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)

Rotenone, a pesticide and complex I inhibitor, causes nigrostriatal degeneration similar to Parkinson disease pathology in a chronic, systemic, in vivo rodent model [M. Alam, W.J. Schmidt, Rotenone destroys dopaminergic neurons and induces parkinsonian symptoms in rats, Behav. Brain Res. 136 (2002) 317-324; R. Betarbet, T.B. Sherer, G. MacKenzie, M. Garcia-Osuna, A.V. Panov, J.T. Greenamyre, Chronic systemic pesticide exposure reproduces features of Parkinson's disease, Nat. Neurosci. 3 (2000) 1301-1306; S.M. Fleming, C. Zhu, P.O. Fernagut, A. Mehta, C.D. DiCarlo, R.L. Seaman, M.F. Chesselet, Behavioral and immunohistochemical effects of chronic intravenous and subcutaneous infusions of varying doses of rotenone, Exp. Neurol. 187 (2004) 418-429; T.B. Sherer, J.H. Kim, R. Betarbet, J.T. Greenamyre, Subcutaneous rotenone exposure causes highly selective dopaminergic degeneration and alpha-synuclein aggregation, Exp. Neurol. 179 (2003) 9-16.]. To better investigate the role of mitochondria and complex I inhibition in chronic, progressive neurodegenerative disease, we developed methods for long-term culture of rodent postnatal midbrain organotypic slices. Chronic complex I inhibition over weeks by low dose (10-50 nM) rotenone in this system lead to dose- and time-dependent destruction of substantia nigra pars compacta neuron processes, morphologic changes, some neuronal loss, and decreased tyrosine hydroxylase (TH) protein levels. Chronic complex I inhibition also caused oxidative damage to proteins, measured by protein carbonyl levels. This oxidative damage was blocked by the antioxidant alpha-tocopherol (vitamin E). At the same time, alpha-tocopherol also blocked rotenone-induced reductions in TH protein and TH immunohistochemical changes. Thus, oxidative damage is a primary mechanism of mitochondrial toxicity in intact dopaminergic neurons. The organotypic culture system allows close study of this and other interacting mechanisms over a prolonged time period in mature dopaminergic neurons with intact processes, surrounding glia, and synaptic connections.
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PMID:Rotenone induces oxidative stress and dopaminergic neuron damage in organotypic substantia nigra cultures. 1579 May 35

We studied the effect of vitamin C, vitamin E, and beta carotene intake on the risk of Parkinson's disease (PD). We did a systematic review and meta-analysis of observational studies published between 1966 and March 2005 searching MEDLINE, EMBASE, and the Cochrane Library. Eight studies were identified (six case-control, one cohort, and one cross-sectional). We found that dietary intake of vitamin E protects against PD. This protective influence was seen with both moderate intake (relative risk 0.81, 95% CI 0.67-0.98) and high intake (0.78, 0.57-1.06) of vitamin E, although the possible benefit associated with high intake of vitamin E was not significant. The studies did not suggest any protective effects associated with vitamin C or beta carotene. We conclude that dietary vitamin E may have a neuroprotective effect attenuating the risk of PD. These results require confirmation in randomised controlled trials.
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PMID:Intake of vitamin E, vitamin C, and carotenoids and the risk of Parkinson's disease: a meta-analysis. 1590 40

Parkinson's disease (PD) is the most common cause of parkinsonism. Parkinsonism is characterized by resting tremor, bradykinesia, rigidity and gait impairment. There is no specific diagnostic test for PD and it is important for clinicians to understand the clinical signs which help to distinguish PD from parkinsonism. It is equally important to be aware of the clinical signs which can be an indication that the diagnosis is not PD. These so-called Parkinson-plus syndromes include progressive supranuclear palsy (PSP), multiple systems atrophy (MSA), corticobasal degeneration (CBD), vascular parkinsonism (VP) and parkinsonism with dementia (Lewy body dementia, LBD). The differential diagnosis of parkinsonism will be discussed. Initiating pharmacologic therapy for PD must take into consideration the degree of dysfunction the patient is experiencing, the question of neuroprotection, the degree of motor response required, and the potential complications of long-term treatment. Neuropro-tective trials of coenzyme Q10 (CoQ), vitamin C, vitamin E, monoamine oxidase B inhibitors (MAO-I) and dopamine agonists do not support the use of any of these drugs for a neuroprotective effect. There is recent supportive evidence that levodopa may have a neuroprotective effect. Either dopamine agonists or levodopa may be initiated. Dopamine agonists are associated with fewer motor fluctuations and dyskinesias, while levodopa is associated with better motor performance. Initiation of therapy should be tailored to individual patients with the emphasis on symptom control, with the hope that new approaches to treatment of PD (including neuroprotection) will be forthcoming.
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PMID:Parkinson's disease. Diagnosis and the initiation of therapy. 1617 58

