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)

In two trials, we have studied the effectiveness and tolerability of L-deprenyl, a selective MAO B inhibitor, in the treatment of end of dose akinesia in patients with Parkinson's disease. The first trial was designed as an open controlled trial. In the L-deprenyl phase, an improvement in fluctuations in motor function as well as an overall reduction in the sum score of Webster's rating scale from 12.5 to 8.9 was observed, which almost returned to baseline during the placebo phase. The second trial was designed as a randomized trial comparing L-deprenyl therapy with a low-dose bromocriptine regimen. Both therapeutic approaches yielded the same results with respect to fluctuations; the CURS sum score dropped from 37 to 26. As regards tolerability, however, L-deprenyl was superior to bromocriptine.
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PMID:R-(-)-deprenyl in the treatment of end-of-dose akinesia. 312 3

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration causes a Parkinson's disease like syndrome in man and primates, with selective degeneration of the substantia nigra. This discovery has raised the possibility that some environmental or endogenous toxin causes idiopathic Parkinson's disease. MPTP is oxidised to its neurotoxic metabolite, 1-methyl-4-phenylpyridinium (MPP+) by monoamine oxidase B (MAO B). MPTP toxicity is prevented by pretreatment with the MAO B inhibitor selegiline ((-)-deprenyl). We have screened a range of structural analogues of MPTP as possible alternative substrates for the enzyme. All compounds which were found to be substrates for MAO B were tetrahydropyridines, some with substituents on the phenyl ring. The most interesting substrate, ethyl-MTP-carboxylate, did not have a phenyl ring. The precise histochemical localisation of MAO B within the rat and marmoset brain has been established. There was substantial activity within the nigrostriatal pathway of the marmoset; in comparison, the rat had only a low background MAO B level. These results may partially explain why the marmoset is more susceptible to the action of MPTP than the rat.
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PMID:Selegiline and the prophylaxis of Parkinson's disease. 312 4

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) destroys nigrostriatal dopaminergic pathways and thereby produces a syndrome similar to Parkinson's disease. MPTP is oxidized by monoamine oxidase B (MAO B) to the 1-methyl-4-phenylpyridinium ion (MPP+), which is taken up in dopaminergic neurons through the dopamine (DA) uptake system, where it develops its toxic effect. Our observations show a new aspect of the MPP+ mode of action, in which deprenyl in mice has a partially protective effect against MPP+. Furthermore budipine, a therapeutic agent for Parkinsonism, is also able to partially prevent MPP+ toxicity. A MAO B-inhibitory component of budipine, as shown in receptor binding studies previously, could contribute to this effect. Comparable experiments with nomifensine do not exclude the possibility of budipine as an effect as a DA uptake inhibitor. An unexplained after effect of budipine leads to a large increase in 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels five weeks after the last administration.
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PMID:Intracerebroventricular administration of 1-methyl-4-phenylpyridinium ion in mice: effects of simultaneously administered nomifensine, deprenyl, and 1-t-butyl-4,4-diphenylpiperidine. 312 44

Cerebrospinal fluid levels of homovanillic acid (HVA) in unmedicated patients with Parkinson's disease were 45% of levels in control subjects. Levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) and platelet monoamine oxidase activity (MAO) did not differ. Within the Parkinson's disease group platelet MAO B activity correlated with HVA (an MAO B substrate) but not MHPG (an MAO A substrate). A mild global dementia was found that did not correlate with the more severe motor deficit. There was a negative correlation between the motor deficit and HVA levels but not with MHPG. Cognitive functioning correlated positively with platelet MAO, and the ratio of HVA to MHPG levels and negatively with MHPG alone. It is postulated that dopaminergic and noradrenergic activity or the functional balance between these systems may contribute to the observed cognitive dysfunction.
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PMID:Central catecholamine metabolism in vivo and the cognitive and motor deficits in Parkinson's disease. 664 14

