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 acetylenic selective monoamine oxidase (MAO) type B suicide inhibitor, l-deprenyl (l-selegiline), has proved to be a useful adjuvant to L-dopa therapy and monotherapy of Parkinson's disease. Although not all features of its antiParkinson action are known, studies that used brains obtained at autopsy from patients who took l-deprenyl show that the selective inhibition of MAO-B with a concomitant increase of phenylethylamine and dopamine, but not of serotonin or noradrenaline, in the basal ganglia may be responsible for its mode of action. The increased life expectancy noted in patients with Parkinson's disease who received long-term therapy (9 years in an uncontrolled study) is another unexpected feature of the drug. These exciting data, if confirmed in other long-term clinical trials, may herald a neuroprotective approach to the treatment of this degenerative disease. More recent studies indicate that Parkinson's disease may eventually turn out to be a neurotoxic event resulting from oxidative stress-induced free radical species in the substantia nigra. Thus selective MAO-B inhibitors could represent a unique class of drugs, having symptomatic actions with possible neuroprotective and neurorescue actions in one.
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PMID:Pharmacological actions of l-deprenyl (selegiline) and other selective monoamine oxidase B inhibitors. 799 14

Intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in four cats produced akinesia, bradykinesia, crouched posture, feeding difficulty, and so on, lasting for two weeks. Madopar therapy ameliorated these motor impairments. Reduction of the concentration of dopamine and its metabolites was determined in the substantia nigra and putamen by high performance liquid chromatography (HPLC). Depletion of noradrenaline, serotonin and their metabolites was also seen. Loss of nerve cells and proliferation of glial cells in the substantia nigra were observed under the light microscope. The results indicate that MPTP-induced Parkinsonism in the cat provides an animal model that can be used for basic and therapeutic research on Parkinson's disease.
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PMID:Parkinsonism induced with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in cats: behavioral, biochemical and pathological studies. 803 69

Major motor fluctuations in patients with Parkinson's disease during levodopa treatment include "wearing-off" fluctuations, "on-off" fluctuations, freezing, and early morning dystonia. Other fluctuations, such as drug resistant "off periods," complicated "end-of-dose" effects and "resistant fluctuators" can also occur. In this paper, the underlying pathophysiologic mechanisms of the major motor fluctuations are reviewed, and practical approaches to manage these problems are discussed. "Wearing-off" fluctuations are most common, and several different mechanisms appear to be operating, including the interference of food in the gastrointestinal absorption of levodopa, inhibition of transport of levodopa to the brain by large neutral amino acids or 3-O-methyldopa, and progression of the degeneration of dopaminergic nerve terminals. The mechanisms of "on-off" fluctuations and freezing are not well understood. Loss of cerebral noradrenaline that results from locus coeruleus degeneration may, in part, be responsible for freezing. To minimize the occurrence of these motor fluctuations, multiple classes of antiparkinsonian drugs need to be used, so that the dose of levodopa can be maintained at a reasonably low level.
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PMID:Various aspects of motor fluctuations and their management in Parkinson's disease. 804 58

The last decades have been characterized by impressive research activity in connection with Parkinson's disease (PD). A wealth of new results have enriched our knowledge of the pathophysiology of the disorder and led to new approaches for its therapy. Whereas anticholinergic drugs remained the main, though unsatisfactory, treatment of PD for almost 100 years, the situation has changed since the 1960s. An impetus for this turning-point was given by the finding that the striatum of rats contained a high concentration of dopamine (DA) which until then had been considered to be a mere intermediate of the biosynthesis of noradrenaline and adrenaline, without a physiological role in its own right. Subsequently, the role of dopamine as neurotransmitter and the importance of dopaminergic pathways for the control of extrapyramidal motricity were firmly established. As a consequence, new therapeutic possibilities emerged and the anticholinergic drugs, although still in use, lost their supremacy. The present minireview will be restricted to new treatments which have been developed and introduced since 1960 and to recent pharmacotherapeutic approaches with potential future usefulness.
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PMID:Pharmacotherapy of Parkinson's disease: research from 1960 to 1991. 810 13

