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 selective monoamine oxidase (MAO) B inhibitor L-deprenyl (Eldepryl, Jumex, Movergan, Selegiline) has gained acceptance as a useful form of adjunctive therapy in the treatment of Parkinson's disease. It has recently been suggested that deprenyl might be effective in altering the course of Parkinson's disease by actually slowing its progression. The rationale for this "new therapeutic strategy" rests on several lines of evidence which can be categorized as theoretical, experimental and empirical. We present details of an "in progress" double-blind, placebo-controlled, prospective clinical drug trial using deprenyl in patients with early, untreated Parkinson's disease. This study is designed to directly test the hypothesis that deprenyl may be effective in favorably altering its natural history. Rigorously testing this new hypothesis could have a major impact on current concepts regarding the treatment and management of Parkinson's disease.
 ...
PMID:R-(-)-deprenyl as a possible protective agent in Parkinson's disease. 312 6

Deprenyl, a selective inhibitor of monoamine oxidase, type B, which is free of the "tyramine effect," may ameliorate symptom fluctuations in advanced Parkinson's disease (PD). We randomized 96 patients with marked symptom fluctuations at three centers to receive either deprenyl 5 mg b.i.d. or placebo in parallel fashion in addition to a previously optimized levodopa/carbidopa (Sinemet) regimen. Disability was recorded hourly at home by patients 3 days weekly during the 2-week baseline and the 6-week treatment period. Disability during the "on" state was assessed each week by examination. Mean hourly self-assessment of gait improved in 28 of 50 patients (56%) receiving deprenyl (mean degree of improvement 0.25 points on a 0-2 scale) and in 14 of 46 (30.4%) taking placebo (mean 0.15). Mean hourly overall symptom control improved in 29 (58%) taking deprenyl (mean 0.34) and in 12 (26.1%) taking placebo (mean 0.15) (p less than 0.01 for each parameter). No significant improvement occurred in the objective quality of the "on" state with deprenyl. Mean daily Sinemet dosage decreases were 17% in the deprenyl group and 7% in the placebo group. Adverse effects included nausea, light-headedness, dyskinesias, and hallucinations, all of which abated after the Sinemet dose was reduced. We conclude that deprenyl is of moderate benefit in a majority of patients with symptom fluctuations complicating PD and is generally well tolerated.
 ...
PMID:Deprenyl in the treatment of symptom fluctuations in advanced Parkinson's disease. 312 50

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration leads to the selective destruction of the dopaminergic neurons of the nigrostriatal pathway in experimental animals including monkeys and mice. The neurotoxicity of MPTP is dependent upon its monoamine oxidase-B (MAO-B)-catalyzed conversion to the 1-methyl-4-phenylpyridinium species (MPP+). A methylated analog of MPTP. A methylated analog of MPTP, namely 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'Me-MPTP), is a more potent dopaminergic neurotoxin than MPTP in mice. Although the selective inhibition of MAO-B is sufficient to protect mice against MPTP-induced neurotoxicity, it is reported here that complete inhibition of MAO-B failed to prevent 2'Me-MPTP-induced dopaminergic neurotoxicity. However, the neurotoxicity of 2'Me-MPTP was completely prevented and 2'Me-MPP+ formation was markedly attenuated in mice in which both MAO-A and MAO-B were almost totally inhibited. This information about the role of MAO-A in the bioactivation of 2'Me-MPTP may be of relevance to those who speculate that the MAO-B catalyzed bioactivation of MPTP or a similar compound may be the cause of idiopathic Parkinson's disease.
 ...
PMID:Role for monoamine oxidase-A (MAO-A) in the bioactivation and nigrostriatal dopaminergic neurotoxicity of the MPTP analog, 2'Me-MPTP. 313 Nov 49

Monoamine oxidase-B (MAO-B) activity of platelets of an age- and sex-matched group of controls was compared with several groups of inpatients having non-familial dementia of Alzheimer type (DAT), Parkinson's disease (PD), multi-infarct dementia (MID), mixed types of these 3 diseases and a group of other central nervous system (CNS) organic disorders. All patients were subjected to several psychometric tests, including the Sandoz Clinical Assessment--Geriatric Scale, Hamilton Rating Scale for Depression, Mini-Mental State Examination and the Organic mental Disorder Scale (OMDS). A statistically significant enhancement of MAO-B activity could be observed in DAT patients and in PD patients, whereas the MID group showed a mean activity similar to that of the control group and the group with other organic CNS disorders. In DAT patients the degree of dementia in the OMDS test and the enhancement of MAO activity were positively correlated, but PD did not show such a correlation. It is concluded that the increase of MAO activity in PD and in DAT might be due to a disease-related enhanced affinity to oxygen and to such oxygen-derived radicals as superoxide or hydroxyl radicals. However, a possible drug-induced enhancement of MAO activity in PD cannot be excluded. Furthermore, the MAO-B activity values in platelets of individual patients or controls are not indicative of diagnosis or prognosis of any of these diseases and are of no disease-related specificity.
 ...
PMID:Platelet MAO-B activity and the psychopathology of Parkinson's disease, senile dementia and multi-infarct dementia. 322 31

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.
 ...
PMID:Inhibition of monoamine oxidase by 3,4-dihydroxyphenyl 1-alanine and its analogs. 324 97

