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Thomas Müller - One of the best experts on this subject based on the ideXlab platform.
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Management with Monoamine Oxidase B inhibitors in Parkinson's disease
Diagnosis and Management in Parkinson's Disease, 2020Co-Authors: Thomas MüllerAbstract:Abstract Neurotransmission of biogenic Monoamines such as dopamine is important for brain function. Biogenic amine degradation uses Monoamine Oxidase B in neuronal and glial cells. Inhibition Monoamine Oxidase B elevates biogenic amine concentration in the synaptic cleft. Thus Monoamine Oxidase B inhibitors provide a symptomatic effect on motor symptoms in Parkinson's disease, as shown in clinical trials. Oxidative stress is generated by biogenic amine turnover through Monoamine Oxidase B. Mechanisms of oxidative stress contribute to the progression of chronic neurodegeneration. Experimental researchers showed that inhibitors of Monoamine Oxidase B slow progression in experimental models of Parkinson's disease. With concomitant inhibition of Monoamine Oxidase B, levodopa dosages increased less, and curves of levodopa increases diverged from that of the placebo arm. This may indicate a disease-modifying effect of inhibition of Monoamine Oxidase B in addition to the proven symptomatic benefits of the irreversible inhibitors selegiline and rasagiline and the reversible inhibitor safinamide.
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Pharmacokinetics of Monoamine Oxidase B inhibitors in Parkinson's disease: current status.
Expert Opinion on Drug Metabolism & Toxicology, 2019Co-Authors: Thomas Müller, Jan-dominique MöhrAbstract:ABSTRACTIntroduction: Brain function depends considerably on the neurotransmission of biogenic Monoamines. Their metabolism employs Monoamine Oxidase-B in neuronal and glial cells. Inhibition of Monoamine Oxidase-B elevates biogenic amine levels. Accordingly, Monoamine Oxidase-B inhibitors provide a symptomatic effect via dopamine on motor symptoms in patients with Parkinson’s disease.Areas covered: This narrative review aims to describe the pharmacokinetic characteristics of the available reversible and irreversible Monoamine Oxidase B inhibitors for the treatment of Parkinson’s disease in daily practice. All these compounds are administered on a daily basis.Expert opinion: Reversibility or irreversibility of available Monoamine Oxidase-B inhibition is not relevant, due to their daily intake and half-life in clinical practice. Irreversible Monoamine Oxidase-B inhibitors slowed the progression of neuronal dying in experimental models of Parkinson’s disease. In patients, concomitant inhibition of Monoamine...
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determination of Monoamine Oxidase a and b activity in long term treated patients with parkinson disease
Clinical Neuropharmacology, 2017Co-Authors: Thomas Müller, Peter Riederer, Edna GrunblattAbstract:BACKGROUND Biogenic amines and Monoamine Oxidase inhibitors influence peripheral Monoamine Oxidase enzyme activity in chronic levodopa/dopa decarboxylase inhibitor-treated patients with Parkinson disease. Rasagiline is an irreversible inhibitor of Monoamine Oxidase B. Safinamide blocks this isoenzyme in a reversible fashion. OBJECTIVES The aim of this study was to determine Monoamine Oxidase A (plasma) and B (platelets) enzyme activity in long-term levodopa-treated patients without and with additional oral intake of 50- or 100-mg safinamide or 1-mg rasagiline or first-time intake of rasagiline. RESULTS Monoamine Oxidase A enzyme activity did not differ between all groups. Patients on rasagiline or safinamide showed lower Monoamine Oxidase-B enzyme activity compared with patients without Monoamine Oxidase B inhibitor intake. No impact of the number of previous oral levodopa intakes was found. DISCUSSION Rasagiline and safinamide did not essentially differ in terms of inhibition of Monoamine Oxidase B despite their different pharmacology regarding reversibility of Monoamine Oxidase B inhibition. In view of the observed, considerable heterogeneity of enzyme activities, we suggest to determine activities of Monoamine Oxidase A and B to reduce the risk for tyramine-induced hypertension and the serotonergic syndrome during chronic therapy with rasagiline or safinamide.
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Use of Monoamine Oxidase inhibitors in chronic neurodegeneration.
