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)

Exposure of mouse thymocytes to dopamine caused apoptosis (programmed cell death). This was manifested by cellular condensation and membrane damage shown by flow cytometry measurements and scanning electron microscopic study. Dopamine also affected thymocytic nuclei and their genomic DNA integrity. Most of the DNA molecules accumulated in a subdiploid peak in flow cytometry analysis, indicating DNA fragmentation to small particles. DNA analysis showed the typical pattern of 'DNA ladder' caused by internucleosomal DNA cleavage. X-ray microanalysis of the cellular elements of dopamine-treated cells showed elevation of sodium (Na), chloride (Cl) and calcium (Ca) peaks, accompanied by reduction in phosphate (P) concentrations. Comparison of the potassium (K) and P concentrations showed significant differences between the two major death processes: necrosis (induced by exposure to sodium azide (NaN3)) and apoptosis (induced by dopamine). High concentrations of K indicated cell viability while reductions in P and elevations in Ca levels were found to be typical of apoptotic cell death. The antioxidant dithiothreitol (DTT) suppressed dopamine-induced apoptosis in thymocytes, suggesting that its toxicity may be mediated via generation of reactive oxygen radicals. Our study suggests that under certain circumstances, dopamine and/or its metabolites, may induce a process of apoptotic cell death of the dopamine-producing cells in the substantia nigra. Increased accessibility of dopamine to the nigral cell nucleus or inability to scavenge excess free radicals generated from dopamine oxidation triggering programmed cell death, may cause the progressive nigral degeneration in Parkinson's disease.
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PMID:Dopamine-induced programmed cell death in mouse thymocytes. 766 5

Reactive oxygen species (ROS), including hydrogen peroxide, are supposed to be involved in the degeneration of dopaminergic neurons in Parkinson's disease. The potential role of astrocytes against neurotoxic effects of ROS was studied in cocultures of rat mesencephalic neurons and rat striatal or cortical astrocytes. Neuronal [3H]dopamine uptake, a marker of dopaminergic neuron integrity, was enhanced by striatal astrocytes, but not by cortical astrocytes, compared to uptake in mesencephalic neurons cultured alone. Whereas hydrogen peroxide at concentrations up to 100 microM reduced the [3H]dopamine uptake in neuronal cultures, no reduction of the uptake was observed in cocultures, regardless of the origin of the supporting astrocytes. These results suggest that astrocyte mediated protection of neurons against hydrogen peroxide induced toxicity is not directly related to a region-specific neurotrophic effect.
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PMID:Cultured rat striatal and cortical astrocytes protect mesencephalic dopaminergic neurons against hydrogen peroxide toxicity independent of their effect on neuronal development. 767 99

Manganese is an essential trace element for human metabolism, but at higher concentrations it is a potent neurotoxin that presents clinical symptoms similar to those of Parkinson's disease. Since the toxicity of manganese may be related to its ability to accelerate the oxidation of catecholamines, we have examined the effect of aqueous Mn2+ on the formation and decay of the dopamine semiquinone radical ion. ESR spectroscopy was used to measure the kinetics of the disappearance of the semiquinone radical spectrum and the simultaneous appearance of the six-line spectrum of aqueous Mn2+ in Tris buffer. From the proposed mechanism for the autoxidation of dopamine to the quinone, the rate expression for semiquinone radical disappearance has the functional form -rate = k'[D(OH)2][Mn2+] at constant pH and molecular oxygen concentration, while the pH dependence is given by -log(rate) = log(constant) + (2 x pH), in agreement with the experimental results. The autoxidation of dopamine is catalyzed by manganese through the formation of a highly reactive complex. The effect of manganese is due to the fact that it can participate in a redox cycle which involves intramolecular electron transfer between manganese and the dopamine ligand.
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PMID:Mechanism of the manganese-catalyzed autoxidation of dopamine. 770 54