1. Dopamine beta-hydroxylase is stored and released with catecholamines by exocytosis from secretory vesicles in noradrenergic neurons and chromaffin cells. Although dopamine beta-hydroxylase enzymic activity is measurable in cerebrospinal fluid, such activity is unstable, and its relationship to central noradrenergic neuronal activity in humans is not clearly established. To explore the significance of cerebrospinal fluid dopamine beta-hydroxylase, we applied a homologous human dopamine beta-hydroxylase radioimmunoassay to cerebrospinal fluid, in order to characterize the properties and stability of cerebrospinal fluid dopamine beta-hydroxylase, as well as its relationship to central noradrenergic neuronal activity and its variation in disease states such as hypertension, renal failure, Parkinsonism and congenital dopamine beta-hydroxylase deficiency. 2. Authentic, physically stable dopamine beta-hydroxylase immunoreactivity was present in normal human cerebrospinal fluid at a concentration of 31.3 +/- 1.4 ng/ml (range: 18.5-52.5 ng/ml), but at a 283 +/- 27-fold lower concentration than that found in plasma. Cerebrospinal fluid and plasma dopamine beta-hydroxylase concentrations were correlated (r = 0.67, P = 0.001). Some degree of local central nervous system control of cerebrospinal fluid dopamine beta-hydroxylase was suggested by incomplete correlation with plasma dopamine beta-hydroxylase (with an especially marked dissociation in renal disease) as well as the lack of a ventricular/lumbar cerebrospinal dopamine beta-hydroxylase concentration gradient. 3. Cerebrospinal fluid dopamine beta-hydroxylase was not changed by the central alpha 2-agonist clonidine at a dose that diminished cerebrospinal fluid noradrenaline, nor did cerebrospinal fluid dopamine beta-hydroxylase correspond between subjects to cerebrospinal fluid concentrations of noradrenaline or methoxyhydroxyphenylglycol; thus, cerebrospinal fluid dopamine beta-hydroxylase concentration was not closely linked either pharmacologically or biochemically to central noradrenergic neuronal activity. 4. Cerebrospinal fluid dopamine beta-hydroxylase was not changed in essential hypertension. In Parkinson's disease, cerebrospinal fluid dopamine beta-hydroxylase was markedly diminished (16.3 +/- 2.9 versus 31.3 +/- 1.4 ng/ml, P < 0.001) and rose by 58 +/- 21% (P = 0.02) after adrenal-to-caudate chromaffin cell autografts. In congenital dopamine beta-hydroxylase deficiency, lack of detectable dopamine beta-hydroxylase immunoreactivity in cerebrospinal fluid or plasma suggests absent enzyme (rather than a catalytically defective enzyme) as the origin of the disorder. 5. We conclude that cerebrospinal fluid dopamine beta-hydroxylase immunoreactivity, while not closely linked to central noradrenergic neuronal activity, is at least in part derived from the central nervous system, and that its measurement may be useful in both the diagnosis and treatment of neurological disease.
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PMID:Dopamine beta-hydroxylase immunoreactivity in human cerebrospinal fluid: properties, relationship to central noradrenergic neuronal activity and variation in Parkinson's disease and congenital dopamine beta-hydroxylase deficiency. 814 25

There is a short-term up-regulation of beta-adrenoceptors on peripheral blood mononuclear cells (PBMC) after reduction of central sympathetic outflow by clonidine in normal individuals. We have studied beta-adrenoceptor number and affinity on PBMC in idiopathic Parkinson's disease (PD), pure autonomic failure (PAF), and multiple system atrophy (MSA; Shy-Drager syndrome) patients and age- and sex-matched normal controls (NC) before and after intravenous administration of clonidine, an alpha 2-adrenoceptor agonist which lowers blood pressure predominantly by reducing CNS sympathetic outflow. Basal beta-adrenoceptor density was high in PAF but within the normal range in PD and MSA patients. After clonidine there was a decrease in plasma levels of noradrenaline (NA) and adrenaline (Ad) in PD, MSA, and NC, and an increase in growth hormone (GH) in PD, PAF, and NC. NC. In PAF, NA and Ad remained unchanged. In MSA, there was no increase in GH levels. There was an up-regulation of beta-adrenoceptors on PBMC at 30 and 60 minutes after clonidine administration, which returned to baseline values after 2 hours, and the affinity of the receptors was decreased in NC and PD patients. Intracellular production of cAMP after isoproterenol stimulation demonstrated that the up-regulation was not functional. Up-regulation after clonidine did not occur in PAF and MSA patients. The observed correlation of plasma NA and sympathetic defect with basal and clonidine-induced up-regulation of beta-adrenoceptors on PBMC may provide insight into beta-adrenoceptor changes in other tissues and also help in differentiating subgroups of autonomic failure patients.
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PMID:Beta-adrenoceptor expression on circulating mononuclear cells of idiopathic Parkinson's disease and autonomic failure patients before and after reduction of central sympathetic outflow by clonidine. 817 May 65

In order to determine whether, besides the severe striatal dopamine (DA) loss, other brain neurotransmitter changes may be a constant biochemical feature of idiopathic Parkinson's disease (iPD), we measured the concentration of the three major brain monoamines noradrenaline (NA), DA, and serotonin (5-HT) and their metabolites in five rostro-caudal subdivisions of the hypothalamus of eight control patients and nine patients with morphologically confirmed iPD. In the whole hypothalamus of the iPD patients we found a mild to moderate mean reduction of NA (-52%, P < 0.05), DA (-25%), and 5-HT (-26%). At the subregional level, the most consistently affected area was the intermediate subdivision of the hypothalamus proper where all three monoamines were statistically significantly reduced. Evaluation of individual patient values indicated that, in contrast to the constant and severe DA reduction present in putamen of each of the iPD patients (DA loss ranging from 96% to 99%), several of these patients had whole (and subregional) hypothalamic monoamine values well within the range of controls. We conclude that, although possibly involved in autonomic and/or endocrine disturbances in some patients with iPD, none of the observed monoamine changes in the hypothalamus is an obligatory feature of iPD. Our study demonstrates the need for evaluation of individual patient values rather than mean differences in order to permit valid conclusions to be drawn as to whether an observed neurochemical change can be regarded as specific to a given brain disorder.
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PMID:Noradrenaline, dopamine and serotonin levels and metabolism in the human hypothalamus: observations in Parkinson's disease and normal subjects. 818 Aug 36

