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)

Oxidative stress has been implicated in the pathogenesis of Parkinson's disease. In the present study, reactive oxygen species (ROS) formation and antioxidant enzyme superoxide dismutase (SOD) activities were examined in cultured cortical, striatal and mesencephalic mouse astrocytes after 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP(+)) treatment. Linear regression analysis showed that control mesencephalic (slope coefficient=0.01) astrocytes had a three-fold (F-test, p<0.05) greater rate of change in ROS production when compared to cortical (0.003) or striatal (0.003) astrocytes. However, when treated with 500 microM MPTP for 120 min, mesencephalic and striatal astrocytes demonstrated a decreased and increased rate of change in ROS production respectively. On the other hand, when treated with 10 microM MPP(+), a significant increase in the rate of change in ROS formation was observed in both mesencephalic and striatal astrocytes, with mesencephalic astrocytes producing a four-fold greater increase when compared to striatal astrocytes. Cortical astrocytes did not show any significant changes in ROS production when treated with MPTP or MPP(+). When astrocytes were treated with MPTP over a 24 h period, striatal astrocytes demonstrated significant increases in SOD activity to 12 h, followed by a return towards control levels after 8 h treatment. In contrast, mesencephalic astrocytes showed trends for a decrease in SOD production as well as a significant decrease in ATP levels by 24 h MPTP treatment. The present results suggested that mesencephalic astrocytes are more vulnerable to oxidative stress when compared to striatal astrocytes, given their greater rates of ROS production at basal and MPP(+) conditions. Striatal astrocytes, on the other hand, may have a more protective capacity against oxidative stress by producing greater SOD activities.
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PMID:Oxidative stress induced by MPTP and MPP(+): selective vulnerability of cultured mouse astrocytes. 1041 27

Recent information suggests that free radicals are closely involved in the pathogenesis and/or progression of Parkinson's disease (PD). High-dose levodopa therapy has been suggested to increase oxidative stress, thereby accelerating the progression of PD. Based on this viewpoint, free radical scavenging, antioxidant and neuroprotective agents which may prevent the progression of PD have recently attracted considerable attention. For example, ergot derivative dopamine (DA) agonists have been reported to scavenge free radicals in vitro and show a neuroprotective effect in vivo. Non-ergot DA agonists have also recently been used in the treatment of PD despite the lack of substantial evidence for any free radical scavenging activity or antioxidant activity. The present study was conducted to assess the in vitro free radical scavenging and antioxidant activities of ropinirole, a non-ergot DA agonist, as well as its glutathione (GSH), catalase and superoxide dismutase (SOD) activating effects and neuroprotective effect in vivo. Ropinirole scavenges free radicals and suppresses lipid peroxidation in vitro, but these activities are very weak, suggesting that the antioxidant effect of ropinirole observed in vitro may be a minor component of its neuroprotective effect in vivo. Administration of ropinirole for 7 days increased GSH, catalase and SOD activities in the striatum and protected striatal dopaminergic neurons against 6-hydroxydopamine (6-OHDA) in mice. Pre-treatment with sulpiride prevented ropinirole from enhancing striatal GSH, catalase and SOD activities and abolished the protection of dopaminergic neurons against 6-OHDA. Our findings indicate that activation of GSH, catalase and SOD mediated via DA D2 receptors may be the principal mechanism of neuroprotection by ropinirole.
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PMID:Dopamine D2 receptor-mediated antioxidant and neuroprotective effects of ropinirole, a dopamine agonist. 1044 16

Both reactive dopamine metabolites and mitochondrial dysfunction have been implicated in the neurodegeneration of Parkinson's disease. Dopamine metabolites, dopamine quinone and reactive oxygen species, can directly alter protein function by oxidative modifications, and several mitochondrial proteins may be targets of this oxidative damage. In this study, we examined, using isolated brain mitochondria, whether dopamine oxidation products alter mitochondrial function. We found that exposure to dopamine quinone caused a large increase in mitochondrial resting state 4 respiration. This effect was prevented by GSH but not superoxide dismutase and catalase. In contrast, exposure to dopamine and monoamine oxidase-generated hydrogen peroxide resulted in a decrease in active state 3 respiration. This inhibition was prevented by both pargyline and catalase. We also examined the effects of dopamine oxidation products on the opening of the mitochondrial permeability transition pore, which has been implicated in neuronal cell death. Dopamine oxidation to dopamine quinone caused a significant increase in swelling of brain and liver mitochondria. This was inhibited by both the pore inhibitor cyclosporin A and GSH, suggesting that swelling was due to pore opening and related to dopamine quinone formation. In contrast, dopamine and endogenous monoamine oxidase had no effect on mitochondrial swelling. These findings suggest that mitochondrial dysfunction induced by products of dopamine oxidation may be involved in neurodegenerative conditions such as Parkinson's disease and methamphetamine-induced neurotoxicity.
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PMID:Dopamine oxidation alters mitochondrial respiration and induces permeability transition in brain mitochondria: implications for Parkinson's disease. 1046 4

