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 investigated the anatomic localization of dopamine D1 and D2 receptors in the human brain using selective high affinity ligands for both types of dopamine receptors and the technique of receptor autoradiography. Dopamine D1 receptors were labeled in postmortem human brain tissue sections using the antagonist [3H]SCH 23390. Dopamine D2 receptors were labeled in consecutive tissue sections using the agonist [3H]205-502 and the antagonist [3H]spiroperidol. D1 and D2 dopamine receptors presented a heterogeneous distribution in the human brain. The highest concentrations of both D1 and D2 receptors were found in parts of the basal ganglia, particularly the nucleus caudatus and putamen. Lower concentrations were seen in other areas for example, the lateral globus pallidus was enriched in D2 receptors and the medial globus pallidus in D1 receptors. The substantia nigra contained intermediate densities of both D1 and D2, D1 receptors being present in higher concentrations. Dopamine D1 receptors were also localized in areas outside of the basal ganglia, particularly in the neocortex, amygdala and hippocampal formation. Dopamine D2 receptors were also present in areas outside of the basal ganglia, the most significant densities being found in the hippocampal formation. We observed a marked age-dependent decline in the density of D1 receptors during the first decades of life. In contrast, D2 receptor concentrations appeared to be unaltered with age. The distribution and densities of dopamine receptors were examined in 12 cases of Parkinson's disease and compared to a control adult population. No significant differences in density and distribution were seen for either D1 nor D2 receptors.
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PMID:Mapping dopamine receptors in the human brain. 296 52

In 9 patients with progressive supranuclear palsy and in 27 controls, dopamine and homovanillic acid concentrations, choline acetyltransferase (CAT) activity, and the number of [3H]spiperone and [3H]quinuclidinyl benzilate binding sites were measured post mortem in the striatum (caudate nucleus, putamen, and nucleus accumbens), substantia innominata, and frontal cortex. Dopamine and homovanillic acid concentrations were reduced in the caudate nucleus and putamen but not in the nucleus accumbens or frontal cortex, indicating that the nigrostriatal dopaminergic system is lesioned in patients with progressive supranuclear palsy (as in those with Parkinson's disease) but not the mesocortical and mesolimbic dopaminergic systems, which are lesioned in parkinsonian patients. CAT activity and [3H]spiperone binding decreased in parallel fashion in all the structures. In the striatum, this suggests that the cholinergic neurons, which are target cells of the nigrostriatal system, also degenerate in this disease. This might explain the decrease in the number of dopamine receptors as well as the inefficacy of levodopa or anticholinergic therapy in these patients. The decrease in CAT activity in the substantia innominata and the frontal cortex indicates that the innominatocortical cholinergic system is lesioned in patients with progressive supranuclear palsy and may play a role in the intellectual deterioration observed. This lesion is also found in demented patients with Alzheimer's and Parkinson's diseases.
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PMID:Dopaminergic and cholinergic lesions in progressive supranuclear palsy. 300 Feb 80

The Parkinson-syndrome is the most important syndrome under the extrapyramidal disease. The therapy with L-DOPA has a prominent place in the therapy of Parkinson disease since the introduction of oral effective drugs. Dopamin has an effect to the basalganglia as a neurotransmitter and perhaps an inhibition effect to specific synapses of brain. The inhibition or the optimal balance of the cholinergic systems is the effect of Dopamin and Noradrenalin. The therapy with low dosis of L-DOPA in combination with a decarboxylase-inhibitor will be prevent the side-effects of nerv-cells.
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PMID:[Thoughts on the neurobiological aspects of Parkinson syndrome]. 301 Mar 57

