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)

Post-mortem brain material from control and Parkinson's disease patients was examined to elucidate further the neurochemistry of this disease and to determine the mechanism of action of L-dopa as a therapeutic agent. The activities of L-aromatic amino acid decarboxylase (dopa D), tyrosine hydroxylase, monoamine oxidase and catechol-O-methyl transferase were examined; in addition the tissue levels of dopa, 3-O-methyldopa, dopamine (DA) and homovanillic acid (HVA) were determined. In the non-dopa-treated Parkinsonian patients, the greatest decreases were detected for striatal DA and dopa D, with homovanillic acid and tyrosine hydroxylase levels showing a lesser change. The activities of monoamine oxidase and catechol-O-methyl transferase in the striatal nuclei were not different from the controls. The putamen was consistently the most severely affected region. Dopa and 3-O-methyldopa were detectable in all brain areas only in those patients treated with L-dopa shortly before death. The mean concentrations of DA in the striatum of these patients were 1) 9 to 15 times higher than those in non-dopa-treated patients, 2) related to the time before death of the last dose of L-dopa and 3) greater in the striatum of patients clinically classified as "good responders" as compared to "poor responders." Although L-dopa therapy increased homovanillic acid levels in all brain areas, a preferential increase was observed in the striatum. It was concluded that L-dopa's principal therapeutic effects in Parkinson's disease are consistent with its transformation to DA in the striatum.
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PMID:The neurochemistry of Parkinson's disease: effect of L-dopa therapy. 0 Apr 89

Deprenyl is an inhibitor of monoamine oxidase type B, the enzyme responsible for 2-phenylethylamine oxidation, and is used in conjunction with L-Dopa therapy in Parkinson's disease. Post-mortem studies in human brain tissue have shown that after (-)deprenyl administration to parkinsonian patients amphetamine is present in concentrations up to 56 ng/g. It also could be shown that phenylethylamine concentrations are substantially increased in such patients. Phenylethylamine and amphetamine have been investigated using a gas chromatographic technique.
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PMID:Amphetamine and 2-phenylethylamine in post-mortem Parkinsonian brain after (-)deprenyl administration. 74 19

Since there is substantial evidence for a nigrostriatal dopamine defect in Parkinson's disease and since monoamine oxidase (MAO) appears to be essential for the degradation of dopamine, we investigated whether this enzyme is involved in the pathogenesis of this disease or in the therapeutic action of L-dopa. To gain a solid basis for our analysis we studied some properties of platelet MAO, at present the only practical in vivo source for human MAO. Substrate and inhibitor pattern clearly pointed to a predominant B-type character of this enzyme. By using 3 substrates, m-iodobenzylamine, p-methoxybenzylamine, and tyramine, we found a marked age and sex difference in MAO activity. In untreated parkinsonian patients, platelet MAO was slightly reduced as compared with age- and sex-matched controls. Treatment with L-dopa induced a further reduction of platelet MAO activity in both sexes, but more in men than in women. We conjecture that the action of L-dopa on parkisonian patients is twofold: L-dopa is known to enhance the release of gonadotropins and thus to increase the production of sex hormones which in turn are capable of reducing MAO activity. Dopamine, formed from L-dopa, may thus have a better chance for survival in reaching the dopaminergic receptor. A new form of therapy, based on this concept, is proposed.
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PMID:Molecular biology of neurological and psychiatric disorders. I. Effect of parkinsonism, age, sex and L-dopa on platelet monoamine oxidase. 97 97

Studies indicate that selegiline, a monoamine oxidase type B inhibitor, slows progression of Parkinson's disease (PD) and delays the need for levodopa. While dopamine agonists also delay the need for levodopa because of their symptomatic, antiparkinsonian effect, only recently has it been proposed that agonists may also have a protective effect. When dopamine agonists are used as monotherapy in newly diagnosed PD patients, fewer patients improve than on levodopa, but fewer patients develop response fluctuations. This might indicate that dopamine agonists have a protective, as well as a symptomatic, effect, as the lack of response fluctuations may indicate that dopamine agonists protect nigral neurons. Response fluctuations may result from destruction of nigral neurons.
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PMID:Dopamine agonists used as monotherapy in de novo PD patients: comparisons with selegiline. 135 73

