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)

Ergoline-derived dopamine receptor agonists, like pergolide or bromocryptine, have recently attracted attention as potential neuroprotective drugs. The classical mixed type dopamine D1 and D2 receptor agonist apomorphine, although used clinically in the therapy of Parkinson's disease, has never been examined for any properties related to neuroprotection. In this paper, we examine the effects of 0.1-100 microM apomorphine on ascorbate/iron-stimulated free radical processes in rat brain mitchondrial fraction. Lipid peroxidation as assayed by the thiobarbituric acid reaction can be completely inhibited by submicromolar concentrations of apomorphine (0.3 microM with 2.5 microM Fe2+ and 0.6 microM with 5.0 microM Fe2+), which proved to be more than twice as effective as desferrioxamine and twenty times as compared with dopamine. The inhibition of lipid peroxidation in mitochondria correlates with an increased rate of apomorphine oxidation. The formation of protein carbonyls, which is generally less sensitive to antioxidants, could be significantly reduced by apomorphine. In the model system we employed, apomorphine was more active than dopamine, desferrioxamine, or pergolide in preventing the formation of thiobarbituric reactive substances. The time course of the reaction suggests that apomorphine acts as a radical scavenger and that its iron chelating properties may not be of major importance. Since oxidative stress has been implicated in Parkinson's disease, the role of apomorphine as a neuroprotective is worthy of examination.
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PMID:Apomorphine is a highly potent free radical scavenger in rat brain mitochondrial fraction. 884 Jan 35

A new formulation of a sublingual tablet with 10 mg apomorphine was examined in 13 patients with Parkinson's disease. Vitamin C (250 mg) was added sublingually to lower the salivary pH. Four patients received sublingual apomorphine and nine received sublingual apomorphine as well as vitamin C. Subcutaneous apomorphine was given to all patients. The study was designed as a randomized three-way cross-over study. Tmax, Cmax, and bioavailability (F) were determined. Clinical efficacy was assessed by hand-tapping during 30 s, walking time over 25 m, and a 4-point tremor score. The mean Tmax after subcutaneous apomorphine was 14.5 +/- 1.9 min with a mean Cmax of 19.2 +/- 3.8 ng/ml. The mean clearance of all patients was 3.8 +/- 0.6 L/min. The mean Tmax after sublingual apomorphine was 61.1 +/- 6.9 min vs. 61.7 +/- 8.2 min with vitamin C. The mean Cmax was 7.4 +/- 1.0 ng/ml (- vitamin C) vs. 4.3 +/- 1.3 ng/ml (+ vitamin C). These data resulted consequently in a not significantly different mean bioavailability, varying from 17.6% (- vitamin C) to 6.1% (+ vitamin C). The latency of onset of clinical efficacy varied between 25.0 +/- 8.5 min (- vitamin C) and 26.0 +/- 5.3 min (+ vitamin C). The duration of effect was lower (not significantly) when vitamin C was added: 88.0 +/- 12.5 min (- vitamin C) vs. 61.0 +/- 11.9 min (+ vitamin C). These data show that 10 mg apomorphine sublingually was effective in 56% of the patients. The combination with vitamin C did not significantly change the latency of onset or duration of clinical efficacy. Sublingual apomorphine should be considered as an alternative in the treatment of "off"-periods in Parkinson's disease, in particular when patients have the capacity to anticipate their off-periods.
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PMID:A new sublingual formulation of apomorphine in the treatment of patients with Parkinson's disease. 891 88

It has been suggested that dietary antioxidants reduce Parkinson's disease (PD) risk by neutralizing free radicals, thus preventing injury to neurons in the substantia nigra. This case-control study examined the possible role of long-term dietary antioxidant intake in PD etiology. Cases (n = 57) were males 45-79 years old with at least two cardinal signs of PD and no evidence of other forms of parkinsonism or dementia. Age-matched friend controls (n = 50) were chosen from lists provided by the cases. Usual dietary intake 20 years ago, including vitamins E and C and carotenoids, was assessed by a 102-item food frequency questionnaire. Odds ratios and 95% confidence intervals were calculated using conditional logistic regression. Antioxidant intake, adjusted for age, education, smoking, rural living, and total energy intake, was not associated with reduced PD risk. Trends toward greater PD risk were associated with higher intakes of vitamin C and carotenoids, especially xanthophylls, reflecting higher intakes by PD cases of fruit and certain vegetables. Intakes of sweet foods, including fruit, were associated with higher PD risk, suggesting that the observed trends may be due to a preference for sweet foods. This study does not provide support for a protective effect of long-term dietary antioxidant intake on PD risk.
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PMID:Dietary antioxidants and other dietary factors in the etiology of Parkinson's disease. 908 77