Many agents are being considered for treatment of Parkinson disease (PD). Given the large number of agents and the limited resources to evaluate new agents, it is essential to reduce the likelihood of advancing ineffective agents into large, long-term Phase III trials. Futility design methodology addresses this goal. The authors describe how a single-arm Phase II futility study uses a short-term outcome to compare a treatment group response to a predetermined hypothesized or historically based control response. The authors present advantages and limitations of futility designs along with examples derived from the data archive of a large Phase III efficacy study of treatments to delay PD progression, the Deprenyl And Tocopherol Antioxidative Therapy Of Parkinsonism (DATATOP) trial. Using the same control progression rate and treatment effect assumptions used to power the original DATATOP trial, the authors calculated the number of subjects needed to conduct two 12-month futility studies. DATATOP was designed to enroll 800 patients. Using data on 124 consecutive subjects randomized into each of the DATATOP treatment groups, the authors identified tocopherol as futile and deprenyl as worthy of further study. Using Phase II information, DATATOP could have been simplified from a 2 x 2 factorial design to a comparison of deprenyl vs placebo. While not testing efficacy, futility designs provide a strategy for discarding treatments unlikely to be effective in Phase III. A limitation is the dependence on historical data or hypothesized outcomes for untreated controls. Futility studies may decrease the time to identify treatments unworthy of further pursuit and reduce subjects' exposure to futile treatments.
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PMID:Optimizing the ongoing search for new treatments for Parkinson disease: using futility designs. 1653 98

Free radicals are reactive compounds that are naturally produced in the human body. They can exert positive effects (e.g. on the immune system) or negative effects (e.g. lipids, proteins or DNA oxidation). To limit these harmful effects, an organism requires complex protection - the antioxidant system. This system consists of antioxidant enzymes (catalase, glutathione peroxidase, superoxide dismutase) and non-enzymatic antioxidants (e.g. vitamin E [tocopherol], vitamin A [retinol], vitamin C [ascorbic acid], glutathione and uric acid). An imbalance between free radical production and antioxidant defence leads to an oxidative stress state, which may be involved in aging processes and even in some pathology (e.g. cancer and Parkinson's disease). Physical exercise also increases oxidative stress and causes disruptions of the homeostasis. Training can have positive or negative effects on oxidative stress depending on training load, training specificity and the basal level of training. Moreover, oxidative stress seems to be involved in muscular fatigue and may lead to overtraining.
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PMID:Oxidative stress : relationship with exercise and training. 1657 58

The use of nutritional supplements has almost doubled in the elderly population in the United States (US) in the past decade. We evaluated the use of nutritional supplements in Parkinson's disease (PD) patients to determine the prevalence of their use and whether patients were aware of possible side effects and drug interactions in the supplements they were taking. Consecutively selected PD patients from an academic movement disorders center completed a 33-item questionnaire regarding their use of nutritional supplements. A total of 120 PD patients completed the questionnaire and were included in the data analysis (mean age +/- SD = 68.2 +/- 11.65 years, 67 [55.8%] men and 53 women). Seventy-six patients (63%) took nutritional supplements at the time of data collection. Vitamins were the most common nutritional supplements used, and vitamin E was the most commonly used vitamin. Thirty-six patients (47%) who took nutritional supplements consulted with their doctor before taking them, and only 4% of patients who took nutritional supplements were aware of possible side effects from their use. Twenty patients (16.7%) reported that they were currently taking nutritional supplements because of symptoms related to their Parkinson's disease. The vast majority of PD patients surveyed were not aware that nutritional supplements could cause adverse side effects. Less than half of the patients who took nutritional supplements consulted their physician before starting them. Greater awareness of nutritional supplement use in PD patients is warranted to avoid potentially harmful effects and drug interactions.
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PMID:Use of nutritional supplements in Parkinson's disease patients. 1705 46

Oxidative stress is involved in the degeneration of the nigrostriatal dopaminergic system in Parkinson's disease (PD). Vitamin E (alpha-tocopherol) is a potent antioxidant in the cell membrane that can trap free radicals and prohibit lipid peroxidation. The retention and secretion of vitamin E are regulated by alpha-tocopherol transfer protein (TTP) in the brain and liver. Dysfunction of TTP results in systemic deficiency of vitamin E in humans and mice, and increased oxidative stress in mouse brain. In this study, we investigated the effect of vitamin E deficiency in PD development by generating an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD using TTP knockout (TTP-/-) mice. Vitamin E concentration in the brains of TTP+/- mice was half that in TTP+/+ mice, and in TTP-/- mice, was undetectable. MPTP treatment tended to decrease striatal dopamine, but the effect was comparable and not significant in any of the three genotypes. Furthermore, the extent of loss of dopaminergic cell bodies in the substantia nigra did not differ among the groups. One the other hand, oral administration of vitamin E resulted in the partial protection of striatal dopaminergic terminals against MPTP toxicity. Our results suggest that vitamin E does not play a major protective role in MPTP-induced nigrostriatal dopaminergic neurodegeneration in the brain.
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PMID:Genetic vitamin E deficiency does not affect MPTP susceptibility in the mouse brain. 1678 2

