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 administration of high doses of methamphetamine causes long lasting damage to central dopaminergic and serotonergic neurons through a mechanism known to involve presynaptic, cytoplasmic stores of those transmitters and thought to be dependent upon a free radical reaction. The following studies were designed to determine if differential inhibition of the subtypes of monoamine oxidase would alter the magnitude of the methamphetamine induced neuronal damage. In addition, since monoamine oxidase type B increases with age, the effects of high dose administration of methamphetamine were evaluated in senescent mice. It was observed that inhibition of monoamine oxidase type A, and to a lesser degree, type B, increased the magnitude of methamphetamine-induced neuronal damage and that aged mice were more sensitive to the toxic action of methamphetamine. These results are interpreted with respect to the use of monoamine oxidase inhibitors in the treatment of Parkinson's disease.
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PMID:Evaluation of the effects of inhibition of monoamine oxidase and senescence on methamphetamine-induced neuronal damage. 190 57

Identification, cellular localization, and cDNA cloning of MAO subtypes A and B have increased the insight into the pharmacology of these enzymes, whose primary functions are intra- and extraneuronal inactivation of neurotransmitter (dopamine, noradrenaline and serotonin) and other biogenic amines. In addition, MAO oxidizes the inert uncharacteristic tertiary amine, MPTP, to the parkinson inducing dopaminergic neurotoxin, MPP+, and the novel secondary amine anticonvulsant milacemide to the inhibitory amino acid neurotransmitter, glycine. These recent developments have provided new therapeutic perspectives for the management of Parkinson's disease and seizure disorders via the use of selective inhibitors and amino acid amine prodrug substrates of MAO-B.
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PMID:New directions in monoamine oxidase A and B selective inhibitors and substrates. 198 26

Xenobiotic enzymic systems have been studied in Parkinson's disease. Platelet monoamine oxidase-B activity is increased by the use of phenylethylamine but decreased by the use of dopamine as substrate. Enzymes involved with sulfur oxidation and methylation are underactive.
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PMID:Xenobiotic enzyme profiles and Parkinson's disease. 204 91

Monoamine oxidase inhibitors that have been available in the United States are nonselective and thus act equally on peripheral and brain monoamine oxidase. Recently, selegiline, a selective monoamine oxidase inhibitor, has been approved for use in the management of Parkinson's disease. Clinical trials demonstrate that selegiline in combination with carbidopa/levodopa is effective in relieving symptoms and prolonging remission. The dosage of carbidopa/levodopa can usually be reduced, resulting in diminished side effects. Selegiline is relatively nontoxic and appears to be a valuable addition in the management of Parkinson's disease.
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PMID:Selegiline for Parkinson's disease. 210 24

Clinical studies suggest that deprenyl may retard the progression of Parkinson's disease, an effect that may be related to its monoamine oxidase (MAO) inhibiting properties. Deprenyl also protects against the neurodegenerative effects of the noradrenergic toxin DSP-4. In this study we investigated the role of MAO B inhibition in this protection. C57BL/6 mice were given DSP-4 (50 mg/kg i.p.) 1 h. 24 h or 4 days after the administration of deprenyl (10 mg/kg i.p.) or the selective MAO B inhibitor MDL 72974 (1.25 mg/kg), and then killed 1 week later for assay of hippocampal norepinephrine. The MAO B inhibiting effects of deprenyl or MDL 72974 were also determined after these same intervals of time. Deprenyl and MDL 72974 produced comparable degrees of enzyme inhibition 1 h (greater than 95%), 24 h (greater than 90%) or 4 days (greater than 70%) after their administration. Given 1 h before, deprenyl totally blocked the norepinephrine-depleting effects of DSP-4, but this protection declined sharply when 24 h or 4 days was allowed to elapse between deprenyl and DSP-4 administration. MDL 72974 failed to protect at any time point. In vitro, we detected no activity using DSP-4 as a substrate for MAO. These findings suggest that the ability of deprenyl to protect against DSP-4-induced neuronal degeneration may not depend on its MAO B inhibiting properties.
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PMID:Protection against DSP-4-induced neurotoxicity by deprenyl is not related to its inhibition of MAO B. 212 76

Increased oxidation of dopamine by monoamine oxidase (MAO) in the striatum is associated with an oxidant stress, expressed as a rise in the level of oxidized glutathione. Oxidation of glutathione is suppressed by MAO inhibitors, such as deprenyl and clorgyline. These observations related to Parkinson's disease and to the clinical trial of deprenyl as an agent that may retard progression of the disease.
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PMID:Monoamine oxidase and oxidative stress at dopaminergic synapses. 212 99