Dopamine can form reactive oxygen species and other reactive metabolites that can modify proteins and other cellular constituents. In this study, we tested the effect of dopamine oxidation products, other generators of reactive oxygen species, and a sulfhydryl modifier on the function of glutamate transporter proteins. We also compared any effects with those on the dopamine transporter, a protein whose function we had previously shown to be inhibited by dopamine oxidation. Preincubation with the generators of reactive oxygen species, ascorbate (0.85 mM) or xanthine (500 microM) plus xanthine oxidase (25 mU/ml), inhibited the uptake of [3H]glutamate (10 microM) into rat striatal synaptosomes (-54 and -74%, respectively). The sulfhydryl-modifying agent N-ethylmaleimide (50-500 microM) also led to a dose-dependent inhibition of [3H]glutamate uptake. Preincubation with dopamine (100 microM) under oxidizing conditions inhibited [3H]glutamate uptake by 25%. Exposure of synaptosomes to increasing amounts of dopamine quinone by enzymatically oxidizing dopamine with tyrosinase (2-50 U/ml) further inhibited [3H]glutamate uptake, an effect prevented by the addition of glutathione. The effects of free radical generators and dopamine oxidation on [3H]glutamate uptake were similar to the effects on [3H]dopamine uptake (250 nM). Our findings suggest that reactive oxygen species and dopamine oxidation products can modify glutamate transport function, which may have implications for neurodegenerative processes such as ischemia, methamphetamine-induced toxicity, and Parkinson's disease.
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PMID:Inhibition of glutamate transport in synaptosomes by dopamine oxidation and reactive oxygen species. 928 42

The interaction between sodium ascorbate and dopamine was investigated by three different parameters: radical intensity, prooxidant action, and cytotoxicity induction. Sodium ascorbate and dopamine produced the doublet and quartet ESR signals under alkaline conditions (pH 8.0-9.5), respectively. Addition of increasing concentrations of sodium ascorbate completely scavenged the dopamine radical and replaced the latter with its own radical. Similarly, dopamine slightly, but significantly reduced the radical intensity of sodium ascorbate. These two compounds stimulated the methionine oxidation and hydrogen peroxide generation in culture medium, but in combination, their stimulation activities were weakened. Both of these two compounds dose-dependently reduced the viable cell number of human oral squamous carcinoma HSC-4 cells, and their cytotoxic activity was significantly reduced by catalase. When these two compounds were mixed together before adding to HSC-4 cells, both of their cytotoxic activities were diminished. The present study demonstrates the interaction between sodium ascorbate and dopamine, which might modify their biological activities and generation of nerve disorders such as Parkinson's disease.
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PMID:Interaction between sodium ascorbate and dopamine. 987 May 54

This paper reviews what is currently known about the redox state of the glutamate synapse and its possible role in modulating synaptic plasticity and thus learning and neurocomputation. The hypothesis is presented that the growth or pruning of the synaptic spine is controlled in part by the balance in the synapse between neurodestructive pro-oxidants (e.g., nitric acid radical and hydrogen peroxide) and neuroprotective antioxidants (e.g., ascorbate and carnosine). In addition, there may be a role for catecholamines, in particular dopamine, related to its role in reinforcement signalling. Activation of the dopamine D2 receptor induces the synthesis of an antioxidant enzyme, possibly catalase. Dopamine may also affect the redox balance in the glutamate synapse directly by diffusion from the adjacent dopaminergic bouton-en-passage. Catecholamines are powerful antioxidants, scavengers of free radicals and iron chelators. Catecholamine-iron complexes are potent dismuters of superoxide ions. Additional agents participating in spine pruning may be neurotoxic catecholamine o-quinones present in the brain. This system may be at fault in schizophrenia and Parkinson's disease. Experiments to test the hypothesis are suggested.
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PMID:Redox mechanisms at the glutamate synapse and their significance: a review. 1032 73

Much of the excess iron reported in the substantia nigra of subjects with Parkinson's disease (PD) implicates nonneuronal (glial) cellular compartments. Yet, the significance of these glial iron deposits vis-a-vis toxicity to indigent nigrostriatal dopaminergic neurons remains unclear. Cysteamine (CSH) induces the appearance of iron-rich (peroxidase-positive) cytoplasmic inclusions in cultured rat astroglia, which are identical to glial inclusions that progressively accumulate in substantia nigra and other subcortical brain regions with advancing age. We previously demonstrated that the iron-mediated peroxidase activity in these cells oxidizes dopamine and other catechols to potentially neurotoxic semiquinone radicals. In the present study, we cocultured catecholamine-secreting PC12 cells (as low-density dispersed cells or high-density colonies) atop monolayers of either CSH-pretreated (iron-enriched) or control rat astroglial substrata. In some experiments, the PC12 cells were differentiated with nerve growth factor (NGF). The nature of the glial substratum did not appreciably affect the growth characteristics of the PC12 cells. However, undifferentiated PC12 cells grown atop CSH-pretreated astrocytes (a senescent glial phenotype) were far more susceptible to dopamine(1 microM)-H2O2(1 microM)-related killing than PC12 cells cultured on control astroglia. Differentiated PC12 cells behaved similarly although the fraction killed was about half that seen with the undifferentiated PC12 cells. In the latter experiments, PC12 cell death was abrogated by coadministration of the antioxidants, ascorbate (200 microM), melatonin (100 microM), or resveratrol (50 microM) or the iron chelator, deferoxamine (400 microM), attesting to the role of oxidative stress and catalytic iron in the mechanism of PC12 cell death in this system. The aging-associated accumulation of redox-active iron in subcortical astrocytes may facilitate the bioactivation of dopamine to neuronotoxic free radical intermediates and thereby predispose the senescent nervous system to PD and other neurodegenerative disorders.
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PMID:Cysteamine pretreatment of the astroglial substratum (mitochondrial iron sequestration) enhances PC12 cell vulnerability to oxidative injury. 1061 54

