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)

Dopamine is equally well deaminated oxidatively by monoamine oxidase (MAO) A and B types. Selegiline (L-deprenyl), a selective inhibitor of MAO-B, ameliorates the "wearing off" akinesia and delays the need for levodopa in mild, previously untreated Parkinson's disease. The therapeutic potential of selective inhibition of MAO-A in Parkinson's disease has not been examined in detail. MAO-A accounts for only about 20% of total MAO activity in the human basal ganglia, and it differs from MAO-B in distribution. In contrast to MAO-B, which is confined to the extraneuronal compartment, MAO-A is found both extraneuronally and within the presynaptic dopaminergic terminals. The inhibition of MAO-A might alter the intraneuronal handling of dopamine reuptaken from synaptic clefts and thereby prolong oral levodopa benefit. We have given moclobemide, a selective, reversible inhibitor of MAO-A, to nondepressed patients with Parkinson's disease receiving standard levodopa/peripheral decarboxylase inhibitor or levodopa with dopaminergic agonist (bromocriptine, pergolide). Selegiline was discontinued at least 8 weeks earlier. A standard oral levodopa challenge was performed at the patient's entry to the study and repeated on the 22nd day of moclobemide treatment (150 mg thrice daily). The overall time spent "on" and "off" before the onset of treatment and during the last week on the drug was estimated from the patients' diaries. Neuropsychological assessments were also made before and after 3 weeks of moclobemide to measure possible effects on cognitive performance and mood. In acute levodopa challenge, the latency of motor response was significantly shortened and its duration was prolonged during moclobemide treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The therapeutic potential of moclobemide, a reversible selective monoamine oxidase A inhibitor in Parkinson's disease. 759 32

Dopamine-containing neurons of the midbrain are required to control voluntary movements, behavior and motivation. Damage of these neurons in the substantia nigra zona compacta (SNc) is considered as the cause of Parkinson's disease. In this work, the firing characteristics of SNc neurons were studied in vitro. Neurons were identified by intracellular labeling tyrosine hydroxylase (TH) immunocytochemistry, and their electrophysiological characteristics. TH-positive neurons displayed three different firing modes. At around -55 mV neurons exhibited a regular single spike firing mode (pacemaking). At around -65 mV, neurons discharged in an irregular single spike firing mode (idling). At around -75 mV, many neurons exhibited a mode of discharge characterized by low threshold spikes (LTS), oscillations and, on some occasions, bursting. When present, bursts were of short duration and commonly made up of incomplete somatodendritic action potentials. TH-negative neurons also exhibited single spikes and bursting modes of firing. Both types of SNc neurons generated LTS oscillations following a hyperpolarization. However, LTS in TH-negative neurons could be evoked from less negative membrane potentials and produced more prolonged bursts. LTS from both types of neurons could be differentiated. LTS were blocked by 100 microM Ni2+ and became prolonged in the presence of TEA.
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PMID:Firing patterns in substantia nigra compacta identified neurons in vitro. 762 Feb 87

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

Dopamine agonists have been indicated as treatment for disorders such as Parkinson's disease, cardiogenic shock and dopamine insufficiency. A unique relationship exists between dopamine and carcinogenicity. Chronic prolactin stimulation has been identified as a promoter of carcinogenicity. Prolactin secretion is regulated through dopamine receptor activation. Dopaminergic agonists inhibit prolactin release and antagonists increase release. High levels of prolactin have been shown to suppress production of estrogen and progesterone. As a result of these findings, a series of experiments were designed to examine the effects of a specific dopamine agonist, SKF 38393, against MCF-7 cells. MDA-MB231 and MCF-10 cells were used as negative controls. The breast cancer in vitro screening procedure involved the plating of MCF-7, MDA-MB231 and MCF-10 cells in a 96-well plate assay. After 1 day, the cells were exposed to SKF 38393 for 2 days and cell growth was determined by the Alamar blue dye reagent method. The optical density data was analyzed and IC50 values determined. The results indicated that SKF 38393 caused a significant decrease in proliferation of MCF-7 cells. The IC50 value was 0.1 +/- 0.03 microM. The results also indicated no significant effect on MDA-MB231 and MCF-10 cells.
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PMID:The growth inhibitory properties of a dopamine agonist (SKF 38393) on MCF-7 cells. 767 Jan 47