The effects of 6-hydroxydopamine lesions of the prefrontal cortex in monkeys were investigated on two cognitive tests of prefrontal function, spatial delayed response, and attentional set shifting. The latter test provided a componential analysis of the Wisconsin Card Sort Test, a commonly used clinical test of frontal lobe function in man. Acquisition of a visual compound discrimination requiring a shift of attention from one dimension to another (extradimensional shift), for example, shapes to lines, was significantly improved. This enhancement was behaviorally specific in that there were no effects on acquisition of a discrimination that required the continued maintenance of an attentional set toward one particular dimension (intradimensional shift), nor any effects on a series of visual or spatial discrimination reversals that involved the repeated shifting of responding between two exemplars from the same dimension. In contrast, spatial delayed response performance was impaired, in agreement with previous results. Neurochemical measures showed a marked depletion of dopamine limited to the prefrontal cortex and a smaller loss of prefrontal noradrenaline. This was accompanied by a long-term adaptive change in the striatum such that extracellular dopamine in the caudate nucleus, as measured by in vivo microdialysis, was elevated in response to potassium stimulation as long as 18 months postsurgery. It is proposed that attentional set shifting is mediated by a balanced interaction between prefrontal and striatal dopamine, and that elevated dopamine contributes to the improvement in attentional set-shifting ability. This interpretation is consistent with the impairment in attentional set-shifting ability observed in patients with Parkinson's disease or with damage to the frontal lobes using the same test as used here for infrahuman primates.
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PMID:6-Hydroxydopamine lesions of the prefrontal cortex in monkeys enhance performance on an analog of the Wisconsin Card Sort Test: possible interactions with subcortical dopamine. 818 26

In addition to impaired dopaminergic neurotransmission a dysfunctional noradrenergic system has been demonstrated in Parkinson's disease. L-threo-3,4-dihydroxyphenylserine (DOPS), a synthetic precursor of noradrenaline (NA), appears to be effective in the treatment of some akinetic symptoms in parkinsonian patients. In the present study the possible effect of DOPS was studied in rats, in which catalepsy was induced with haloperidol as a model for parkinsonian akinesia. Intravenous infusion of NA (1.5 and 15 micrograms/kg) or DOPS (2 and 4 mg/kg) in male Wistar rats (240-290 g) significantly decreased catalepsy. The effect of DOPS was abolished by pretreatment with the peripheral decarboxylase inhibitor benserazide (2 mg/kg). Pretreatment with Ro 40-7592, a catechol-O-methyltransferase inhibitor, potentiated and prolonged the anticataleptic effect of DOPS. The findings suggest a peripheral site of NA mediated anticataleptic action. Therapy with DOPS may be successful only without a peripheral decarboxylase inhibitor. Moreover, the therapeutic effect of DOPS may be potentiated by COMT inhibition.
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PMID:Attenuation of haloperidol-induced catalepsy by noradrenaline and L-threo-DOPS. 821 60

Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to the goldfish causes a reversible, Parkinson's disease-like syndrome which includes loss of noradrenaline and dopamine from the brain, accumulation of the toxic metabolite 1-methyl-4-phenylpyridinium species (MPP+), and substantial reduction in movement. L-Deprenyl, a selective monoamine oxidase-B inhibitor, protects the goldfish from loss of movement, but clorgyline, a selective monoamine oxidase-A inhibitor, has no such protective action. L-Deprenyl and clorgyline primarily inhibit goldfish brain monoamine oxidase-B and monoamine oxidase-A, respectively. The mechanism by which MPTP causes reduced movement in goldfish is to cause an increase in resting time. Otherwise normal average velocity occurred during periods of movement. L-Deprenyl protection results in entirely 'normal' levels of resting time and average velocity during times of movement. Equivalent observations regarding l-deprenyl and clorgyline have been made in primate models of MPTP toxicity, and l-deprenyl is used for treatment of Parkinson's disease in humans. Therefore it is suggested that the evolutionarily equivalent subcortical circuitry and neural density of the goldfish brain may provide a useful model upon which to search for drugs relevant to human Parkinson's disease.
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PMID:L-deprenyl confers specific protection against MPTP-induced Parkinson's disease-like movement disorder in the goldfish. 824 37


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