Oxidative mechanisms play an important role in the pathogenesis of Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases. To assess whether the oxidation of brain lipoproteins plays a role in the development of these pathologies, we investigated whether the lipoproteins of human cerebrospinal fluid (CSF) are susceptible to oxidative modification in vitro. We studied oxidation time-course for up to 100 h of human CSF in the absence (autooxidation) or presence of exogenous oxidants. Autooxidation of diluted CSF was found to result in a slow accumulation of lipid peroxidation products. The time-course of lipid hydroperoxide accumulation revealed three consecutive phases, lag-phase, propagation phase and plateau phase. Qualitatively similar time-course has been typically found in human plasma and plasma lipoproteins. Autooxidation of CSF was accelerated by adding exogenous oxidants, delayed by adding antioxidants and completely inhibited by adding a chelator of transition metal ions. Autooxidation of CSF also resulted in the consumption of endogenous ascorbate, alpha-tocopherol, urate and linoleic and arachidonic acids. Taking into account that (i) lipid peroxidation products measured in our study are known to be derived from fatty acids, and (ii) lipophilic antioxidants and fatty acids present in CSF are likely to be located in CSF lipoproteins, we conclude that lipoproteins of human CSF are modified in vitro during its autooxidation. This autooxidation appears to be catalyzed by transition metal ions, such as Cu(II) and Fe(III), which are present in native CSF. These data suggest that the oxidation of CSF lipoproteins might occur in vivo and play a role in the pathogenesis of neurodegenerative diseases.
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PMID:Time-course of oxidation of lipids in human cerebrospinal fluid in vitro. 1065 81

Degeneration of nigrostriatal dopaminergic neurons is the major pathogenic substrate of Parkinson's disease (PD). Inhibitors of monoamine oxidase B (MAO-B) have been used in the treatment of PD and at least one of them, i.e., deprenyl, also displays antioxidant activity. Dopamine (DA) autoxidation produces reactive oxygen species implicated in the loss of dopaminergic neurons in the nigrostriatal pathway. In this study we compared the effects of melatonin with those of deprenyl and vitamins E and C in preventing the hydroxyl radical (8OH) generation during DA oxidation. The rate of production of 2,3-dihydroxybenzoate (2,3-DHBA) in the presence of salicylate, an *OH scavenger, was used to detect the in vitro generation of *OH during iron-catalyzed oxidation of DA. The results showed a dose-dependent effect of melatonin, deprenyl and vitamin E in counteracting DA autoxidation, whereas vitamin C had no effect. Comparative analyses between the effect of these antioxidants showed that the protective effect of melatonin against DA autoxidation was significantly higher than that of the other compounds tested. Also, when melatonin plus deprenyl were added to the incubation medium, a potentiation of the antioxidant effect was found. These findings suggest that antioxidants may be useful in brain protection against toxicity of reactive oxygen species produced during DA oxidation, and melatonin, alone or in combination with deprenyl, may be an important component of the brain's antioxidant defenses to protect it from dopaminergic neurodegeneration.
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PMID:Comparative effects of melatonin, L-deprenyl, Trolox and ascorbate in the suppression of hydroxyl radical formation during dopamine autoxidation in vitro. 1098 23

This review covers certain novel aspects of catecholamine signaling in neurons that involve redox systems and synaptic plasticity. The redox hypothesis suggests that one important factor in neurocomputation is the formation of new synapses and the removal of old ones (synaptic plasticity), which is modulated in part by the redox balance at the synapse between reactive oxygen species (ROS) (such as hydrogen peroxide and the nitric oxide radical) and neuroprotective antioxidants (such as ascorbate, glutathione, and catecholamines). Catecholamines, in particular dopamine, which signals positive reinforcement, may play a key role in this activity. Dopamine has powerful antioxidant properties by several separate mechanisms-direct ROS scavenging, activation of the synthesis of antioxidant proteins, and possibly via dismuting complexes with iron inside endosomes or in catecholaminergic synaptic vesicles. This may contribute to synaptic growth and reinforcement-directed learning. On the other hand, catecholamines are easily oxidized to toxic quinones on the neuromelanin pathway. This might contribute under certain circumstances to synaptic deletion. Evidence is presented that abnormalities in this system may contribute to the pathogenesis of Parkinson's disease and schizophrenia.
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PMID:Redox aspects of signaling by catecholamines and their metabolites. 1122 69


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