Expert opinion on drug metabolism & toxicology, 2017Co-Authors: Peter Riederer, Thomas MüllerAbstract:ABSTRACTIntroduction: Neurotransmission by biogenic Monoamines is important for brain function. Biogenic amine turnover employs the enzymes catechol-O-methyltransferase and Monoamine Oxidase in neuronal and glial cells. Inhibition of these enzymes elevates biogenic amine levels in the synaptic cleft. Subtype selectivity of inhibition is lost during long-term use of ‘selective’ Monoamine Oxidase inhibitors.Areas covered: This narrative review discusses use of Monoamine Oxidase inhibitors in the context with chronic neurodegeneration.Expert opinion: Antidepressant drugs increase synaptic concentrations of biogenic amines. In the aging brain, then one of the two enzymes involved in degrading synaptic amines, catechol-O-methyl transferase, increasingly catalyzes methylation processes. Therefore, metabolism by Monoamine Oxidase plays an incremental, predominant role in biogenic amine turnover, leading to greater oxidative stress. In patients with chronic neurodegenerative disorders, symptoms, such as depressio...
Moussa B.h. Youdim - One of the best experts on this subject based on the ideXlab platform.
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The therapeutic potential of Monoamine Oxidase inhibitors.
Nature reviews. Neuroscience, 2006Co-Authors: Moussa B.h. Youdim, Dale E. Edmondson, Keith F. TiptonAbstract:Monoamine Oxidase inhibitors were among the first antidepressants to be discovered and have long been used as such. It now seems that many of these agents might have therapeutic value in several common neurodegenerative conditions, independently of their inhibition of Monoamine Oxidase activity. However, many claims and some counter-claims have been made about the physiological importance of these enzymes and the potential of their inhibitors. We evaluate these arguments in the light of what we know, and still have to learn, of the structure, function and genetics of the Monoamine Oxidases and the disparate actions of their inhibitors.
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The interactions of milacemide with Monoamine Oxidase
Biochemical pharmacology, 1994Co-Authors: Eimear M. O'brien, Keith F. Tipton, John M. Mccrodden, Moussa B.h. YoudimAbstract:The interactions of the anticonvulsant drug milacemide (2-n-pentylaminoacetamide) with rat liver mitochondrial Monoamine Oxidases-A and -B have been studied. The compound acts as a substrate for the B-form of the enzyme, with an apparent Km value of 49 +/- 4.7 microM and a Vmax value of 1.1 +/- 0.2 nmol/min/mg. It is also a time-dependent irreversible inhibitor of that enzyme. Any activity of Monoamine Oxidase-A towards this substrate was too low to allow accurate determinations to be made by either luminometric determination of H2O2 formation or spectrophotometric coupling of aldehyde formation to NAD+ reduction in the presence of aldehyde dehydrogenase. Milacemide was a reversible competitive inhibitor towards Monoamine Oxidase-A. The inhibitor constant (Ki) was 115 +/- 35 microM indicating a higher affinity than that towards Monoamine Oxidase-B, which was also competitively inhibited in the absence of enzyme-inhibitor preincubation (Ki = 331 +/- 185 microM). Determination of the formation of H2O2 and the aldehyde product of the oxidative cleavage of milacemide by purified Monoamine Oxidase-B from ox liver indicated that cleavage resulted solely in the formation of pentanal and glycinamide. There was no evidence for alternative cleavage to pentylamine and oxamaldehyde.
Roy B. Mccauley - One of the best experts on this subject based on the ideXlab platform.
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The insertion of Monoamine Oxidase A into the outer membrane of rat liver mitochondria.
The Journal of biological chemistry, 1992Co-Authors: Zhengping Zhuang, Bernard H. Marks, Roy B. MccauleyAbstract:Human Monoamine Oxidase A that had been synthesized in a reticulocyte lysate translation system was capable of binding to and inserting into either rat liver mitochondria or isolated mitochondrial outer membranes. The inserted form was as resistant to proteinase K as endogenous mitochondrial Monoamine Oxidase A. The insertion, but not the binding, of Monoamine Oxidase A was prevented by depleting the reaction mixture of either ATP (with apyrase) or ubiquitin (with purified antibodies against this polypeptide). Addition of ATP or ubiquitin, respectively, to these depleted mixtures restored the insertion of the enzyme. In the absence of mitochondria, in vitro synthesized Monoamine Oxidase A did not catalyze its own alkylation by the mechanism-based inhibitor, [3H]clorgyline. However, both Monoamine Oxidase A that had been membrane-inserted in vitro and Monoamine Oxidase A that had been bound to the mitochondria under conditions of ATP depletion catalyzed adduct formation. Furthermore, reaction of either clorgyline or another mechanism-based inhibitor, pargyline, with the membrane-bound enzyme during ATP depletion inhibited the insertion of Monoamine Oxidase A when ATP was restored. These observations indicate that Monoamine Oxidase A acquired a catalytically active conformation on interaction with the mitochondrial outer membranes prior to its ATP and ubiquitin-dependent insertion into the membrane.
Rona R Ramsay - One of the best experts on this subject based on the ideXlab platform.