Oxidative stress plays a central role in the pathogenesis of Parkinson's disease (PD). L-DOPA, the gold standard in PD therapy, may paradoxically contribute to the progression of the disease because of its pro-oxidant properties. The issue, however, is controversial. In this study, we evaluated peripheral markers of oxidative stress in normal subjects, untreated PD patients and PD patients treated only with L-DOPA. We also measured platelet and plasma levels of L-DOPA, 3-O-methyldopa (the long-lasting metabolite of the drug), and dopamine. We found that isolated platelets of treated PD patients form higher amounts of 2,3-dihydroxybenzoate, an index of hydroxyl radical generation, than platelets of controls or untreated patients. In treated patients, platelet levels of 2,3-dihydroxybenzoate were positively correlated with platelet levels of L-DOPA, 3-O-methyldopa, and with the score of disease severity. Disease severity was correlated with platelet and plasma levels of L-DOPA, as well as with the daily intake of the drug. No significant differences in platelet levels of cytosolic and mitochondrial isoforms of the antioxidant enzyme superoxide dismutase were found between PD patients, either treated or untreated, and controls. Our findings lend further support to the hypothesis that L-DOPA might promote free radical formation in PD patients.
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PMID:Peripheral markers of oxidative stress in Parkinson's disease. The role of L-DOPA. 1046 18

The present study was conducted to characterize the possible interaction of Al3+ and Fe2+ with synthetic melanin in the potentiation of lipid peroxidation in liposomes and rat caudate-putamen homogenates. Al3+ stimulated melanin-initiated lipid peroxidation as measured by the production of 2-thiobarbituric acid-reactive substances (TBARS) and conjugated dienes. The effect of A13+ was dependent on melanin (10-100 microg/ml) and A13+ (2.5-250 microM) concentrations and no synergism between Fe2+ and Al3+ was observed. The prooxidant effect of Al3+ was partially inhibited by superoxide dismutase indicating the involvement of O2*- . Ga3+ and Be2+ which can increase NADH oxidation in the presence of O2*-, also were shown to stimulate melanin-initiated TBARS production. Based on the effect of Al3+ and other non redox metals, we suggest that Al3+ does not act through either the induction of melanin free radicals, or the induction of changes in membrane physical properties. Results show that Al3+ enhances melanin-initiated lipid peroxidation in part through an interaction with O2*- generated from the autoxidation of melanin. We speculate that Al3+ contributes to neuromelanin-mediated oxidative damage in dopaminergic neurons and subsequent neuronal degeneration and death in Parkinson's disease.
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PMID:Aluminum enhances melanin-induced lipid peroxidation. 1047 39

Hydroxyl radical (.OH) levels in blood, superoxide dismutase (SOD) activity in plasma (plasma-SOD) and in red blood cells (RBC) relative to Cu,Zn-SOD (SOD1) protein (RBC-SOD/SOD1), SOD1 protein in RBC (SOD1/RBC) and plasma (SOD1/plasma), and Mn-SOD protein in plasma (SOD2/plasma) were measured in patients with Parkinson's disease (PD), multiple-system atrophy (MSA) with parkinsonism, and in control subjects. Patients with PD had significantly higher.OH and plasma-SOD values and significantly lower RBC-SOD/SOD1 and SOD1/RBC values than the corresponding MSA and control values. In PD, RBC-SOD/SOD1 values were significantly lower in older patients and were negatively correlated with age.OH levels were significantly higher in PD patients with early onset, a long period of illness or severe Yahr stage, and were negatively correlated with onset and positively correlated with duration of illness. RBC-SOD/SOD1 values in PD patients who received pergolide therapy were significantly higher than those in PD patients who received neither pergolide nor bromocriptine therapy. Therefore, the higher.OH level and the lower SOD1 activity may play a role in the onset and progression of PD, and pergolide may act neuroprotectively by inducing SOD1 activity.
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PMID:Hydroxyl radical and superoxide dismutase in blood of patients with Parkinson's disease: relationship to clinical data. 1056 21

Tryptophan hydroxylase, the initial and rate limiting enzyme in the biosynthesis of serotonin (5-HT), is inactivated by the quinone of L-DOPA. L-DOPA itself has no effect on enzyme activity. The inactivation of tryptophan hydroxylase could be prevented by glutathione (GSH), dithiothreitol, cysteine, and ascorbic acid but not by scavengers of hydrogen peroxide (catalase), hydroxyl radical (DMSO), or superoxide (superoxide dismutase). All cysteinyl residues within tryptophan hydroxylase are modified after treatment with L-DOPA-quinone as revealed by loss of DTNB-reactivity and formation of cysteinyl-DOPA residues. L-DOPA-quinone also converts tryptophan hydroxylase to a redox-cycling quinoprotein. These results suggest a possible mechanism of 5-HT neuronal damage in Parkinson's Disease by a redox-cycling quinoprotein.
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PMID:L-DOPA-quinone inactivates tryptophan hydroxylase and converts the enzyme to a redox-cycling quinoprotein. 1058