The major neuropathology of Parkinson's disease (PD) is the degeneration of nigrostriatal dopamine (DA), resulting in a deficiency of DA, and of the enzyme tyrosine hydroxylase (TH), which catalyzes the synthesis of L-dopa. The symptomatic treatment of PD consists of replenishing DA by administering L-dopa, which is enzymatically converted to DA in the striatum. The increase of TH activity by modification of the enzyme leads to an increased synthesis of striatal L-dopa, and thereby replenishes the missing DA more efficiently. The activity of TH is increased by protein kinase-dependent phosphorylation of the enzyme or by inhibition of dephosphorylation with specific phosphatase inhibitors. Thus, modification of TH results in an activated form of the enzyme, which might provide a basis for developing new strategies in the treatment of PD. The extraneuronal enzyme, catechol-O-methyl transferase (COMT), inactivates catecholamines by O-methylation, and its inhibition leads to increased levels of striatal DA. The availability of selective and nontoxic COMT inhibitors makes it possible to assess their therapeutic role in treatment of PD. The intraneuronal enzymes, monoamine oxidase (MAO)-A and MAO-B, inactivate catecholamines and other biogenic amines, such as serotonin, by deamination. Inhibition of these enzyme activities leads to increased levels of striatal DA. The irreversible MAO-B inhibitor selegiline was shown to exert antiparkinsonian activity, especially in the early stages of parkinsonism. Selegiline also prevents the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in MPTP-treated mice and monkeys. Its role in the prevention of the disease is under investigation in several clinical centers.
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PMID:The role of the regulatory enzymes of catecholamine synthesis in Parkinson's disease. 834 92

Selegiline, a selective monoamine oxidase type B inhibitor, is beneficial in the treatment of Parkinson's disease. However, this beneficial effect is only transient, and patients must ultimately resort to treatment with standard levodopa therapy. We studied the effects of chronic selegiline treatment on the rat nigrostriatal pathway, to elucidate a neurochemical correlate for this adaptive clinical response. Selegiline treatment for 3, 7, 14, or 21 days decreased tyrosine hydroxylase (the enzyme that catalyzes the rate-limiting step in catecholamine biosynthesis) activity in the cell body regions (substantia nigra) of the nigrostriatal pathway. However, tyrosine hydroxylase activity measurements in the major terminal field region (corpus striatum) of the pathway did not correspond to those in the substantia nigra; in the corpus striatum, tyrosine hydroxylase activity was decreased at 3 and 7 days of treatment and recovered by 14 days. We tested whether the decrease in tyrosine hydroxylase activity was mediated by a decrease in tyrosine hydroxylase mRNA. Northern blot and RNA dot blot analyses (using a tyrosine hydroxylase-specific cDNA probe) of substantia nigra homogenates revealed a significant decrease in tyrosine hydroxylase mRNA at 3, 7, and 14 days of selegiline treatment, compared with controls. Conversely, after 21 days of selegiline, tyrosine hydroxylase mRNA levels were significantly higher (3-fold) than controls; this finding was not reflected in substantia nigra tyrosine hydroxylase activity. The 21-day increase in mRNA may be associated with the rebound in tyrosine hydroxylase activity observed in the corpus striatum. Thus, it is possible that the recovery in tyrosine hydroxylase activity in the corpus striatum is mediated through an increase in tyrosine hydroxylase protein transport from the substantia nigra to the corpus striatum and/or that the tyrosine hydroxylase enzyme exists in a more stabilized state during this period of time. These results demonstrate that monoamine oxidase type B-selective inhibitory doses of selegiline are capable of inducing transient decreases in tyrosine hydroxylase activity and tyrosine hydroxylase mRNA levels. Furthermore, these reversible effects may represent adaptive responses associated with pharmacological tolerance and the transient beneficial actions of this drug in Parkinson's disease.
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PMID:Chronic selegiline administration transiently decreases tyrosine hydroxylase activity and mRNA in the rat nigrostriatal pathway. 135 Mar 20

The nation-wide collaborative study on the bromocriptine monotherapy and bromocriptine-levodopa combination therapy was completed in November 1990, and the results were reported during the symposium on the Long-Term Treatment of Parkinson's Disease held in Tokyo in October 1991. The author briefly reviewed the history of treatment of Parkinson's disease, and current and future trends in its drug therapy as an introductory remark. The personal view on the principle of drug treatment for parkinsonian patients is the judicious concomitant use of several different classes of anti-parkinsonian drugs, including levodopa, dopamine agonists, monoamine oxidase inhibitors, anticholinergics, and amantadine HCl utilizing the smallest effective dose for each drug. The treatment of Parkinson's disease seems to be moving slowly from mere symptomatic therapy to the one which is aiming the protection of nigral cells. Recent progress in this field is also briefly reviewed.
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PMID:Drug therapy of Parkinson's disease. An overview. 135 14