VEPs were recorded with three different spatial frequencies of stimulation in patients affected by idiopathic Parkinsonism and by Parkinsonian syndromes. The detection of VEP abnormalities in Parkinson's disease was dependent on the spatial frequency of the visual stimulus (a vertical square wave grating). The VEP latency was normal in Parkinsonian syndrome patients (except in one patient affected by familial Parkinsonism). Dopamine precursor therapy differently reduced the VEP latency, depending on the spatial frequency of the visual stimulus. These findings suggest that the dopaminergic mechanism involved in the generation of VEP delays is sensitive to stimulus spatial frequency. The study of VEPs before and after the administration of haloperidol confirmed this hypothesis. VEP latency did not correlate with the major clinical symptoms of Parkinson's disease and could not predict the results of chronic dopaminergic therapy.
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PMID:Visual evoked potentials in parkinsonism and dopamine blockade reveal a stimulus-dependent dopamine function in humans. 302 51

In experimental Parkinson's disease, we studied the effects of chronic administration (30 days), withdrawal, and reinstitution of bromocriptine. Dopamine (DA) receptor supersensitivity was produced by 6-hydroxydopamine and reversed by chronic bromocriptine administration. Drug holiday reestablished sensitivity of DA receptors, but reinstitution of bromocriptine again downregulated receptors. The effects of a drug holiday on DA receptors are short-lived, and long-term clinical improvement cannot be expected. Apomorphine-induced contralateral turning produced by the lesion was unaffected by any drug regimen.
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PMID:Bromocriptine holiday: effects on dopamine receptors and turning behavior in rats. 308 31

Dopamine-denervated rat striata exhibit increased synaptosomal gamma-aminobutyric acid (GABA) synthetic capacity (glutamate decarboxylase activity) without an alteration in GABA transport capacity. Stimulating denervated striatal dopamine receptors with apomorphine selectively increases in vivo steady-state striatal GABA turnover. The striatal response in animals to isolated loss of dopamine innervation is an increase in glutamate decarboxylase activity, not the decrease frequently found in the brains of patients with Parkinson's disease. Neurochemical expression of denervated striatal dopamine receptor stimulation may involve increased synaptic activity of striatal GABA neurons. For these reasons, enhancement of basal ganglia GABA function may improve responsiveness to dopamimetic therapies in patients with Parkinson's disease.
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PMID:Striatal dopamine depletion, dopamine receptor stimulation, and GABA metabolism: implications for the therapy of Parkinson's disease. 308 62

We studied the effect of intracerebroventricular infusion of dopamine and dopamine agonists in animal models of dopamine deficiency as an experimental approach to the treatment of levodopa induced fluctuations in Parkinson's disease. Dopamine deficiency was produced in rats by unilateral lesion of the nigrostriatal pathway or by chronic treatment with reserpine. Monkeys were lesioned by intravenous injection of MPTP. The animals were treated with intracerebral infusions of dopamine (with or without associated intraperitoneal administration or intracerebroventricular infusion of pargyline), lisuride and pergolide. The intracerebroventricular infusion of these drugs was performed with osmotic minipumps in rats and with infusaid pumps in the monkeys. The infusion of dopamine or dopamine agonists in rats with unilateral lesions by 6-OH-dopamine produced a persistent rotation contralateral to the lesioned and implanted side. The infusion of dopamine reversed reserpine-induced akinesia only when pargyline was associated. In the range of concentration used, maximum allowed by solubility of compounds, the effects of dopamine were more potent than those of the agonists. In spite of the stability of dopamine "in vitro" when dissolved in antioxidants and at low pH, a pigment, product of autooxidation, was found in the brains of the animals infused with dopamine. The monkeys were implanted with infusaid pumps and infused for up to 3 weeks. The pump was not well tolerated due to its huge size for the animals. One monkey showed reversal of the MPTP-induced akinesia while the other, whose catheter had moved from the correct implantation site, remained unchanged. In both monkeys there was evidence of autooxidation of dopamine. Intracerebral infusion of dopamine agonists may be a possible experimental alternative to the treatment of levodopa induced fluctuations in Parkinson's disease but stable and soluble dopamine agonists and suitable delivery systems are needed.
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PMID:Continuous intracerebroventricular infusion of dopamine and dopamine agonists through a totally implanted drug delivery system in animal models of Parkinson's disease. 316 32