Asymmetries in turning and scanning were investigated in rats with different degrees of neostriatal dopamine depletion after unilateral injections of 6-hydroxydopamine into the substantia nigra. Animals with severe lesions, i.e., residual dopamine levels of < 20%, spontaneously turned ipsiversive and showed more scanning behavior with the side ipsilateral to the lesion. These asymmetries were reversed by the dopamine receptor agonist apomorphine. Animals with less severe dopamine depletion, i.e., residual dopamine levels of 20-65%, did not show an asymmetry in spontaneous turning, but an ipsilateral asymmetry in scanning was still observed, indicating a greater sensitivity of this measure for moderate striatal dopamine depletions. Furthermore, in animals with residual dopamine levels of 45-65%, the dopamine receptor agonist apomorphine did not lead to a behavioral reversal as with severe lesions, but induced ipsilateral scanning and ipsiversive turning. These ipsiversive asymmetries are discussed in relation to asymmetries in self-regulatory mechanisms of the nigro-striatal dopamine system, such as dopamine autoreceptors controlling the release of this transmitter. Dopamine receptor-stimulated behavioral asymmetry in animals with moderate depletions of dopamine is suggested as a preclinical model to study mechanisms affected in the early state of Parkinson's disease.
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PMID:Behavioral indices of moderate nigro-striatal 6-hydroxydopamine lesion: a preclinical Parkinson's model. 768 Apr 95

Dopamine projections to the cerebral cortex have been implicated in normal and pathological cognitive processes, notably, Parkinson's disease and schizophrenia. To help elucidate the function of these dopamine axons, they were characterized by serial section electron microscopy in individual layers of monkey prefrontal cortex. Dopamine immunoreactivity was visualized with a silver precipitation technique that allowed clear resolution of the internal structures and cell membranes of labeled axons. Apart from the occasional large microtubule-filled axon, dopamine axons were thin and varicose with many clear synaptic vesicles and fewer dense-core vesicles. With few exceptions, dopamine synapses were symmetric and quite small, seen in only one to three serial sections. A determination of the "synaptic incidence" showed that only 39% of labeled varicosities formed identifiable synapses. However, it is certain that some small synapses could not be visualized even in serial sections, and it is possible that the vast majority if not all varicosities form synapses. Except for one soma, dendritic spines and shafts were the recipients of dopamine synapses. Many postsynaptic shafts were small and spiny, indicating that they were distal pyramidal dendrites. However, some postsynaptic shafts especially in supragranular layers had distinctly nonpyramidal features. These lacked spines, had a high density of synaptic inputs, and often had a strikingly varicose morphology. The data suggest that the majority of dopamine synapses in all layers are on pyramidal cells, but that a significant fraction are on presumed GABAergic nonpyramidal cells.
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PMID:Heterogeneous targets of dopamine synapses in monkey prefrontal cortex demonstrated by serial section electron microscopy: a laminar analysis using the silver-enhanced diaminobenzidine sulfide (SEDS) immunolabeling technique. 768 95

The occurrence of late side effects of long term levodopa therapy (fluctuations in motor performance, abnormal movements, and symptoms unresponsive to dihydroxyphenylalanine) led to the search for novel anti-Parkinsonian drugs. Dopamine agonists are one of the newer families of anti-Parkinsonian agents, and they include ergot derivatives and apomorphine, which can be used in the different stages of Parkinson's disease. Ergot derivatives (bromocriptine, lisuride, pergolide) are believed to act independently of the dying cells of the substantia nigra, acting instead directly on postsynaptic dopamine receptors in the striatum. They are usually used in combination with levodopa when late side effects occur, especially 'wearing-off' or decreased efficacy of levodopa. They can also be prescribed earlier in combination with levodopa in de novo Parkinsonian patients, and in this setting are thought to delay the occurrence of late adverse motor effects. In some patients, monotherapy with relatively high doses of ergot derivatives can be used as initial treatment. However, their efficacy often decreases after 1 to 3 years, thus justifying a late combination with levodopa. Apomorphine is a non-ergot derivative dopamine agonist, which is used subcutaneously for the treatment of severe 'off' refractory periods, in combination with other dopaminergic drugs without changing the patient's routine drug regimen.
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PMID:Current status of dopamine agonists in Parkinson's disease management. 769 30

