Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The novel neuropsychotropic agent milacemide hydrochloride (2-n-pentylaminoacetamide HCl) is a highly selective substrate of the B form of monoamine oxidase (EC 1.4.3.4; MAO). Under the in vitro conditions used in the present study, milacemide acts as an enzyme-activated, partially reversible inhibitor of MAO-B. A reversible inhibition of MAO-A activity is also observed at high concentrations. The inhibitory activity of milacemide is significantly greater for MAO-B. In vivo, after single or repeated oral administration, a specific inhibition of MAO-B is apparent in brain and liver, with a lack of inhibition of the MAO-A activity. In contrast to the irreversible inhibitory action of L-deprenyl, the recovery of MAO-B activity in vivo after milacemide administration is significantly faster, a result suggesting that it is a partially reversible inhibitor. The selective inhibitory effect of milacemide for MAO-B in vivo is confirmed by its potentiation of phenylethylamine-induced stereotyped behavior, whereas vasopressor responses to tyramine were not affected. These observations suggest that milacemide could enhance dopaminergic activity in the brain and could be used as therapy for Parkinson's disease in association with L-3,4-dihydroxyphenylalanine.
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PMID:The novel neuropsychotropic agent milacemide is a specific enzyme-activated inhibitor of brain monoamine oxidase B. 276 56

The tetrahydro-beta-carboline derived from the condensation of N-methyltryptamine and formaldehyde, a semirigid tricyclic analogue of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) tha has been detected in the brains of normal laboratory rats, is biotransformed in a monoamine oxidase B (MAO-B) catalyzed reaction to the corresponding dihydro compound at a rate that is approximately 0.5% of that observed with MPTP. The corresponding tetrahydroindenopyridine in which the double bond beta,gamma to the nitrogen atom retains allylic character is a somewhat better MAO-B substrate. The steric bulk of the nitrogen and methylene bridges in addition to ring strain present in the proposed carbon-centered radical intermediates derived from these types of tricyclic structures may contribute to their relatively poor MAO-B substrate properties. Although no MPTP-like neurotoxic properties were observed following acute administration of the test compounds to mice, we speculate that the chronic accumulation of beta-carbolinium type metabolites could contribute to the rate of nigrostriatal cell loss associated with idiopathic Parkinson's disease.
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PMID:Studies on semirigid tricyclic analogues of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 278 13

The in vivo dopaminergic neurotoxicity of a series of quinoline and isoquinoline derivatives was assessed in rats using an intrastriatal microdialysis technique that measures the release of dopamine. The N-methyl quaternary salts of these two heterocyclic aromatic systems displayed about 10% of the potency of MPP+ in this assay. Furthermore, tetrahydroisoquinoline, which has been reported to be present in human brain, and N-methyltetrahydroisoquinoline were found to be MAO-B substrates, being oxidized at about 3% the rate of MPTP. Thus, although tetrahydroisoquinoline and N-methyltetrahydroisoquinoline are not neurotoxic, it is conceivable that the chronic endogenous formation of quaternary species could cause neuronal lesions that contribute to the etiology of idiopathic Parkinson's disease.
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PMID:Intracerebral microdialysis neurotoxicity studies of quinoline and isoquinoline derivatives related to MPTP/MPP+. 278 53

MPTP causes a Parkinson's disease-like syndrome in man and certain other animals. The toxic effect occurs if monoamine oxidase B is available, indicating that an MPTP metabolite may cause the toxic effect. We tested the effect of MPDP+, the first product of MPTP oxidation, and found that it, like MPTP, caused a non-reversible decrease in synaptic transmission in the mouse brain slice preparation. As the second oxidation product, MPP+ had been shown not to cause a similar, non-reversible decrease in synaptic transmission, MPDP+ is a better candidate for the role of toxic substance.
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PMID:MPDP+ causes a non-reversible decrease in neostriatal synaptic transmission in mouse brain slice. 282 46

Parkinson's disease is characterized especially by a degeneration of pigmented brain regions, like substantia nigra. These changes are accompanied by a variety of biochemical disturbances of dopaminergic and noradrenergic systems. Also the reduction of serotonin can be related to degenerative processes occurring in subareas of the raphe. Furthermore amino acid transmitters like GABA and a variety of peptidergic neuromodulators are changed. Additional cholinergic hypofunction due to degeneration of the nucleus basalis Meynert is able to impair the quality of life due to loss of intellectual capacity. A variety of biochemical mechanisms compensate for a long time the progression of neuronal loss. Modern treatment strategies (combined L-dopa therapy, dopaminergic agonists, MAO-B inhibitors, amantadine) are able to substitute the deficiency especially of the catecholamines. For the development of more causal therapies, a new animal model has been developed 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes parkinsonism after peripheral administration and leads to denervation of the dopaminergic nigrostriatal system. It is the hope that this new model, which is described here in detail, will lead to decisive data underlying the cause of Parkinson's disease.
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PMID:[Neurobiologic and pharmacologic studies on the pathogenesis of Parkinson disease]. 287 40

The effects of a COMT-inhibitor, U-0521, and a MAO-B-inhibitor, 1-deprenyl, on L-dopa-induced circling behaviour were compared in 6-OHDA-lesioned rats. The actions of U-0521 and 1-deprenyl on the anti-cataleptic effect of L-dopa were also studied. Both U-0521 and 1-deprenyl were found to potentiate L-dopa-induced circling behaviour and anti-cataleptic effect of L-dopa. In both test systems the L-dopa potentiation of 1-deprenyl was longer-lasting than that caused by U-0521. Thus inhibition of COMT, like inhibition of MAO, is able to enhance the central effects of L-dopa. This principle might be beneficial in the treatment of Parkinson's disease especially if COMT-inhibitors with greater performance can be developed.
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PMID:Potentiation of central effects of L-dopa by an inhibitor of catechol-O-methyltransferase. 296 Jul 78