In a previous study we found copper dyshomeostasis in patients with Alzheimer's disease. In this study, levels of copper in plasma, of ceruloplasmin in serum and ceruloplasmin oxidative activity as well as superoxide dismutase (SOD) activity in erythrocytes were determined in 40 patients with Parkinson's disease and their healthy age- and gender-matched controls. Copper concentrations did not differ significantly in the two groups, whereas both ceruloplasmin concentrations and ceruloplasmin oxidative activity were significantly lower in the patients, also relative to ceruloplasmin mass. SOD activity was not significantly different in the two groups but decreased significantly with the duration of disease. The same was found for ceruloplasmin oxidative activity. Ceruloplasmin oxidative activity and SOD activity did not decrease with age. Levels of serum iron, serum ferritin and total iron binding capacity were determined in about 30 of the patients and an equal number of controls and were not found to differ. Transferrin levels were significantly lower in the patients than in their controls but, conversely, the transferrin saturation was significantly higher in the patients. The results indicate that patients with Alzheimer's disease and Parkinson's disease have defective ceruloplasmin and SOD activities in common and that these defects are not necessarily associated with major disturbances in iron homeostasis.
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PMID:Copper, ceruloplasmin, superoxide dismutase and iron parameters in Parkinson's disease. 1060 87

Free radical are highly reactive chemical species with an unpaired electron in an atomic or molecular orbital. In biological systems, the most important free radicals are superoxide anion and hydrogen peroxide; in the presence of transition metals such as iron, copper and manganese both these free radicals produce hydroxyl radicals. Free radicals attack proteins, nuclei acids and membranes containing large quantities of polyunsaturated fatty acids. Because of their toxicity, the organism has developed ways to deactivate them. The superoxide dismutase enzyme (SOD) catalyzes dismutation of the superoxide radical into hydrogen peroxide and oxygen hydrogen peroxide is in turn reduced to water and oxygen by peroxidase glutathione and catalase enzymes. The production of radicals in the brain is due to catecholamine metabolism such as dopamine and norepinephrine and is increased by the presence of transition metals and by a deficiency of antioxidant agents such as vitamin E. Two main groups of dementia exist in older age: the multi-infarctual dementias, caused by cerebrovascular disorders and the primary degenerative disorders such as Alzheimer, where no vascular disease is evident. Free radicals play an important role in Parkinson's disease, in Alzheimer's disease and in stroke. The value of SOD and CAT activity following the above mentioned degenerative diseases differ among the various studies carried out. In Alzheimer's disease, the value of SOD activity probably increases in the neuropathologically involved areas. In stroke, the SOD value does not vary either in the ischemic area or in the peri-infarctual one during the first 24 hrs after lesion, while the CAT value decreases.
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PMID:Free radicals: important cause of pathologies refer to ageing. 1070 16

Administration of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to mammals causes damage to the nigrostriatal dopaminergic pathway similar to that observed in Parkinson disease (PD). Reactive oxygen species (ROS) are thought to be involved in the pathogenesis of MPTP-mediated dopaminergic neurodegeneration. To further clarify the role of superoxide anion radical (*O2-) and to study the possible involvement of hydroperoxides in MPTP-mediated neurodegeneration, MPTP neurotoxicity was induced in mice deficient in either CuZn superoxide dismutase (SOD), a scavenger enzyme for *O2-, or cellular glutathione peroxidase (GSHPx-1), a scavenger enzyme for hydroperoxides. Littermate control and homozygous deficient mice were injected intraperitoneally with a total cumulative dose of 0, 75, or 150 mg/kg of MPTP delivered over 5 d. All mice were killed 5 d after the last injection and the brains were processed for immunohistological analysis for tyrosine hydroxylase (TH) in the striatum and the substantia nigra pars compacta (SNc), as well as for direct measurements of dopamine concentrations in the striatum. The intensity of TH immunoreactivity in the striatum was evaluated by measuring the relative optical density (OD) with NIH IMAGE, and expressed as Log (OD of striatum)/Log (OD of white matter). Degeneration of TH-containing neurons was assessed by counting TH-positive neurons in the SNc. We found that this MPTP exposure protocol produced dose-dependent depletion of TH immunoreactivity and dopamine in the striatum in littermate control mice and both strains of knockout mice; however. reduction in TH immunoreactivity and dopamine content were significantly greater in CuZn-SOD or GSHPx-1 deficient mice compared with littermate controls. MPTP exposure did not significantly alter the number of TH-positive neurons in the SNc in littermate control or knockout mice. These data suggest that some of the deleterious effects of MPTP on striatal dopaminergic nerve terminals are mediated by both *O2- and hydroperoxides, and that they occur prior to dopaminergic neurodegeneration in the SNc. The similarity between the MPTP model and PD raises the possibility that both types of ROS may play a significant role in the early pathogenesis of dopaminergic neurodegeneration in PD.
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PMID:Enhanced N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in mice deficient in CuZn-superoxide dismutase or glutathione peroxidase. 1074 35


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