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 striatum, in which the nigrostriatal dopaminergic neurons terminate, contains the highest amount of dopamine DA) in the brain. DA, released in the striatum, plays the rate limiting role in the control of motor functions by continuously inhibiting the release of acetylcholine (ACh) from the cholinergic interneurons of the caudate nucleus. DA content of the human caudate nucleus decreases by 13% per decade over the age of 45. Parkinson's disease seems to be a kind of selective, highly accelerated 'premature aging' of the nigrostriatal dopaminergic system, and the DA content of this neuron system shrinks within a short time to less than 10% of the normal level in the premorbid state. Clinical symptoms occur when the striatum loses more than 70% of its DA content. The chemical lesioning of the nigrostriatal dopaminergic neuron in the rat by 6-OH-dopamine (6-OHDA) leads to an increase of cholinergic activity in the striatum. The striatum taken from a rat pretreated with 6-OH dopamine is a useful experimental model for the rapid screening of compounds with potential therapeutic benefit in Parkinson's disease. A more specific neurotoxin than 6-OHDA is 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) which kills the cells in the substantia nigra with high specificity and induces rapidly parkinsonian-like condition in men and monkeys. (-)Deprenyl, the selective inhibitor of B-type MAO protects the striatum from the neurotoxic effects of 6-OHDA and MPTP. The amount of ACh released from the striatum of the rat increases from 372.8 +/- 31.4 to 746.5 +/- 44.0 pmol/g/min in 6-OHDA treated rats, it remains normal (371.1 +/- 34.7) if (-)deprenyl is given 30 minutes before 6-OHDA administration, hut is further increased (956.3 +/- 79.3 pmol/g/min), if clorgyline os injected 30 minutes before 6-OHDA. (-)Deprenyl prevents in a similar manner the neurotoxicity of MPTP in monkeys, whereas clorgyline, the selective inhibitor of MAO-A, is ineffective. The most important effect of deprenyl in the brain is the sensitization of dopaminergic neurons to physiological and pharmacological influences without eliciting an acute increase in dopaminergic activity. The effect of deprenyl is due, on the one hand, to the inhibition of MAO-B and, on the other hand, to inhibition of the uptake of dopamine.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Medicamentous strategy for improving the quality of life in the senescence]. 309 65

The enzyme monoamine oxidase (MAO) plays an important role in the inactivation of both dietary amines and also of neurotransmitter amines. A study of the properties of irreversible inhibitors of this enzyme suggests that the enzyme exists in two broad types--MAO-A and MAO-B. Although irreversible inhibitors of MAO were once widely used as antidepressant agents, they fell from favour because of adverse reactions after the ingestion of amine-containing foodstuffs ("the cheese reaction"). However, these inhibitors (phenelzine and tranylcypromine) are probably best for the treatment of atypical depression providing the patient is aware of dietary reactions. A new series of reversible, MAO-A selective inhibitors are being developed which do not exhibit serious dietary interactions. These reversible inhibitors show promise as rapidly acting antidepressant agents. An atypical irreversible MAO-B selective inhibitor, selegiline (deprenyl) does not exhibit an adverse reaction on the ingestion of amine-containing foods. This drug has been used as an adjuvant in the treatment of Parkinson's disease since it allows the dose of L-dopa to be reduced by approximately 25%. More important, selegiline may slow the degeneration of dopaminergic neurons that is characteristic of Parkinson's disease.
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PMID:The current status of monoamine oxidase and its inhibitors. 311 97