The ability of MPTP to induce persistent parkinsonism in man may provide a vital clue to the cause of the idiopathic disease. However, the peripheral administration of MPTP to rodent species only produces losses in brain dopamine content and damage to the nigrostriatal system in high doses and no persistent motor deficits have been observed. In contrast, in primates, the administration of MPTP rapidly induces a persistent parkinsonian syndrome accompanied by evidence for selective damage to the nigro-striatal dopamine containing system. Other neurotransmitter systems appear unaffected by MPTP treatment. The MPTP-treated primate responds to the administration of L-DOPA and other antiparkinsonian drugs and may provide a useful test-bed for the development of novel antiparkinsonian medication. Administration of MPTP to primates causes an accumulation of MPP+ in a variety of brain areas. The accumulation of MPP+ and the neurotoxic actions of MPTP in primates can be prevented by the prior administration of monoamine oxidase inhibitors. The ability of monoamine oxidase inhibitors to prevent MPTP toxicity is related to the metabolism of MPTP by monoamine oxidase B, probably extraneuronally in glia, to produce MPDP+ and subsequently MPP+. In rodent synaptosomal preparations MPP+ is a substrate for the dopamine uptake mechanism and so would be selectively accumulated in brain dopamine neurones. Administration of MPTP to animals results in the production of a partial model of idiopathic Parkinson's disease as it occurs in man. MPTP treatment produces the major symptoms of Parkinson's disease in primates but the pathology is limited to the nigro-striatal system, whereas in Parkinson's disease pathology is more widespread. Biochemical changes induced by MPTP again seem primarily limited to those induced by damage to the nigro-striatal dopamine containing system. MPP+ (or another metabolite of MPTP) may be responsible for the neurotoxicity of MPTP but not all neurones which accumulate products of MPTP metabolism are damaged. The nigro-striatal system may be peculiarly sensitive to the effects of MPTP.
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PMID:The actions of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in animals as a model of Parkinson's disease. 309 60

Studies have been carried out in the rodent and marmoset to assess (i) the selectivity of MPTP action to the nigrostriatal system, (ii) the possibility that melanin pigmentation may influence the actions of MPTP, (iii) whether the metabolites of MPTP may contribute to its actions on dopamine cells, (iv) the site(s) of action of MPTP in the brain, (v) the mechanism(s) of action of MPTP and whether it is possible to prevent the damaging effects of MPTP/metabolites on the brain dopamine systems. The peripheral administration of MPTP in the mouse causes depletions of dopamine and its metabolites in both the striatal and limbic systems: this action is similar in both white and pigmented mice. The MAO-B inhibitor deprenyl was shown to antagonize the actions of MPTP, and its metabolite formed via oxidation through MAO, MPP+, was shown to disrupt striatal dopamine function as determined behaviorally (as motor impairment) or biochemically (as loss of dopamine and its metabolites) when injected into the cerebral ventricles of mouse or infused into the substantia nigra of rat brain. MPTP and MPP+ act in the midbrain to interfere with dopamine cell functioning, and studies in both the rodent and marmoset are presently analyzing possible additional actions in forebrain regions. It is therefore proposed that the neurotoxic action of MPTP, effected via its metabolite MPP+, may not be selective for the nigrostriatal system. Nevertheless, the nature and profile of neurotoxicity effected by MPTP and, in particular, MPP+ should ensure continuing analyses of the relevance of such action to an understanding of the etiology of, treatment of, and even the possible prevention of Parkinson's disease in man.
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PMID:Neuropharmacological manipulations with MPTP. 309 61

The classical treatment of Parkinson's disease (PD) using L-dopa plus a peripheral decarboxylase inhibitor (DI) often leads after 3-5 years to the onset of the so-called long-term L-dopa syndrome (LTS). LTS could depend on the chronic overload of L-dopa + ID and could be due to a consequent "receptor disease" and derangement of the neuronal functionality mainly in regard to the enzymatic chains, storage mechanisms and hyperactivity of the monoamine oxidase type B (MAO B). Deprenyl is a selective MAO-B inhibitor thought to be able to slow down the catabolism of dopamine and therefore to allow a decrease of the therapeutic regimen of L-dopa while in the meantime to obtain a more stable plasma and tissue levels and a constant therapeutic response. 76 parkinsonian patients were studied. Their L-dopa regimen was halved and 10 days after (-)deprenyl was added. After the decrease of L-dopa therapy a worsening of symptomatology was observed as expected. The association with (-)deprenyl was able to reverse this trend and when the inhibition of MAOB was really effective patients showed an improvement of symptoms even when compared to baseline values. No relevant side effects were observed and no patients dropped out.
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PMID:The role of MAO-b inhibitors in the treatment of Parkinson's disease. 309 57

Specific binding of 3H-MPTP to brain homogenates is displaced predominantly by MAO-A inhibitor clorgyline in rat, and by MAO-B inhibitor deprenyl in monkey. A covalently bound metabolite is formed by MAO-B in vitro from MPTP, through a reaction almost completely inhibited by physiological concentrations of glutathione and significantly reduced by other sulfhydryl containing compounds. The difference in binding site pharmacological properties may account for the relative resistance of rat to the neurotoxic effect produced by MPTP in primates. The glutathione-prevented metabolic conversion to a reactive intermediate may be important for the mechanism of MPTP neurotoxicity and relevant to idiopathic Parkinson's disease.
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PMID:Primate-rodent 3H-MPTP binding differences, and biotransformation of MPTP to a reactive intermediate in vitro. 309 60


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