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Dietary inhibitors of Monoamine Oxidase A
Journal of Neural Transmission, 2011Co-Authors: Sarah E. Dixon Clarke, Rona R RamsayAbstract:Inhibition of Monoamine Oxidase is one way to treat depression and anxiety. The information now available on the pharmacokinetics of flavonoids and of the components of tobacco prompted an exploration of whether a healthy diet (with or without smoking) provides active compounds in amounts sufficient to partially inhibit Monoamine Oxidase. A literature search was used to identify dietary Monoamine Oxidase inhibitors, the levels of these compounds in foods, the pharmacokinetics of the absorption and distribution, and tissue levels observed. An estimated daily intake and the expected tissue concentrations were compared with the measured efficacies of the compounds as inhibitors of Monoamine Oxidases. Norharman, harman and quercetin dietary presence, pharmacokinetics, and tissue levels were consistent with significant levels reaching neuronal Monoamine Oxidase from the diet or smoking; 1,2,3,4-tetrahydroisoquinoline, eugenol, 1-piperoylpiperidine, and coumarin were not. Quercetin was equipotent with norharman as a Monoamine Oxidase A inhibitor and its metabolite, isorhamnetin, also inhibits. Total quercetin was the highest of the compounds in the sample diet. Although bioavailability was variable depending on the source, a healthy diet contains amounts of quercetin that might give sufficient amounts in brain to induce, by Monoamine Oxidase A inhibition, a small decrease in neurotransmitter breakdown.
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Secondary structure of Monoamine Oxidase by FTIR spectroscopy.
Biochemical and biophysical research communications, 1995Co-Authors: Jacques Wouters, Rona R Ramsay, Erik Goormaghtigh, Jean Marie Ruysschaert, Robert Brasseur, François DurantAbstract:The secondary structure of human Monoamine Oxidase A and bovine Monoamine Oxidase B has been investigated by Fourier Transform Attenuated Total Reflection Spectroscopy (FTIR ATR). The experimental results are compared for both isoenzymes and the data are incorporated in a statistical attribution of secondary structure of the enzyme describing the distinct folding and molecular specificity of the two types of Monoamine Oxidase.
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Kinetic mechanism of Monoamine Oxidase A.
Biochemistry, 1991Co-Authors: Rona R RamsayAbstract:Steady-state kinetic data for Monoamine Oxidase A in crude extracts suggest an exclusively ping-pong mechanism, in contrast to those for Monoamine Oxidase B, which indicate alternate mechanisms involving either a binary or ternary complex. In this study, with use of purified Monoamine Oxidase A, steady-state data for the inhibition by D-amphetamine of the oxidation of primary amines indicate the possibility of a ternary complex mechanism for Monoamine Oxidase A also. Stopped-flow studies demonstrate that the rate of reoxidation of reduced enzyme is enhanced by substrates but not by the product, 1-methyl-4-phenylpyridinium. Thus, for the A enzyme, the ternary complex with substrate, but not product, is reoxidized at a faster rate than the free, reduced enzyme. For both the A and B forms of Monoamine Oxidase, the mechanism is determined by competition between alternate pathways on the basis of the relative rate constants and dissociation constants.
Sidney H. Kennedy - One of the best experts on this subject based on the ideXlab platform.
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Monoamine Oxidase Inhibitors
Antidepressants: Past Present and Future, 2004Co-Authors: Sidney H. Kennedy, A. Holt, Glen B. BakerAbstract:The Monoamine Oxidase inhibitors (MAOIs) have been in clinical use for five decades. The coincidental discovery that inhibiting brain Monoamine Oxidase resulted in antidepressant benefits indirectly led to the norepinephrine (NE) and serotonin hypotheses for depression. Phenelzine (PLZ) and tranylcypromine (TCP) typify the classical, nonselective and irreversible inhibitors; selegiline (SEL) selectively but irreversibly inhibits MAO-B and is an established adjunct therapy for Parkinson's disease; while moclobemide and befloxatone represent examples of selective and reversible inhibitors. These agents provide opportunities to examine brain amine and amino acid levels during treatment and have also contributed to emerging aware of neurogenesis and neuronal rescue as potential antidepressant properties. Also of emerging interest are the extended sites of action beyond MAO for these agents including γ-aminobutyric acid (GABA) and imidazoline binding sites.
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metabolism of Monoamine Oxidase inhibitors
Cellular and Molecular Neurobiology, 1999Co-Authors: Glen B. Baker, Liana Urichuk, K F Mckenna, Sidney H. KennedyAbstract:1. The principal routes of metabolism of the following Monoamine Oxidase inhibitors (MAOIs) are described: phenelzine, tranylcypromine, pargyline, deprenyl, moclobemide, and brofaromine.