1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) has been shown to produce a parkinsonian syndrome in humans and other primates. Recent studies have demonstrated that in humans the hypothalamus has the highest binding density for (3H) MPTP, which corresponds to monoamine oxidase type B (MAO-B). There is evidence that the conversion of MPTP to the toxic compound MPP+ takes place in the hypothalamus; subsequently, MPP+ is transported to the striatal system, where destruction of nigrostriatal dopamine neurons occurs. Thus, the hypothalamus appears to be a primary target organ of MPTP toxicity. This assumption is supported by the observation that monkeys exposed to MPTP exhibit extensive pathological lesions in the hypothalamus which are manifested clinically by the development of life-threatening anorexia requiring forced feeding to overcome. We discuss the clinical implications of MPTP-induced hypothalamic damage to the pathophysiology of MPTP-induced parkinsonism and to Parkinson disease. It is suggested that consideration of hypothalamic involvement in MPTP-induced parkinsonism may provide a broader understanding of the pathophysiology of parkinsonism and may, in addition, account for the preliminary observations that MAO-B inhibitors retard the progression of Parkinson disease and possibly prolong life expectancy.
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PMID:The hypothalamus in MPTP-induced parkinsonism. 224 19

Several epidemiological studies have indicated that there may be an inverse relationship between smoking and Parkinson's disease. The purpose of this study was to determine whether chronic exposure to cigarette smoke alters the parkinsonian-like neurochemical changes caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. Following 4 weeks of brief, intermittent exposure to smoke, mice were treated with MPTP, 10 mg/kg. Smoke exposure was found to reduce the decrease in striatal dopamine and metabolite levels caused by MPTP. Although smoke exposure inhibited cerebral MAO-B activity, tissues from smoke-treated mice were able to metabolize MPTP in a normal fashion. This suggests that inhibition of cerebral MAO may not be a major mechanism for the apparent protective effect of cigarette smoke.
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PMID:Attenuation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity by tobacco smoke. 232 34

A relation between neuromelanin synthesis and vulnerability of dopaminergic neurons is suggested by the fact that heavily pigmented cells are preferentially lost in aging and Parkinson's disease and that the dopaminergic neurotoxin MPP+ (1-methyl-4-phenyl-pyridine) binds to neuromelanin. To elucidate the mechanism of neuromelanin synthesis, we studied the formation of melanin in homogenates of human and rat substantia nigra tissue "in vitro". It was found that enzymatic processes accounted for 70% and 90% of the melanin formation in homogenates of human and rat tissue, respectively. The enzymatic synthesis was due to the activity of monoamine oxidase (MAO), since it was prevented by selective inhibitors of this enzyme. Both MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and MPP+ inhibited melanin formation, probably due to their ability to inhibit MAO. No evidence was found for involvement of cytochrome P-450 monooxigenases, which have been postulated to exist in central catecholaminergic neurons. Proadifen reduced melanin formation, not necessarily because it is an inhibitor of P-450 monooxigenases, but rather as it is also a potent inhibitor of MAO. Some antioxidants like ascorbic acid, but not agents destroying hydrogen peroxide, inhibited melanin formation. The findings suggest that the formation of neuromelanin in the substantia nigra involves MAO and non-enzymatic oxidative processes.
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PMID:Neuromelanin synthesis in rat and human substantia nigra. 235 68

The aim of this study was to determine whether there were differences in the oxidative deamination of dopamine in patients with Parkinson's disease who demonstrated a long-duration response (LDR) to treatment with dopa and carbidopa and in patients who demonstrated only a short-duration response (SDR) to the drugs. The patients who demonstrated LDR had received dopa and carbidopa for a shorter time (3.4y) than had the SDR patients (9.5y). The concentrations of dopamine and 3-methoxytyramine and their deaminated metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid were measured in 24-h urine samples collected from patients in both groups. The ratios of homovanillic acid to 3-methoxytyramine and dopamine were greater in SDR than in LDR patients suggesting increased oxidative deamination of dopamine in this group. Increased oxidative deamination could be caused by an increase in MAO activity as Parkinson's disease progresses or by the treatment with L-dopa.
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PMID:MAO and L-dopa treatment of Parkinson's disease. 235 3


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