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)

The neurotransmitter dopamine has biological attributes that make it amenable to study by positron emission tomography, unlike many of the 40 or so neurotransmitters that have been identified in the brain. Dopamine deficiency in the nigrostriatal system is a characteristic of Parkinson's disease, and a disturbance of dopamine metabolism is still widely held to be responsible for the syndrome of schizophrenia. Despite its importance in the regulation of locomotion and mood, it has been impossible to visualize the intracerebral distribution of dopamine and measure its regional metabolism in man. In the first demonstration of the regional distribution of a neurotransmitter in the brain of conscious normal man, we show here that L-3,4-dihydroxyphenylalanine (L-dopa) labelled in the 6-position with the positron-emitting radionuclide fluorine-18, localizes specifically in the dopaminergic pathways of the human brain where its turnover could be measured atraumatically by positron emission tomography.
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PMID:Dopamine visualized in the basal ganglia of living man. 660 27

Dopamine is predominantly oxidized by a (-)-deprenyl sensitive form of MAO in the human striatum, and (-)-deprenyl, acting at some suitably low selective inhibitory concentration may, therefore, be of benefit in Parkinson's disease. 10(-6)M was the most effective (-)-deprenyl concentration in vitro for discriminating between the inhibition of MAO A and B. The correlation between the A/B ratio present in different human brain regions and the sensitivity of dopamine oxidation to 10(-6)M deprenyl was 0.84 (p<0.001). This suggests that all dopamine oxidation can be accounted for by the joint contribution of MAO A and B and that it is unnecessary to postulate a special form of the enzyme which metabolizes dopamine. In the brain, the striatum has the highest proportion of MAO B, and in several cortical regions, relatively more dopamine is oxidized by MAO A. In other human tissues also the deprenyl sensitivity of dopamine oxidation correlated with the known A/B ratio, the placenta, lung and jejeunum having the lowest sensitivity and being the richest in MAO A. Km values for dopamine for MAO A and B are similar, 130 and 140 uM respectively, so that the proportion oxidized by the two forms should not vary with substrate concentration.
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PMID:Dopamine oxidation and its inhibition by (-)-deprenyl in man. 677 35

Dopamine beta hydroxylase (DBH), The noradrenaline-synthesizing enzyme, and phenyl-ethanolamine-N-methyltransferase (PNMT), the adrenaline-synthesizing enzyme, were assayed in 18 areas of brain stem in eight cases of parkinsonian syndromes and of four age- and postmortem delay-matched controls. Dissection was performed by the "punch" technique and enzyme activities assayed by radiometric methods. No significant change was found for PNMT activity. DBH activity was significantly increased in the A2-C2 area of the medulla oblongata (including the nucleus tractus solitarius) in the cases of Parkinson's disease. The A2-C2 area is known to be implicated in the control of blood pressure in rats. These findings are discussed in relation to orthostatic hypotension and the influence of L-dopa therapy.
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PMID:Increase in noradrenaline-synthesizing enzyme activity in medulla oblongata in Parkinson's disease. 680 13

Receptor binding studies with a variety of dopaminergic ligands have confirmed behavioral and biochemical findings that the central nervous system and peripheral nervous system contain several dopamine receptor subtypes. These subtypes can be discriminated on the basis of their agonist-antagonist pharmacological specificities, linkage to adenylate cyclase, cellular location, regulation by guanine neucleotides and ions, and involvement in several human diseases. Although questions remain unanswered, progress is rapidly being made in equating the subgroupings arrived at by these different experimental approaches. Dopamine receptors are regulated by a number of factors. Acutely, guanine nucleotides and some ions regulate agonist but not antagonist binding and are essential for receptor coupling with adenylate cyclase. Chronically, changes in the level of dopaminergic stimulation modulate the number of at least some receptor subtypes, resulting in "up or down regulation." An increase in receptor number appears central to the pathology of Parkinson's disease, tardive dyskinesia, and perhaps schizophrenia. Animal models indicate that it may be possible to exploit inherent capabilities for receptor modulation in clinical therapy. The therapeutic precedents set by the indentification of distinct subtypes of adrenoreceptors. histamine, and cholinergic receptors portends and exciting future for dopamine receptor research.
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PMID:Dopamine receptors: subtypes, localization and regulation. 700 83

Dopamine (DA) is an important neurotransmitter or neuromodulator in the mammalian nervous system. As such, it is implicated in the aetiology and therapy of various disease conditions--for example, Parkinson's disease, schizophrenia, Huntington's disease and tardive dyskinesia. However, only limited electrophysiological information is presently available concerning dopamine receptors in the mammalian nervous system, and there are only three reports in which intracellular techniques have successfully recorded the action of DA on individual central neurones. In all cases, DA depolarised the respective neurones. In the periphery, DA is reported to hyperpolarise superior cervical ganglia. However, this hyperpolarisation has been shown to be due to activation of alpha-adrenoreceptors and not to a response of DA on a DA receptor. Peripheral DA actions have also been described presynaptically, but are difficult to study electrophysiologically for technical reasons. As a result, little is known at the membrane level about the effects of drugs thought to modulate or interact with DA receptors. In the present report, we describe a depolarising action for DA on the cat dorsal root ganglion.
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PMID:Dopamine depolarisation of mammalian primary afferent neurones. 735 66

