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)

We have recently shown that dopamine (DA) can trigger apoptosis, an active program of cellular self-destruction, in various neuronal cultures and proposed that inappropriate activation of apoptosis by DA and or its oxidation products may initiate nigral cell loss in Parkinson's disease (PD). Since DA toxicity may be mediated via generation of oxygen-free radical species, we examined whether DA-induced cell death in PC12 cells may be inhibited by antioxidants. We have found that the thiol containing compounds, reduced glutathione (GSH), N-acetyl-cysteine (NAC), and dithiothreitol (DTT) were markedly protective, while vitamins C and E had lesser or no effect. The thiol antioxidants and vitamin C but not vitamin E, prevented dopamine autooxidation and production of dopamine-melanin. Their protective effect has also manifested by inhibiting DA-induced apoptosis; DNA fragmentation was prevented as was shown histochemically by the in situ end-labeled DNA technique (TUNEL). Intracellular GSH and other thiols constitute an important natural defense against oxidative stress. We have found that depletion of cellular GSH by the addition of phoron, a substrate of glutathione transferase, and buthionine sulfoximine (BSO), an inhibitor of gamma-glutamyl transpeptidase, significantly enhanced DA toxicity. Cotreatment with NAC rescued the cells from the toxic effect of BSO+DA, and phoron+ DA, while addition of GSH provided only partial protection from BSO+DA toxicity. Our data indicate that the thiol family of antioxidants, but not vitamins C and E, are highly effective in rescuing cells from DA-induced apoptosis. Further study of the mechanisms underlying the unique protective capacity of thiol antioxidants may lead to the development of new neuroprotective therapeutic strategies for PD.
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PMID:Prevention of dopamine-induced cell death by thiol antioxidants: possible implications for treatment of Parkinson's disease. 879 65

Parkinson's disease, known also as striatal dopamine deficiency syndrome, is a degenerative disorder of the central nervous system characterized by akinesia, muscular rigidity, tremor at rest, and postural abnormalities. In early stages of parkinsonism, there appears to be a compensatory increase in the number of dopamine receptors to accommodate the initial loss of dopamine neurons. As the disease progresses, the number of dopamine receptors decreases, apparently due to the concomitant degeneration of dopamine target sites on striatal neurons. The loss of dopaminergic neurons in Parkinson's disease results in enhanced metabolism of dopamine, augmenting the formation of H2O2, thus leading to generation of highly neurotoxic hydroxyl radicals (OH.). The generation of free radicals can also be produced by 6-hydroxydopamine or MPTP which destroys striatal dopaminergic neurons causing parkinsonism in experimental animals as well as human beings. Studies of the substantia nigra after death in Parkinson's disease have suggested the presence of oxidative stress and depletion of reduced glutathione; a high level of total iron with reduced level of ferritin; and deficiency of mitochondrial complex I. New approaches designed to attenuate the effects of oxidative stress and to provide neuroprotection of striatal dopaminergic neurons in Parkinson's disease include blocking dopamine transporter by mazindol, blocking NMDA receptors by dizocilpine maleate, enhancing the survival of neurons by giving brain-derived neurotrophic factors, providing antioxidants such as vitamin E, or inhibiting monoamine oxidase B (MAO-B) by selegiline. Among all of these experimental therapeutic refinements, the use of selegiline has been most successful in that it has been shown that selegiline may have a neurotrophic factor-like action rescuing striatal neurons and prolonging the survival of patients with Parkinson's disease.
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PMID:Oxidative stress and antioxidant therapy in Parkinson's disease. 883 Mar 46

How much vitamin E is enough? An established use of supplemental vitamin E in humans is in the prevention and therapy of deficiency symptoms. The cause of vitamin E deficiency, characterized by peripheral neuropathy and ataxia, is usually malabsorption-a result of fat malabsorption or genetic abnormalities in lipoprotein metabolism. Genetic abnormalities in the hepatic alpha-tocopherol transfer protein also cause vitamin E deficiency-defects in this protein cause an impairment in plasma vitamin E transport. Impaired delivery of vitamin E to tissues, thereby, results in deficiency symptoms. Also discussed is the use of supplemental vitamin E in chronic diseases such as ischemic heart disease, atherosclerosis, diabetes, cataracts, Parkinson's disease, Alzheimer's disease, and impared immune function, as well as in subjects receiving total parenterol nutrition. In healthy individuals, a daily intake of about 15-30 mg of alpha-tocopherol is recommended to obtain "optimal plasma alpha-tocopherol concentrations" (30 microM or greater).
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PMID:Vitamin E in humans: demand and delivery. 883 30