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

L-deprenyl is a potent, well tolerated and safe inhibitor agent of MAO-B. Administration in daily dosage of 10 mgs produces an almost complete inhibition of the enzyme. Clinical trials of the use of l-deprenyl in Parkinson's disease have shown the following: l-deprenyl as monotherapy in Parkinson's disease does not control its symptoms. In those on a therapeutic regimen containing levodopa and experiencing fluctuating responses, particularly the "wearing off" type, the addition of l-deprenyl results in their attenuation or control. It is not fully agreed by all investigators whether such as effect is enduring or begins to wane after two or three years, nor that other symptoms of parkinsonism are improved. One investigator has reported that the combined use of these agents has resulted in an increase in life expectancy in Parkinson's disease. They have suggested that these findings indicate that l-deprenyl may be capable of preventing degeneration of the nigro-striatal system and halting progression of the Parkinson's disease process. This has raised the issue of initiating treatment with l-deprenyl during the early phases of Parkinson's disease.
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PMID:R-(-)-deprenyl and parkinsonism. 312 5

It was the aim of our study based on a group of 460 patients suffering from Parkinson's disease to find out possible pathogenetic linkups for the so-called "on-off" phenomenon. The method was based on two questionnaires of different structure, and in 90 cases we also called personally on the patient in his home. The patients were either known from neurological treatment they received at the Department of Neurology of the University of Essen, or were approached on-target via their membership in the German Parkinson Association. After evaluation, 43 patients with an on-off phenomenon and 81 with end-of-dose akinesia, as well as 336 patients without fluctuations of motility, could be classified and evaluated further. All patients with an on-off phenomenon or end-of-dose akinesia had received L-dopa treatment for several years; the average treatment period was 8.4 years in a patient with on-off phenomenon and 7.3 years in case of end-of-dose akinesia. Compared therewith, patients without fluctuations had only an average L-Dopa intake period of 5 years. It is a striking fact that in the patient group without fluctuations (n = 336) 51 patients (15.7%) had never taken an L-dopa preparation. 72.1% of the on-off group suffered from hyperkinesia before abrupt onset of the phase, while at the same time a recession of L-dopa efficacy was seen after several years of treatment. In about 40% of the questioned on-off patients we found that end-of-dose akinesia had preceded the on-off condition, and that the time correlation of the akinesia with the intake of the preparation was gradually abandoned. The age of the patients with on-off or end-of-dose patterns was, at the time of diagnosis, 55.6 or 54.2 years respectively. These patients were therefore much younger on the average than those of the comparative group without any disturbance of motility (60.1 years). On-off patients suffered comparatively more often from concomitant cardiovascular disease and their more active smoking habits were very noticeable. Taking the pathological specialities into consideration, it is recommended to critically reconsider the early use of L-dopa in relatively young patients with concomitant cardiovascular diseases, and to give preference in case of an indication for L-dopa to a combination treatment especially with MAO-B inhibitors and dopamin antagnonists in order to keep the daily L-dopa dose low. Arguments against L-dopa to be taken three times daily are discussed, as are the pros and cons of concomitant therapy.
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PMID:[Clinical aspects and pathogenesis of the "on-off" phenomenon in Parkinson syndrome]. 312 21

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

In summary, the parkinsonism induced by MPTP in man closely resembles time-telescoped Parkinson's disease. Parkinsonian symptoms can be duplicated in all aspects under controlled conditions in subhuman primates; the biochemical changes are replicated in mice, dogs, and to varying degrees in other species. Mechanisms of bioactivation by MAO-B of MPTP to MPP+, concentration of MPP+ in neurons with a catecholamine uptake system, and vulnerability to cellular toxic effects of MPP+ are the basis for the specificity of MPTP targeting of nigrostriatal dopaminergic neurons. It is hoped that an understanding of the mechanism of species specificity and cellular toxicity will in time explain the pathogenesis of idiopathic Parkinson's disease and suggest new opportunities for effective therapy.
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PMID:MPTP toxicity: implications for research in Parkinson's disease. 312 82