Oxidative stress has been linked to the destruction of dopaminergic neurons in the substantia nigra and may be a significant factor in both Parkinson's disease and MPTP toxicity. Using primary cultures of embryonic rat mesencephalon and standard immunocytochemical techniques, we have examined the survival of tyrosine hydroxylase-containing (TH+) neurons cultured in the presence of antioxidants and/or in an environment of low oxygen partial pressure. The number of TH+ neurons increased approximately twofold if superoxide dismutase, glutathione peroxidase (GP), or N-acetyl cysteine (NAC) were added to the culture media. Exposure of the neurons to a 5% oxygen environment (38 torr, i.e., 38 mm Hg) also increased the survival of TH+ neurons by about twofold. A dramatic enhancement of survival, however, was seen when NAC was used in combination with the 5% oxygen environment. In this case, the number of TH+ neurons increased fourfold from nontreated controls. Morphological changes were also noted. GP increased the average neurite length while NAC increased the average area of the cell body in the TH+ neuron. These results suggest that manipulation of oxidative conditions by changing the ambient O2 tension or the level of antioxidants promotes survival of TH+ neurons in culture and may have implications for transplantation therapies in Parkinson's disease.
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PMID:Protection from oxidation enhances the survival of cultured mesencephalic neurons. 772 Aug 26

Oxidative stress and subsequent energy crisis have been proposed as the cause of nigral neuronal cell death in Parkinson's disease. We have reported defects in the mitochondrial respiratory chain and increased amount of deleted mitochondrial genome in the nigrostriatal system of patients with Parkinson's disease. Deletion in mitochondrial DNA could be ascribed to somatically acquired premature aging leading to cell death. To elucidate the contribution of maternally transmitted point mutations in mitochondrial DNA to the premature DNA damages, we employed a direct sequencing system and analyzed the total nucleotide sequences of mitochondrial DNA in the brains of five patients with idiopathic Parkinson's disease. There were no predominant point mutations among the patients in contrast to some neuromuscular diseases. However, each patient had several point mutations that would result in a significant change in the gene products. Some of these mutations may be involved either in the increased production of oxygen radicals from the mitochondrial respiratory chain or in the increased susceptibility of the respiratory chain components to oxidative damage. We propose that some of these mutations can be regarded as one of the risk factors accelerating degeneration of nigrostriatal pathway in Parkinson's disease.
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PMID:Point mutations of mitochondrial genome in Parkinson's disease. 772 27

Regional cerebral blood flow (rCBF) was measured using the stable xenon enhanced CT method in previously untreated 13 patients with Parkinson's disease to evaluate CBF abnormality related to dysfunction of the nigrostriatal dopaminergic neurons. The patients comprised 5 men, 8 women with Hoehn-Yahr stage II-III. Age at onset ranged from 51 to 73 years (mean +/- SD, 61.8 +/- 8.9) and the duration of illness ranged from 1 to 96 months (15.1 +/- 24.1 months). In this series, there was no clinical evidence of hypertension, diabetes mellitus and cognitive impairment. rCBF was measured during 4-5-minutes inhalation of 33% stable xenon gas-67% oxygen. The first measurement of rCBF was performed in all of the patients before L-dopa treatment. After initiation of L-dopa treatment (333.3 +/- 47.1 mg/day), the second measurement was carried out in 6 patients (1 man and 5 women) who had shown symptomatic improvement. The interval between both measurements was 57.7 +/- 16.9 days. The following results were obtained. 1) No significant CBF asymmetry was noted in any of the striatum, pallidum, thalamus, cerebrum, cerebellum and frontal lobe in untreated patients with Parkinson's disease. 2) After L-dopa treatment, rCBF was significantly increased only in the striatum as compared with the pretreatment level (51.9 +/- 9.3-->63.1 +/- 9.9 ml/100 g/min, p < 0.01). 3) This increase was significantly greater on the more severely affected side (contralateral to the predominantly symptomatic limb) (p < 0.05). These results suggest that the increase of rCBF in the striatum is closely related to functional improvement of the nigrostriatal dopaminergic neurons.
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PMID:[The effects of dopamine on regional cerebral blood flow in patients with Parkinson's disease before and after L-dopa--measurement by Xe-enhanced CT]. 772 88