A large body of evidence indicates that the progression of Parkinson's disease (PD) may be fast in the preclinical stage as well as during the first years of the disease, with a subsequent slowing down of the disease process. As has been shown in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) study, the Unified Parkinson's Disease Rating Scale (UPDRS) motor examination scores declined at a rate of 8 to 9% per year in untreated patients. A subgroup of levodopa-naive DATATOP patients ("survivors") showed a much slower rate of progression, in the order of 3% per year, suggesting a more benign disease course. A number of clinical factors that may govern the rate of motor decline, such as age at onset, disease duration, gender, and clinical phenotype (akinetic-rigid versus tremulous) have been proposed; however, none of them is proven. In contrast, dopaminergic substitution undoubtedly has had a major impact on the natural history of PD, resulting in a reduction of the mortality ratio from about 3.0 to 1.5. This benefit has been noted particularly in patients in whom levodopa therapy was started early. The positive impact of levodopa is largely derived from its symptomatic action; its influence on the disease process itself remains controversial.
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PMID:The natural history of Parkinson's disease. 895 83

Progression of Parkinson's disease (PD) can be detected through changes in clinical ratings or disability assessments. A clinical trial, Deprenyl and Alpha-Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP), used a novel study end point: increase in parkinsonian disability to the extent that investigators determined the need for treatment with levodopa. We analyzed DATATOP results to learn if this operationally defined end point could be reproduced from elements of the Unified PD Rating Scale (UPDRS) and other conventional clinical scales. Our analysis involved UPDRS, Schwab and England Activities of Daily Living (S-E ADL), and Hoehn and Yahr (H-Y) scores when DATATOP subjects reached the study end point. Various UPDRS components were examined, including subscores measuring severity of impaired ADL, bradykinesia, postural instability and gait difficulty, tremor, and rigidity. Data from subjects reaching the end point were compared with assessments of those DATATOP subjects who did not, matched for the same duration of enrollment. All measures showed subjects who reached the end point had significantly greater mean impairment than did controls, although the two groups had substantial overlap. Multivariate analysis by using conditional logistic regression suggested that the end point was determined more by functional (S-E ADL and the UPDRS ADL scores) than by clinical examination criteria. The method of classification and regression trees suggested a simple decision tree splitting, respectively, on S-E ADL, UPDRS ADL, H-Y score, and UPDRS ADL again, with an estimated overall misclassification probability of 18%. We conclude that the DATATOP end point cannot be fully reproduced from the traditional clinical measures, although it can give results that are consistent with these scales in a well-designed clinical trial.
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PMID:The need for levodopa as an end point of Parkinson's disease progression in a clinical trial of selegiline and alpha-tocopherol. Parkinson Study Group. 908 76

Dopamine (DA) neurons are uniquely vulnerable to damage and disease. Their loss in humans is associated with diseases of the aged, most notably, Parkinson's Disease (PD). There is now a great deal of evidence to suggest that the destruction of DA neurons in PD involves the accumulation of harmful oxygen free radicals. Since the antioxidant hormone, melatonin, is one of the most potent endogenous scavengers of these toxic radicals, we tested its ability to rescue DA neurons from damage/death in several laboratory models associated with oxidative stress. In the first model, cells were grown in low density on serum-free media. Under these conditions, nearly all cells died, presumably due to the lack of essential growth factors. Treatment with 250 microM melatonin rescued nearly all dying cells (100% tau+ neurons), including tyrosine hydroxylase immunopositive DA neurons, for at least 7 days following growth factor deprivation. This effect was dose and time dependent and was mimicked by other antioxidants such as 2-iodomelatonin and vitamin E. Similarly, in the second model of oxidative stress, 250 microM melatonn produced a near total recovery from the usual 50% loss of DA neurons caused by neurotoxic injury from 2.5 microM 1-methyl-4-phenylpyridine (MPP+). These results indicate that melatonin possesses the remarkable ability to rescue DA neurons from cell death in several experimental paradigms associated with oxidative stress.
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PMID:Melatonin rescues dopamine neurons from cell death in tissue culture models of oxidative stress. 936 31

