parkinson's disease (PD) patients and presumably worsen L-DOPA therapy. Consequently, the histaminergic system represents a viable target for modulating the effectiveness of L-DOPA therapy in Parkinson's disease.
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PMID:Histamine H(3) receptor ligands modulate L-dopa-evoked behavioral responses and L-dopa derived extracellular dopamine in dopamine-denervated rat striatum. 1852 2

The biochemical and cellular changes that occur following the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are remarkably similar to that seen in idiopathic Parkinson's disease(PD). There is growing evidence indicating that reactive oxygen species (ROS), reactive nitrogen species (RNS) and inflammation are a major contributor to the pathogenesis and progression of PD. Hence, we investigated whether 7-nitroindazole [neuronal nitric oxide synthase (nNOS) inhibitor], edaravone (free radical scavenger), minocycline [inducible NOS (iNOS) inhibitor], fluvastatin [endothelial NOS (eNOS) activator], pitavastatin (eNOS activator), etodolac [cyclooxygenase-2 (COX-2) inhibitor] and indomethacin (COX inhibitor) can protect against MPTP neurotoxicity in mice under the same conditions. For the evaluation of each drug, the levels of dopamine, DOPAC and HVA were quantified using HPLC with an electrochemical detector. Four administrations of MPTP at 1-h intervals to mice produced marked depletion of dopamine, DOPAC (3,4-dihydroxyphenylacetic acid) and HVA (homovanilic acid) in the striatum after 5 days. 7-Nitroindazole prevented dose-dependently a significant reduction in dopamine contents of the striatum 5 days after MPTP treatment. In contrast, edaravone, minocycline, fluvastatin, pitavastatin, etodolac and indomethacin did not show the neuroprotective effect on MPTP-induced striatal dopamine, DOPAC and HVA depletions after 5 days. The present study demonstrates that the overexpression of nNOS may play a major role in the neurotoxic processes of MPTP, as compared with the production of ROS, the overexpression of iNOS, the modulation of eNOS and the involvement of inflammatory response. Thus our pharmacological findings provide further information for progressive neurodegeneration of the nigrostriatal dopaminergic neuronal pathway.
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PMID:Comparative pharmacological study of free radical scavenger, nitric oxide synthase inhibitor, nitric oxide synthase activator and cyclooxygenase inhibitor against MPTP neurotoxicity in mice. 1864 14


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