Neuroprotective therapy for Parkinson's disease (PD) is a treatment intended to prevent or reduce neuronal degeneration. Since clinical studies to evaluate such an effect would be prolonged, the choice of agents for use as possible neuroprotective therapy is based on the results of in vitro and animal experiments. Free radicals are currently regarded as the most important factor in the progression of PD. One current possible neuroprotective therapy is reduction of levodopa dose, since levodopa is a source of free radical formation. Dopamine (DA) metabolism inhibition, and administration of the DA agonist bromocriptine that eliminates hydroxyl free radicals have neuroprotective effects experimentally. The other candidates for neuroprotective agents are still under development. However, those whose clinical use is permitted should be considered for use, since patients with long-standing PD cannot wait until the neuroprotective efficacy of these agents is confirmed by clinical study.
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PMID:Possible neuroprotective therapy for Parkinson's disease. 750 77

Evoked potential studies have confirmed visual pathway impairment in Parkinson's disease. Dopamine is also known to be involved in retinal color vision mechanisms. In this study, pattern evoked potentials were recorded in 20 parkinsonian patients in "on" and "off" conditions to compare the sensitivity of black-and-white and color pattern stimuli. Evoked responses to colored patterns proved more sensitive to L-DOPA therapy. This finding supports the proposed dopamine modulation of the retinal color system and suggests that color pattern evoked potential studies might be used in monitoring dopamine therapy in parkinsonian patients.
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PMID:Color VEPs in Parkinson's disease. 751 14

Dopamine antibodies (DAb) were found in the blood serum of parkinsonian patients, middle-aged and elderly, but not young. There was a correlation between the DAb incidence and dominant symptom in the middle-aged and elderly patients and between DAb and anginal parkinsonism in the elderly patients. DAb-binding serum gamma-globulins of parkinsonian patients injected into rat caudate nuclei induced the pathogenetic mechanism of Parkinson's syndrome (the generator of pathologically enhanced excitation-GPEE) in this brain part and evoked main parkinsonian symptoms (oligokinesia, rigidity and tremor). This effect was more expressed in the elderly rats compared with the young animals. The DAb role in the Parkinson's syndrome pathogenesis and in L-DOPA therapeutic tolerance formation is discussed.
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PMID:[Dopamine antibodies in parkinsonism patients and their possible role in the pathogenesis of the parkinsonian syndrome]. 751 81

Neurotransmitter receptors and neurotransmitter transporters were studied postmortem in the brains of 9 PSP patients by receptor autoradiography. Densities of dopamine uptake sites and neurotensin receptors were significantly reduced in striatum and substantia nigra consistent with a localization of these binding sites on degenerating dopaminergic nigrostriatal projection neurons. The densities of dopamine D1 receptors were unchanged. Dopamine D2 receptors were unaltered when labeled by [125I]-Iodosulpride or [3H]-CV 205 502, but appeared to be significantly reduced when labeled by [3H]-spiperone. Levels of D2 mRNA were comparable to control levels, suggesting that only subtypes of Dopamine D2-like receptors may be affected in PSP. Serotonin (5-HT) uptake sites and 5-HT receptors were not altered. The density of muscarinic receptors was reduced in striatum, possibly related to a degeneration of cholinergic striatal interneurons, but increased in internal globus pallidus. GABAA/BZ receptor binding sites were significantly reduced in both segments of globus pallidus, probably as a consequence of severe degeneration of intrinsic pallidal neurons in PSP. Binding of substance P in striatum tended to be decreased but failed to reach statistical significance. Compared to Parkinson's disease, the densities of more neurotransmitter receptors were altered in PSP. With the exception of increased muscarinic receptor binding sites in medial globus pallidus, the alterations seen in PSP seem to reflect cell loss rather than functional changes.
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PMID:Alterations of neurotransmitter receptors and neurotransmitter transporters in progressive supranuclear palsy. 752 68

Recent reports have stressed an accumulation of iron and enhanced levels of lipid peroxides in the substantia nigra as essential factors in the pathogenesis of Parkinson's disease. Many investigators believe that tissue antioxidants, such as ascorbate, play a protective role. On the other hand, L-DOPA, which is used extensively to treat Parkinson's disease, undergoes autoxidation (as does dopamine), thus generating reactive oxygen species. We studied lipid peroxidation (LPO) in mouse brain homogenates and evaluated the effects of iron (5 microM ferric-ADP), L-DOPA, dopamine and ascorbic acid, added either alone or in mixtures. Ascorbic acid was used at levels of 0.5 mM or 2.0 mM, approximating those present normally in brain. LPO in brain homogenates was stimulated by the addition of either ascorbic acid or iron, as well as by a combination of the two, in agreement with other reports. The effects of L-DOPA were complex: L-DOPA strongly suppressed LPO both with and without added iron-ADP. In sharp contrast, however, when ascorbic acid was also added, L-DOPA no longer suppressed LPO; indeed, L-DOPA stimulated LPO in the presence of added iron and ascorbic acid. Dopamine behaved similarly to L-DOPA. When ascorbic acid was studied over a concentration range, LPO was stimulated at 0.5, 1, 2 or 3 mM, with or without added iron and/or dopamine; 5 and 10 mM ascorbic acid were either not as effective or suppressed LPO below control levels. Deferoxamine, a powerful iron chelator, greatly suppressed LPO under all conditions, as did diethylenetriaminepentaacetate (DTPA). Added superoxide dismutase had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Lipid peroxidation in brain: interactions of L-DOPA/dopamine with ascorbate and iron. 758 78


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