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The Canadian Journal of Hospital... 2018Monoamine oxidase B (MAO-B) inhibitors are used to treat the motor symptoms of Parkinson disease. Depression is commonly associated with Parkinson disease, and selective... (Review)
Review
BACKGROUND
Monoamine oxidase B (MAO-B) inhibitors are used to treat the motor symptoms of Parkinson disease. Depression is commonly associated with Parkinson disease, and selective serotonin reuptake inhibitors (SSRIs) are often used for its management. Tertiary sources warn that the combination of MAO-B inhibitors and SSRIs can result in increased serotonergic effects, leading to serotonin syndrome.
OBJECTIVE
To explore the mechanism, clinical significance, and management of this potential drug interaction through a review of the supporting evidence.
DATA SOURCES
PubMed, MEDLINE (1946 forward), Embase (1947 forward), PsycINFO (1806 forward), and International Pharmaceutical Abstracts (1970 forward) were searched on February 4, 2017.
STUDY SELECTION AND DATA EXTRACTION
Studies and case reports describing aspects of the potential interaction between MAO-B inhibitors and SSRIs in patients with Parkinson disease and published in English were identified by both title and abstract.
DATA SYNTHESIS
The search identified 8 studies evaluating the potential interaction between SSRIs and the MAO-B inhibitors selegiline and rasagiline. The largest, a retrospective cohort study of 1504 patients with Parkinson disease, found no cases of serotonin syndrome with coadministration of rasagiline and an SSRI. A survey of 63 investigators in the Parkinson Study Group identified 11 potential cases of serotonin syndrome among 4568 patients treated with the combination of selegiline and antidepressants (including SSRIs). In addition, 17 case reports describing the onset of serotonin syndrome with coadministration of an SSRI and either selegiline or rasagiline were identified. Following discontinuation or dose reduction of one or both of the agents, the symptoms of serotonin syndrome gradually resolved in most cases, with none being fatal.
CONCLUSIONS
According to the literature, serotonin syndrome occurs rarely, and the combination of SSRI and MAO-B inhibitor is well tolerated. Therefore, SSRIs and MAO-B inhibitors can be coadministered, provided that their recommended doses are not exceeded and the SSRI dose is kept at the lower end of the therapeutic range. Among the SSRIs, citalopram and sertraline may be preferred.
PubMed: 29955193
DOI: No ID Found -
PloS One 2023Dysphagia is a potentially fatal symptom of Parkinson's disease (PD) and is characterized by frequent silent aspiration, a risk factor for aspiration pneumonia. The...
Dysphagia is a potentially fatal symptom of Parkinson's disease (PD) and is characterized by frequent silent aspiration, a risk factor for aspiration pneumonia. The transdermal dopamine agonist rotigotine alleviates dysphagia in patients with PD and is more effective than oral levodopa, suggesting the importance of continuous dopaminergic stimulation (CDS) in swallowing. Safinamide is a monoamine oxidase B (MAOB) inhibitor that facilitates CDS. In this retrospective open-label evaluator-blinded research, swallowing functions in nine patients with PD were examined using a video fluoroscopic swallowing study (VFSS) before and after treatment with 50 mg of oral safinamide. The VFSS results showed that safinamide significantly improved some swallowing measures during oral and pharyngeal phases, including oral transit time and pharyngeal transit time, without worsening of any measures. Notably, improvements in lip closure, an oral phase component, seemed to be most attributable to improvements in oral phase scores. In conclusion, a medicine for CDS may effectively improve swallowing functions in patients with PD. This is the first study to show that the MAOB inhibitor safinamide partly but significantly improves swallowing function in patients with PD.
Topics: Humans; Parkinson Disease; Deglutition Disorders; Retrospective Studies; Levodopa; Benzylamines; Alanine; Monoamine Oxidase Inhibitors; Antiparkinson Agents
PubMed: 37228084
DOI: 10.1371/journal.pone.0286066 -
Molecules (Basel, Switzerland) Dec 2020The irreversible inhibitors of monoamine oxidases (MAO) slow neurotransmitter metabolism in depression and neurodegenerative diseases. After oxidation by MAO,...
The irreversible inhibitors of monoamine oxidases (MAO) slow neurotransmitter metabolism in depression and neurodegenerative diseases. After oxidation by MAO, hydrazines, cyclopropylamines and propargylamines form a covalent adduct with the flavin cofactor. To assist the design of new compounds to combat neurodegeneration, we have updated the kinetic parameters defining the interaction of these established drugs with human MAO-A and MAO-B and analyzed the required features. The K values for binding to MAO-A and molecular models show that selectivity is determined by the initial reversible binding. Common to all the irreversible inhibitor classes, the non-covalent 3D-chemical interactions depend on a H-bond donor and hydrophobic-aromatic features within 5.7 angstroms apart and an ionizable amine. Increasing hydrophobic interactions with the aromatic cage through aryl halogenation is important for stabilizing ligands in the binding site for transformation. Good and poor inactivators were investigated using visible spectroscopy and molecular dynamics. The initial binding, close and correctly oriented to the FAD, is important for the oxidation, specifically at the carbon adjacent to the propargyl group. The molecular dynamics study also provides evidence that retention of the allenyl imine product oriented towards FADH influences the formation of the covalent adduct essential for effective inactivation of MAO.