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a contaminant found in a synthetic illicit drug, can elicit in humans and monkeys a severe extrapyramidal syndrome similar to Parkinson's disease. It also induces alterations of the dopamine (DA) pathways in rodents. MPTP neurotoxicity requires its enzymatic transformation into 1-methyl-4-phenylpyridinium (MPP+) by monoamine oxidase followed by its concentration into target cells, the DA neurons. Here, we show that mesencephalic glial cells from the mouse embryo can take up MPTP in vitro, transform it into MPP+, and release it into the culture medium. MPTP is not taken up by neurons from either the mesencephalon or the striatum in vitro (8 days in serum-free conditions). However, mesencephalic neurons in culture revealed a high-affinity uptake mechanism for the metabolite MPP+, similar to that for DA. The affinity (Km) for DA uptake is fivefold higher than that for MPP+ (0.2 and 1.1 microM, respectively), whereas the number of uptake sites for MPP+ is double (Vmax = 25 and 55 pmol/mg of protein/min for DA and MPP+, respectively). Mazindol, a DA uptake inhibitor, blocks the uptake of DA and MPP+ equally well under these conditions. Moreover, by competition experiments, the two molecules appear to use the same carrier(s) to enter DA neurons. Small concentrations of MPP+ are also taken up by striatal neurons in vitro. The amount taken up represented less than 10% of the MPP+ uptake in mesencephalic neurons. Depolarization induced by veratridine released comparable proportions of labeled DA and MPP+ from mesencephalic cultures.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine metabolism and 1-methyl-4-phenylpyridinium uptake in dissociated cell cultures from the embryonic mesencephalon. 325 19

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.
 ...
PMID:Design and early clinical evaluation of selective inhibitors of monoamine oxidase. 326 32

It is postulated that endogenous oxidative mechanisms are a major factor in the continuing death of dopaminergic neurons and the progression of Parkinson's disease. Scientific evidence in support of, and negating, the free radical auto-toxicity and dopamine toxicity concepts is reviewed. There is conflicting evidence whether free radicals are involved in the toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and attempts to prevent the toxicity of MPTP with antioxidant therapy have had variable results. The oxidation of dopamine by monoamine oxidase produces toxic metabolites however animal studies with high dose longterm levodopa and MPTP have failed to show clear evidence for autoxidation. Firm supportive evidence is obtained from the monoamine oxidase B inhibitor experience which demonstrated a block of the toxicity of MPTP in animals and probable prolongation of the course of human Parkinson's disease. The scientific data available is inconclusive but there is significant hope of retarding progressive catecholaminergic neuron degenerative changes by augmenting the free radical scavenging system with antioxidants (such as Vitamin E) and slowing catecholamine oxidation by monoamine oxidase B inhibition. Careful clinical trials with these agents must be performed.
 ...
PMID:Antioxidant therapy in Parkinson's disease. 331 49

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) causes selective destruction of dopaminergic neurons of the nigrostriatal pathway in humans and other primates. It is less specific and much less potent in mice and has only slight effects in rats. Differences in rates and sites of metabolism of MPTP to its active, toxic, highly polar metabolite, MPP+ (1-methyl-4-phenylpyridine), appear to influence species specificity. In rats, type B monoamine oxidase (MAO-B), which mediates the conversion of MPTP to MPP+, may act as an enzymatic barrier at brain microvessels, whereas in primates the enzyme, present mainly in astrocytes, appears important for bioactivation of MPTP into the toxic metabolite. MPP+ is a substrate for catecholamine uptake sites and is concentrated in these neurons. The molecular mechanism of MPP+ toxicity has not been established definitively, but conversion to a free radical or uptake by mitochondria and inhibition of mitochondrial respiratory enzymes, leading to calcium release and cell death have been suggested. The discovery of toxin which causes an animal model of Parkinson's disease has stimulated new research on environmental factors that might contribute to this progressive degenerative disorder and provides a means for assessing new approaches to therapy.
 ...
PMID:MPTP: an industrial chemical and contaminant of illicit narcotics stimulates a new era in research on Parkinson's disease. 331 63

The possible involvement of dopaminergic neurons in dementia of Alzheimer type (AD/SDAT) was studied in autopsied brains from 20 patients with AD/SDAT. Dopamine (DA) concentrations were decreased significantly in the temporal cortex, hippocampal cortex and hippocampus in AD/SDAT patients. Levels of homovanillic acid (HVA) were not altered compared to controls. The HVA/DA ratio was significantly higher in the hippocampus of AD/SDAT patients, suggesting overactivity of the remaining DA neurons. Histological findings of substantia nigra suggesting coexistent pathology of Parkinson's disease (PD) found in 25% of cases were associated with lowered levels of DA in striatum and with reduced HVA in CSF. The activity of monoamine oxidase-B was significantly increased in the cortical areas and in the hippocampus, obviously reflecting the underlying cell loss and substantial gliosis in these areas of the brain. In general, DA neurons seemed to be only mildly involved in AD/SDAT. Coexistent PD pathology can explain the loss of DA in the striatum and the presence of clinical PD symptoms in some patients with AD/SDAT. Otherwise the clinical relevance of these dopaminergic alterations is unclear.
 ...
PMID:Dopaminergic system and monoamine oxidase-B activity in Alzheimer's disease. 339 91


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>