Acetylcholinesterase has an action in the central nervous system, independent of hydrolysis of acetylcholine. This study explored the possible interaction between the two molecules: the effects of acetylcholinesterase on the autoxidation of the catecholamine were tested, and, in turn, modification of the catalytic activity of the enzyme by products of dopamine oxidation were studied. Acetylcholinesterase selectively inhibited the speed of quinone production from dopamine as well as accumulation of hydrogen peroxide, whilst the rate of generation of superoxide was increased. Analysis of absorption spectra revealed the formation of a new product, which appeared after mixing acetylcholinesterase and dopamine in neutral pH. In all cases, butyrylcholinesterase was ineffective. Incubation of acetylcholinesterase in the presence of dopamine resulted in a significant decrease in the catalytic activity of the enzyme. The effects of application of preparations modifying autoxidation of dopamine (SOD, catalase, peroxidase) suggested that inactivation of the enzyme occurred as a result of the direct interaction of a quinone and/or semiquinone oxidation product with enzyme, as opposed to any effects of reactive oxygen species. Because acetylcholinesterase and dopamine are co-released from the neurons degenerating in Parkinson's disease, a direct chemical interaction between these two molecules could have significance both for the normal functioning of the substantia nigra and for related pathological states.
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PMID:A possible interaction between acetylcholinesterase and dopamine molecules during autoxidation of the amine. 774 5

Membrane lipid peroxidation has been suggested to participate in the nigral degeneration of Parkinson's disease. In the present study, we demonstrate that bromocriptine inhibits lipid peroxidation in phospholipid liposomes induced by dopa and iron complexes. Because this lipid peroxidation is not mediated by active oxygen species, antioxidant properties of bromocriptine do not seem to be derived from radical scavenging effects in our experimental conditions. Bromocriptine had no scavenging effect on superoxide produced by hypoxanthine-xanthine oxidase when determined by the chemiluminescence assay using MCLA, a Cypridina luciferin analog, as a probe.
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PMID:Inhibitory effects of bromocriptine on phospholipid peroxidation induced by dopa and iron. 774 68

Parkinson's disease, a classic human degenerative disease, is one of the commonest neurological disorders. Although this movement disorder had been defined a century and a half ago, its aetiology remains unknown. Some environmental factors are suspected to play a key role in induction of slow progressive loss of nigral dopaminergic neurons. Nerve cell death seems to be produced via cytotoxic oxygen radicals which are accumulated in the pars compacta of the substantia nigra. The major biochemical abnormality in parkinsonism is a decrease in the dopamine synthesis although other neurotransmitters are affected too. Several animal models of Parkinson's disease have been introduced to study mechanisms of selective degeneration of the substantia nigra and to assess effectiveness of various therapeutic approaches. Present pharmacological treatment, directed toward replacement of missing dopamine, uses high-dosage of levodopa. However, this therapy helps the symptoms but do not halt the disease. Doses of levodopa have to be increased as symptoms increase in severity, which is associated with severe side effects. Neural transplantation of catecholamine-producing cells seems to be a new promising tool for treatment of Parkinson's disease. Grafts of adrenal medulla, carotid body, pheochromocytoma, sympathetic ganglion and embryonic dopaminergic cells, either in a form of solid pieces or cell suspension, were inoculated into the experimentally denervated striatum of rats and subhuman primates. At present, more than 300 parkinsonian patients have received autologous adrenal medulla or human embryonic nigral grafts but results are still controversial. Attempts for transplantation treatment retreated to the laboratories and researchers are currently seeking to select the best king of cells capable of producing dopamine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Parkinson's disease: contemporary state and perspectives. 776 92

Neurodegenerative diseases, e.g. dementia of Alzheimer type and Parkinson's disease, are characterized neurochemically by a transmitter-specific loss of neurons, which progresses and extends to several neuronal systems over the course of the disease. At present, no single specific pathomechanism may explain the heterogeneous disorder of familial and sporadic dementia of Alzheimer type, both with early and late onset of the disease. The hypothesis has been proposed that cellular events involving "oxidative stress" may be one basic pathway leading to neurodegeneration in e.g. dementia of Alzheimer type and Parkinson's disease. There are indications for an increased activity or impaired defense mechanisms of free oxygen radicals in dementia of Alzheimer type, although less clear than in Parkinson's disease. Primary and secondary factors interact and may result in a self-propagating cascade of neurodegenerative events. Since these mechanisms of neuronal death involve different areas of cell metabolism, therapeutic strategies for "neuroprotection" also have to encompass different approaches. Since a specificity of oxygen radical toxicity in dementia of Alzheimer type has not been proven, "partial" neuroprotective drugs might be more beneficial in clinical practice than specific drugs affecting only one selective pathomechanism.
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PMID:Free radical mechanisms in dementia of Alzheimer type and the potential for antioxidative treatment. 776 42


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