The main pathologic hallmark of Parkinson's disease is a degeneration of the dopaminergic cells in the substantia nigra, pars compacta and--to a lesser extent--in the ventral tegmental area. Striatal dopamine concentrations are significantly reduced before clinical symptoms become apparent. Recent neuroanatomic and function studies have revealed that the nigrostriatal dopaminergic projection is only one of the neuronal elements integrated into extensive basal ganglia-thalamocortical circuits that are intimately involved in the regulation of motor activity. The possibilities for therapeutic intervention at the level of the different dopamine receptor subtypes and their effect on the regulation of motor behavior will be briefly reviewed. Dopamine precursors are considered to provide the best symptomatic treatment, whereas dopamine agonists, although less effective, might be important in slowing the progression of the disease. Our results with pergolide as monotherapy and in combination therapy in patients with Parkinson's disease also are discussed.
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PMID:Dopamine agonists in Parkinson's disease. 771 94

Experimental and clinical studies indicate that both dopamine D2-like and D1-like receptors are important in reversing the motor symptoms of Parkinson's disease, and therefore stimulation of both D1 and D2 receptors may be advantageous in its treatment. At present, the role of other receptor subtypes, such as the D3 receptor, remains unknown, although in primates the D3 receptor might be of importance because it exists in significant amounts within the caudate-putamen. Both D1 and D2 agonists induce dyskinesias in drug-naive, MPTP-treated primates and provoke dyskinesias in levodopa-primed animals. D1 agonists in low doses, however, might have antiparkinsonian effects without inducing dyskinesias, and on repeated administration perhaps can diminish the intensity of dyskinesias in levodopa-primed, MPTP-treated primates. The production of dyskinesias in Parkinson's disease might reflect an imbalance in the D1-direct and D2-indirect GABAergic output pathways from the caudate-putamen, which colocalize tachykinins and enkephalins, respectively. Destruction of the nigrostriatal pathway decreases the mRNA for substance P but elevates the mRNA for enkephalin. Treatment with levodopa reverses the decrease in substance P mRNA but has either a partial or no effect on mRNA for enkephalin. This suggests that levodopa treatment leads to a new imbalance between output from the striatum through the direct and indirect pathways. In contrast, dopamine agonists appear less able than levodopa to manipulate basal ganglia outflow. This might reflect their decreased ability to reverse parkinsonian motor deficits or the greater ability of levodopa to provoke dyskinesias. Dopamine agonist drugs also might exert neuroprotective actions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The rationale for the use of dopamine agonists in Parkinson's disease. 771 95

Heavy metals, such as iron and manganese, are involved in neurologic disease. Most often these diseases are associated with abnormal environmental exposures or abnormal accumulations of heavy metals in the body. There is increasing recognition that heavy metals normally present in the body also may play a role in disease pathogenesis through free radical formation. When a part of the brain known as the basal ganglia is affected, movements become disordered. Parkinson's disease is one of the most common movement disorders and is related to destruction of neurons in the substantia nigra pars compacta (SNpc) of the basal ganglia. The combination of high concentration of iron and the neurotransmitter, dopamine, may contribute to the selective vulnerability of the SNpc. Dopamine can auto-oxidize to produce free radicals particularly in the presence of iron and other heavy metals.
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PMID:Heavy metals and the etiology of Parkinson's disease and other movement disorders. 771 90


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