The mechanisms underlying the therapeutic action, the adverse side-effects, and the decline in efficacy upon prolonged administration of L-DOPA in patients with Parkinson's disease are not yet well understood. Therefore, further studies of the biochemical effects of L-DOPA are required. The current article indicates that L-DOPA, D-DOPA and L-alpha-methyl-DOPA can reversibly inhibit monoamine oxidase (MAO) activity. Inhibition of MAO-A of human placental mitochondria by L- and D-DOPA was non-competitive with the substrate kynuramine (Ki = 154 microM and 133 microM, respectively). L-alpha-methyl-DOPA competitively inhibited MAO-A (Ki = 121 microM). MAO-A and MAO-B of human liver mitochondria were also inhibited by L-DOPA (Ki = 152 microM and 275 microM, respectively). These results indicate that L-DOPA or L-alpha-methyl-DOPA might act, to some extent, by perturbing the catabolism of brain biogenic amines, but no direct evidence indicates that the brain concentrations of these drugs achieved during therapy are high enough to inhibit MAO activity.
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PMID:Inhibition of monoamine oxidase by 3,4-dihydroxyphenyl 1-alanine and its analogs. 324 97

1. Selective inhibitors of the monoamine oxidase (MAO) isoenzymes, types A and B, are of potential therapeutic utility. Brain selectivity would overcome the risk of tyramine interactions which have been shown to occur with selective MAO-A but not MAO-B inhibitors. 2. (E)-3-Fluoroallylamines of general structure, FHC = C(R)CH2NH2 have been designed as enzyme-activated, irreversible inhibitors of these enzymes. Two compounds, MDL 72145 (R = 3,4 dimethoxyphenyl) and MDL 72974 (R = 4-fluorophenethyl), are selective and irreversible inhibitors of MAO type B which in vivo show high inhibitory potency against the rat brain enzyme (ED50 0.35 and 0.18 mg/kg p.o., respectively). In animals, these inhibitors do not potentiate the cardiovascular effects of tyramine and have no amphetamine-like effects. However, they do potentiate the central effects of L-Dopa and prevent the neurotoxic effects of MPTP in both mice and monkeys. 3. In early clinical studies, MDL 72145 has been shown to be a potent, long-acting inhibitor of MAO type B. Doses of 16 mg per patient totally inhibit platelet enzyme without potentiating the cardiovascular effects of oral tyramine. Compounds of this type should prove useful in Parkinson's disease. 4. Selective inhibition of brain MAO-A can be achieved by using the bioprecursor amino acid MDL 72394 (E-beta-fluoromethylene-m-tyrosine). This amino acid is decarboxylated by aromatic L-amino acid decarboxylase (AADC) to liberate MDL 72392 (R = 3-hydroxyphenyl), a potent irreversible inhibitor of MAO-A. Combination of MDL 72394 with a peripherally selective inhibitor of AADC (e.g., carbidopa) restricts MAO inhibition to the brain. Consequently, under these conditions, there is a greatly reduced propensity to potentiate the cardiovascular effects of tyramine. 5. This has been confirmed in human volunteers; MDL 72394 (8 mg), combined with carbidopa, substantially decreased urinary MHPG and plasma DHPG concentrations with minimal potentiation of the cardiovascular effects of i.v. tyramine. These results predict that such therapy has potential in the treatment of affective disorders.
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PMID:Design and early clinical evaluation of selective inhibitors of monoamine oxidase. 326 32

Treatment of Parkinson's disease has to be considered as long-term treatment of a progressive illness. Basically we try a substitution of the dopamine deficiency by administration of levodopa in combination with a decarboxylase inhibitor. The occurrence of long-term complications such as fluctuations of mobility (on/off phenomena) and dyskinesias caused the use of lower levodopa doses and the simultaneous application of other antiparkinson drugs, e. g. anticholinergics, amantadines, dopamine agonists and MAO-B-inhibitors. When administering additional drugs, kind and severity of the parkinsonian symptomatology as well as the specific side effects of the different drugs have to be taken in consideration. According to recent experimental and clinical findings MAO-B-inhibitors may have protective effects on the neurons thus delaying the course of the disease.
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PMID:[Parkinson disease--new aspects of therapy]. 328 99


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