The pathogenesis of Parkinson's disease (PD) has been linked to oxidative-mediated events including increased monoamine oxidase (MAO) and free-radical generation. We are investigating the ability of the MAO inhibitor, selegiline (deprenyl), and of the free-radical scavenger, tocopherol, to delay the onset of disability requiring levodopa therapy (primary end point) in patients with early PD. Eight hundred patients with early, untreated PD were enrolled in the multi-center placebo-controlled, double-blind clinical trial 'Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP)'. Subjects were assigned by 2 x 2 factorial design to receive selegiline (10 mg/day), tocopherol (2,000 IU/day), a combination of both drugs, or placebo, and followed to determine if and when disability occurred requiring levodopa therapy. After 12 +/- 5 months of observation, independent monitoring prompted a preliminary analysis indicating that selegiline 10 mg/day significantly extended the time to the primary end point. Selegiline therapy, alone or in combination with tocopherol, resulted in a 57% reduction in the rate of developing disability requiring levodopa therapy (p < 10(-10)) and a 50% reduction in the rate of loss of full-time employment (p = 0.01). Deterioration of motor and mental features was significantly less in selegiline-treated subjects. Adverse effects were minor and infrequent. We conclude from these preliminary results that selegiline (10 mg/day) delays the onset of disability associated with early, otherwise untreated PD. It remains unclear whether these benefits derive from mechanisms that are symptomatic (dopaminergic), protective (anti-neurotoxic), or both. The DATATOP study is ongoing to examine the long-term effects of selegiline and the independent and interactive effects of tocopherol.
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PMID:An interim report of the effect of selegiline (L-deprenyl) on the progression of disability in early Parkinson's disease. The Parkinson Study Group. 142 20

Marked advances in the treatment of neurological disorders which affect the elderly have been established in recent years. Cerebrovascular disorders including stroke and vascular dementia are still among the most frequent diseases in the Japanese elderly. For treatment of hypertensive patients with or without a history of stroke, slight decrease of blood pressure (BP) is recommended since recent PET studies have revealed that an excessive drop of BP markedly decreases cerebral blood flow. Furthermore, 24-hour-monitoring of BP revealed that physiological fluctuation of BP consisting of high daytime BP and low nocturnal BP disappears in hypertensive patients with vascular dementia and those with non-symptomatic vascular lesions on MRI. Recommendable BP levels for the hypertensive elderly must be established. The efficacy of both aspirin and ticlopidine for prevention of stroke has been established. Recent multi-centric trials have revealed that ticlopidine is more effective in preventing stroke but has more dangerous adverse effects than aspirin. Aspirin is reported to improve both the intellectual scale and cerebral blood flow in vascular dementia. In Parkinson's disease (PD), L-DOPA therapy, usually in combination with a dopa decarboxylase inhibitor, is common. Other dopaminergic drugs including bromocriptine, lisuride and pergolide are used clinically or are being studied. Recently selective monoamine oxidase (MAO) B inhibitors have been used in order to slow clinical progression of the disease, in addition to an attempt to increase the potential of dopamine through inhibition of MAO. Neural transplants to the striatum of PD were first applied using autografts of the adrenal medulla in 1985, but resulted in transient or only slight improvements.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Recent therapeutic advances in geriatric neurology]. 143 48

Oxidant stress, due to the formation of hydrogen peroxide and oxygen-derived free radicals, can cause cell damage due to chain reactions of membrane lipid peroxidation. Because the substantia nigra is rich in dopamine, which can undergo both enzymatic oxidation via monoamine oxidase and nonenzymatic autoxidation, hydrogen peroxide and oxyradicals (superoxide anion radical and hydroxyl radical) are generated in this midbrain nucleus. Although proof that oxidant stress actually causes the loss of monoaminergic neurons in patients with Parkinson's disease is lacking, there is a considerable body of evidence from studies in both animals and humans that support the concept. (1) Neurotoxins that selectively destroy the dopaminergic neurons in the nigra, such as 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), appear to act via oxidant stress. (2) The substantia nigra of patients with Parkinson's disease reveals evidence of oxidant stress by the findings of increased lipid peroxidation and decreased reduced glutathione. (3) Total iron is increased and ferritin is reduced in the substantia nigra pars compacta in patients with Parkinson's disease. This combination suggests that this transition metal is in a low molecular weight form, capable of catalyzing nonenzymatic oxidative reactions, especially the conversion of hydrogen peroxide to hydroxyl radical, which is the most reactive of the oxygen radicals. (4) Neuromelanin, a product of dopamine autoxidation, can serve as a reservoir for iron, promoting the generation of oxyradicals. (5) Antioxidant defense mechanisms appear to be reduced in the parkinsonian substantia nigra with the findings of decreased activities of glutathione peroxidase and catalase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The oxidant stress hypothesis in Parkinson's disease: evidence supporting it. 147 73


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