In the past decade, dopamine agonists have emerged as important treatment options for patients with Parkinson's disease. Originally, dopamine agonists were used only in patients with advanced disease in whom the response to levodopa had decreased (levodopa failures). The decreased response to levodopa, usually associated with diurnal oscillations in performance and the 'wearing-off' and 'on-off' phenomena, is secondary to disease progression with continued degeneration of the nigrostriatal neurons. In addition, chronic levodopa treatment itself may contribute to the decreased drug response and the diurnal oscillations in performance. Dopamine receptor agonists bypass the degenerating nigrostriatal neurons and directly stimulate the striatal dopamine receptors. Dopamine receptor agonists also permit a reduction in the dose of levodopa. Five ergoline dopamine agonists--bromocriptine, lergotrile, pergolide, lisuride, mesulergine, and the nonergoline agonist, ciladopa--have undergone clinical trials in Parkinson's disease. In 10 years, we treated a total of 278 patients with advanced Parkinson's disease, a declining response to levodopa, and diurnal oscillations in performance with five ergoline dopamine agonists (in addition to levodopa). The mean duration of treatment was one year (with a range of 1-60 months). Improvement was noted in 140 (50%) of our patients. Adverse effects necessitating discontinuation of the agonist occurred in 131 patients (46%). We compared our results with those of others who, unlike us, began treatment with a dopamine agonist earlier, using the agonist alone or adding it to levodopa before the response to levodopa had decreased. Many of the patients so treated had mild or moderate Parkinson's disease. A total of 1,599 patients were treated with ergoline dopamine agonists. Of these patients, 976 (61%) improved, while 407 (25%) experienced adverse effects. We believe that a greater number of these patients improved and fewer experienced adverse effects, in comparison to our patients, because the patients had less advanced disease.
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PMID:Management of levodopa failures: the use of dopamine agonists. 329 19

The possible involvement of dopaminergic neurons in dementia of Alzheimer type (AD/SDAT) was studied in autopsied brains from 20 patients with AD/SDAT. Dopamine (DA) concentrations were decreased significantly in the temporal cortex, hippocampal cortex and hippocampus in AD/SDAT patients. Levels of homovanillic acid (HVA) were not altered compared to controls. The HVA/DA ratio was significantly higher in the hippocampus of AD/SDAT patients, suggesting overactivity of the remaining DA neurons. Histological findings of substantia nigra suggesting coexistent pathology of Parkinson's disease (PD) found in 25% of cases were associated with lowered levels of DA in striatum and with reduced HVA in CSF. The activity of monoamine oxidase-B was significantly increased in the cortical areas and in the hippocampus, obviously reflecting the underlying cell loss and substantial gliosis in these areas of the brain. In general, DA neurons seemed to be only mildly involved in AD/SDAT. Coexistent PD pathology can explain the loss of DA in the striatum and the presence of clinical PD symptoms in some patients with AD/SDAT. Otherwise the clinical relevance of these dopaminergic alterations is unclear.
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PMID:Dopaminergic system and monoamine oxidase-B activity in Alzheimer's disease. 339 91

Systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is toxic to the nigrostriatal dopaminergic neurons and produces a syndrome similar to Parkinson's disease. Conversion of MPTP to 1-methyl-4-phenylpyridine (MPP+) by monoamine oxidase-B (MAO-B) appears necessary for this neurotoxicity. When MPTP was used as the substrate for the histochemical localization of monoamine oxidase activity on sections of the rat brain, only a few specific sites were found in which MPTP oxidation to MPP+ occurs. These include the noradrenergic and serotoninergic neurons of the brainstem and the histamine neurons of the caudal hypothalamus. Dopamine neurons themselves do not display the capacity to oxidize MPTP. It is proposed that the conversion of MPTP to MPP+ occurs via MAO-B within serotonin and histamine neurons which may innervate the substantia nigra where the toxin MPP+ could be released and then taken up into the dopamine neurons.
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PMID:Histochemistry of MPTP oxidation in the rat brain: sites of synthesis of the parkinsonism-inducing toxin MPP+. 348 52


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