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

The aetiology and pathogenesis of Alzheimer's disease are currently poorly understood, but symptomatic disease is associated with amyloid plaques, neurofibrillary tangles, neuronal loss and numerous alterations of neurotransmitter systems in the CNS. Monoamine oxidase type B is known to be increased in Alzheimer diseased brains. The distribution and abundance of catalytic sites for monoamine oxidases A and B in post mortem human brains of 11 Alzheimer disease cases and five age-matched controls were investigated by quantitative enzyme radioautography. Using tritiated monoamine oxidase inhibitors (Ro41-1049 and lazabemide)--as high affinity substrates selective for monoamine oxidases A and B, respectively--it was found that monoamine oxidase B activity increased up to three-fold exclusively in temporal, parietal and frontal cortices of Alzheimer disease cases compared with controls. This increase was restricted to discrete patches (approximately 185 microns in diameter) which occupied approximately 12% of the cortical areas examined. In other brain regions (hippocampal formation >> caudate-putamen > cerebellum), patches of [3H]lazabemide-enriched binding were less abundant. [3H]Ro41-1049 binding (i.e. monoamine oxidase A) was unchanged in all tissues of diseased versus control brains. The monoamine oxidase B-enriched patches in all cortical regions correlated, in their distribution and frequency, with glial fibrillary acidic protein-immunoreactive clusters of astrocytes. Diffuse and mature beta-amyloid-immunoreactive senile plaques as well as patches of high density binding of [3H]PK-11195--a high-affinity ligand for peripheral-type (mitochondrial) benzodiazepine binding sites in microglia/macrophages--were found throughout Alzheimer diseased cortices. The up-regulation of monoamine oxidase B in plaque-associated astrocytes in Alzheimer's disease--in analogy to its proposed role in neurodegenerative disorders such as Parkinson's disease--might, indirectly, be a potential source of cytotoxic free radicals. Lazabemide, a selective reversible monoamine oxidase B inhibitor, is currently under clinical evaluation for the treatment of Parkinson's and Alzheimer's diseases. We conclude that enzyme radioautography with [3H]lazabemide is a reliable high resolution assay for plaque-associated astroglioses in Alzheimer's disease. Its clinical diagnostic utility for positron emission tomography or single photon emission computer tomography studies is being investigated.
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PMID:Increased monoamine oxidase B activity in plaque-associated astrocytes of Alzheimer brains revealed by quantitative enzyme radioautography. 781 97

Since monoamine oxidase is an enzyme catalyzing bioactive monoamines, inhibitors of monoamines are expected to prolong the activity of monoamines in tissue. Monoamine oxidase type B is an active form in brain, and its preferential substrate is dopamine that is the most constantly reduced monoamine in Parkinson's disease brain. Therefore, it is natural to expect that monoamine oxidase inhibitors, deprenyl or lazabemide, could exhibit beneficial effects on parkinsonism, i.e. symptomatic effects. This short review summarizes characteristics of monoamine oxidase from biochemical and pharmacological points, and then briefly mentions the situation of clinical evaluation studies of deprenyl and lazabemide in terms of antiparkinsonian effects in Japan.
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PMID:Short review on monoamine oxidase and its inhibitors. 782 34

L-Deprenyl (Selegeline) is an enzyme-activated irreversible inhibitor of monoamine oxidase B (MAO B; EC 1.4.3.4). It is used to treat Parkinson's disease at a dose of 5 mg twice a day. Since enzyme inhibition is irreversible, the recovery of functional enzyme activity after withdrawal from L-deprenyl requires the synthesis of new enzyme. We have measured a 40 day half-time for brain MAO B synthesis in Parkinson's disease and in normal subjects after withdrawal from L-deprenyl. This is the first measurement of the synthesis rate of a specific protein in the living human brain. L-Deprenyl is currently used by 50,000 patients with Parkinson's disease in the United States and its use is expected to increase with reports that it may be beneficial in Alzheimer's disease. The slow turnover of brain MAO B suggests that the current clinical dose of L-deprenyl may be excessive and that the clinical efficacy of reduced dosing should be evaluated. Such an evaluation may have mechanistic importance as well as an impact on reducing the side effects and the costs arising from excessive drug use.
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PMID:Slow recovery of human brain MAO B after L-deprenyl (Selegeline) withdrawal. 783 16

An analytical solution to the differential equations describing the kinetics of the suicide inhibition of a two-enzyme system has been derived and the modelling of suicide inhibition of the monoamine oxidases A and B (MAO A and B, EC 1.4.3.4) by a quasi-selective agent, (-)-deprenyl, is presented as an example. A new parameter, the specificity index is defined and used in a model which describes the specific and non-specific binding of (-)-deprenyl to MAO B and MAO A, respectively. This type of analysis may be of therapeutic value by indicating optimal dosage of quasi-selective MAO B inhibitors for the treatment of Parkinson's disease.
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PMID:Suicide inhibition of monoamine oxidases A and B by (-)-deprenyl. A computer-aided solution for determining inhibition specificity. 836 32

Monoamine oxidase type B (MAO-B), which catalyses the breakdown of dopamine (DA) in human brain, is said to be involved in the pathophysiology of Parkinson's disease (PD). Activity of MAO-B in PD has been measured in platelets isolated from blood samples in different studies, with contradictory results, possibly due to the differences in substrate used or to differences in platelet isolation. Therefore we measured MAO activity in whole blood, which is almost identical to MAO-B activity in platelets, in 25 drug-naive PD patients, 25 treated PD patients, 9 multiple system atrophy (MSA) patients and 20 controls, using a spectrofluorimetric method with kynuramin as a substrate. No statistically significant differences between groups were found, nor any correlation with the severity or duration of the disease.
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PMID:Whole blood monoamine oxidase activity in Parkinson's disease and multiple system atrophy patients. 841 65


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