We compared CSF and serum levels, and the CSF/serum ratio of alpha-tocopherol (vitamin E), measured by HPLC, in 34 patients with Parkinson's disease (PD) and 47 controls. CSF and serum vitamin E levels were correlate. The mean CSF and serum vitamin E levels, and the CSF/serum ratio of PD patients did not differ significantly between the groups. There was no influence of antiparkinsonian therapy on CSF vitamin E levels. CSF vitamin E levels did not correlate with age, age at onset, duration of the disease, scores of the Unified Parkinson Disease Rating Scale of the Hoehn and Yahr staging in the PD group. These results suggest that CSF vitamin E concentrations are unrelated with the risk for PD.
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PMID:Cerebrospinal fluid levels of alpha-tocopherol (vitamin E) in Parkinson's disease. 950 74

Alpha-Tocopherol concentrations were determined in the CSF of patients with early untreated Parkinson's disease receiving 2,000 IU vitamin E orally per day. After treatment the concentrations increased significantly (p < 0.001) by 76+/-10 (SE)%. The net increases in CSF alpha-tocopherol concentrations after treatment showed a significant positive correlation with the number of days of vitamin E ingestion (p < 0.001). Thus, high-dose vitamin E treatment results in elevating CSF vitamin E levels and possibly brain vitamin E levels.
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PMID:Alpha tocopherol in CSF of subjects taking high-dose vitamin E in the DATATOP study. Parkinson Study Group. 963 57

Substantial evidence now exists that oxidative stress may play an important role in the etiopathogenesis of DAT. The different sources of oxidative stress in DAT are suggesting several pharmacological opportunities for influencing the disease. It is possible to distinguish 2 major types of possible therapeutic agents according to their pharmacological point of attack. 1. Radical scavengers, agents directly interacting with free radicals. Candidates of this type are gingko biloba, vitamins A, C, E and estrogen. 2. Antioxidants, which are able to prevent or decrease the production of free radicals by use of specific neuropharmacological properties. Candidates are selegiline, a MAO-B inhibitor well established in the therapy of Parkinson's disease, and tenilsetam, which is believed to be an AGE-inhibitor. Recent in vitro studies have demonstrated the efficacy of both types of therapeutic agents by preventing or delaying oxidative neural damage. Some clinical data exist regarding the antidementive properties particularly in terms of gingko biloba, selegiline and vitamin E. The efficacy studies about these compounds seem to indicate a promising future strategy in the therapy of DAT. But it is too early to draw definite conclusions since it is well known that all of our candidate substances do not act specifically as radical scavengers or antioxidants.
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PMID:Free radicals in Alzheimer's dementia: currently available therapeutic strategies. 985 Sep 30

Our objective was to study the placebo response in Parkinson's disease (PD). We conducted a literature search in which placebo response was measured in all studies of PD from 1969 to April 1996. Strict criteria were defined to include or exclude published reports in our survey. The Parkinson Study Group database for Deprenyl & Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) was reviewed and placebo "responders" were compared to placebo "nonresponders" by age, race, religion, level of education, duration of PD, and gender. A significant difference between the efficacy of placebo and that of active drug was reported in 61% (22 of 36) of the articles meeting the required criteria; DATATOP analysis showed no statistically significant epidemiologic differences between 140 placebo responders and 58 placebo nonresponders except in PD effect on current job. Although there is clearly a placebo response in PD patients, our review suggests that the variation in placebo response does not correlate with demographic factors such as age, gender, religion, level of education, or duration of PD.
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PMID:The placebo response in Parkinson's disease. Parkinson Study Group. 1044 49


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