Parkinson's disease (PD) is the most frequent neurodegenerative movement disorder. Mutations in the PINK1 gene are linked to the autosomal recessive early onset familial form of PD. The physiological function of PINK1 and pathological abnormality of PD-associated PINK1 mutants are largely unknown. We here show that inactivation of Drosophila PINK1 (dPINK1) using RNAi results in progressive loss of dopaminergic neurons and in ommatidial degeneration of the compound eye, which is rescued by expression of human PINK1 (hPINK1). Expression of human SOD1 suppresses neurodegeneration induced by dPINK1 inactivation. Moreover, treatment of dPINK1 RNAi flies with the antioxidants SOD and vitamin E significantly inhibits ommatidial degeneration. Thus, dPINK1 plays an essential role in maintaining neuronal survival by preventing neurons from undergoing oxidative stress, thereby suggesting a potential mechanism by which a reduction in PINK1 function leads to PD-associated neurodegeneration.
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PMID:Antioxidants protect PINK1-dependent dopaminergic neurons in Drosophila. 1693 56

Vitamin E is essential for neurological function. This fact, together with a growing body of evidence indicating that neurodegenerative processes are associated with oxidative stress, lead to the convincing idea that several neurological disorders may be prevented and/or cured by the antioxidant properties of vitamin E. In this review, some aspects related to the role of vitamin E against Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and ataxia with vitamin E deficiency will be presented.
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PMID:Vitamin E and neurodegenerative diseases. 1730 57

We report a 53-year-old woman with probable Bassen-Kornzweig syndrome. Her parents were a consanguineous marriage. At two years of age, she developed night blindness. During her childhood she had severe diarrhea that disappeared in adulthood. At 26 years of age, she was diagnosed as having retinitis pigmentosa and her visual acuity became worse thereafter. She noted tremor in the right hand at 37 years of age, gait ataxia at 42, and developed tremor in the bilateral lower extremities at 48. On admission, bilateral visual disturbance, resting and postural tremor, moderately poor coordination, mild distal dominant sensory impairment, an absence of tendon reflex in all four extremities, moderate to severe gait ataxia, and positive Romberg sign were found. Muscle rigidity and akinesia were not observed. Intelligence and muscle power were normal and pathological reflexes were absent. Acanthocytes were found in blood. Serum chemistry showed remarkable decreases in total cholesterol (54 mg/dl, normal 180-220), triglyceride (0 mg/dl, normal 30-150), beta-lipoprotein (3 mg/dl, normal 190-500), apoA-1 protein (66 mg/dl, normal 105-184), apoA-2 protein (11 mg/dl, normal 26-46), apoB protein (0 mg/dl, normal 38-104), apoC-2 protein (1.1 mg/dl, normal 1.2-6.4), vitamin A (297 ng/ml, normal 431-1,041), and vitamin E (0.19 ng/dl, normal 0.75-1.41). While, a marked increase in PIVKA II (703 mAU/ml, normal<40) due to a decrease in vitamin K was found. She was thus diagnosed as having Bassen-Kornzweig syndrome or hypo-betalipoproteinemia. Although brain MRI was normal, single-photon emission CT (SPECT) showed mildly decreased perfusion in the left parietal cortex and right striatum. Motor nerve conduction velocities were normal, but sensory nerve action potentials were not evoked in all four extremities. Surface EMG recorded on the right radial extensor and flexor carpi muscles at rest showed a 4.5 Hz tremor. Vitamin replacement therapy with vitamin A (10,000 IU/day), E (200 mg/day), and K (10 mg/day) was initiated. Several days after treatment, amplitude of resting tremor ameliorated mildly. Clonazepam was administered (0.5 mg/day) for further treatment. After one-month of treatment, vitamin A (656 ng/ml) and E (0.39 mg/dl) levels were elevated and PIVKA II level (29 mAU/ml) decreased. Only a mild right hand tremor remained, but sensory impairment and gait ataxia were not changed. The cause of Bassen-Kornzweig syndrome is a deletion of the microsomal triglyceride transfer protein (MTP) gene. While, familial hypo-betalipoproteinemia, due to a mutation of apolipoprotein B gene, is known to show the same phenotype. Because of the patient's refusal of genetic examination, which disease she has cannot be conclusively determined. Intention tremor was reported in Bassen-Kornzweig syndrome. However, her 4.5 Hz tremor was also present at rest, which resembled resting tremor in Parkinson's disease. Pathophysiology of Bassen-Kornzweig syndrome is known to be due to hypo-vitaminosis. Decreased [18F]-dopa uptake in striatum of patients with long-term hypo-vitamin E has been reported in PET study. Mild hypoperfusion was found in the striatum of the present cases: indicating that her tremor was associated with striatonigral damage. Thus, careful observation of extrapyramidal signs is necessary in abeta- or hypo-betalipoproteinemia.
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PMID:[An adult case of probable Bassen-Kornzweig syndrome, presenting resting tremor]. 1732 79


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