Topics: Binding Sites; Dose-Response Relationship, Drug; Enzyme Activation; Humans; Inhibitory Concentration 50; Kinetics; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Oxidation-Reduction; Protein Binding; Structure-Activity Relationship; Substrate Specificity; Time Factors
PubMed: 33322203
DOI: 10.3390/molecules25245908 -
ACS Omega May 2022Monoamine oxidase (MAO) is a protein with a key function in the catabolism of neuroamines in both central and peripheral parts of the body. MAO-A and -B are two isozymes... (Review)
Review
Monoamine oxidase (MAO) is a protein with a key function in the catabolism of neuroamines in both central and peripheral parts of the body. MAO-A and -B are two isozymes of this enzyme which have emerged to be considered as a drug target for the treatment of neurodenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). Isatin is an endogenous small fragment, reversible inhibitor for MAO enzymes and is more selective for MAO-B than -A. Isatin is responsible for increasing the dopamine level in the brain by the inhibition of an MAO enzyme. The very few selective and reversible inhibitors existing for MAO proteins and the intensity of neurological diseases in humanity have opened a new door for researchers. Isatin has a polypharmacological profile in medicinal chemistry, is a reversible inhibitor for both the MAOs, and shows high selectivity potent inhibition for MAO-B. In this review, we discuss isatins and their analogues phthalide and phthalimide with structure-activity relationships (SARs), and this comprehensive information accelerates the ideas for design and development of a new class of MAO inhibitors for neurodegenerative diseases.
PubMed: 35601305
DOI: 10.1021/acsomega.2c01470 -
European Journal of Pharmacology Sep 2021Treatment of Parkinson's disease (PD) includes the use of monoamine oxidase-B (MAO-B) inhibitor drugs. In this work we have evaluated the possible gamma-decanolactone...
Treatment of Parkinson's disease (PD) includes the use of monoamine oxidase-B (MAO-B) inhibitor drugs. In this work we have evaluated the possible gamma-decanolactone (GD) effect in vitro to inhibit the A and B isoforms of human monoamine oxidase (hMAO) enzyme and their citotoxicity in human hepatoma cell line (HepG2). Also, binding studies to A, A A and A adenosine receptors were performed. A docking study of gamma-decanolactone has been carried out with the molecular targets of MAO-A and MAO-B isoforms. The physicochemical properties and ability to cross physiological barriers, as the blood brain barrier (BBB), was elucidated by computational studies. The in vivo assays, the rota-rod test, body temperature assessment and open field test were performed in reserpinized mice (1.5 mg/kg, i.p.; 18:00 before) to evaluate the effect of gamma-decanolactone (300 mg/kg), alone or associated with Levodopa plus Benserazide (LD + BZ, 100:25 mg/kg, i.p.). Gamma-decanolactone inhibited preferentially the MAO-B in a reversible manner, with an inhibitory concentration of 50% (IC) 55.95 ± 9.06 μM. It was shown to be a safe drug since only at the highest concentration decreased the viability of HepG2 cells. It also does not bind to adenosine receptors investigated in this study. The molecular docking study show that the gamma-decanolactone ligand adopts a relatively compact conformation in the active site of hMAO-B, while we note an extended conformation of gamma-decanolactone ligand in the hMAO-A isoform. The physicochemical properties obtained, and the theoretical models utilized for the evaluation of ability to cross the BBB, predict a good gamma-decanolactone bioavailability and access to the central nervous system (CNS). In the in vivo studies, gamma-decanolactone partially reversed the ataxia of the reserpinized mice at 01:00 h and 01:30 h post-administration. Concomitant treatment of gamma-decanolactone with LD + BZ, at 01:30 h showed a potentiation of the reversibility of ataxia and facilitated the reversal of hypothermia caused by reserpine for all measured times (P <0.01 vs vehicle), except at 24:00 h, but not reversed the hypokinesia in the open field test. In summary, the results herein obtained and in conjunction with previous studies, suggest that gamma-decanolactone could be a drug with potential utility as antiparkinsonian drug.
Topics: Animals; Antiparkinson Agents; Blood-Brain Barrier; Disease Models, Animal; Drug Evaluation, Preclinical; Enzyme Assays; Hep G2 Cells; Humans; Lactones; Male; Mice; Molecular Docking Simulation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Parkinson Disease; Parkinson Disease, Secondary; Permeability; Receptors, Purinergic P1; Recombinant Proteins; Reserpine; Structure-Activity Relationship
PubMed: 34174267
DOI: 10.1016/j.ejphar.2021.174276 -
The Journal of Pharmacology and... Nov 2021The endogenous catecholamines dopamine (DA), norepinephrine (NE), and epinephrine (EPI) play key roles in neurobehavioral, cardiovascular, and metabolic processes;...
The endogenous catecholamines dopamine (DA), norepinephrine (NE), and epinephrine (EPI) play key roles in neurobehavioral, cardiovascular, and metabolic processes; various clinical disorders; and effects of numerous drugs. Steps in intracellular catecholamine synthesis and metabolism were delineated long ago, but there remains a knowledge gap. Catecholamines are metabolized by two isoforms of monoamine oxidase (MAO), MAO-A and MAO-B, and although the anatomic localization of MAO-A and MAO-B and substrate specificities of enzyme inhibitors are well characterized, relative susceptibilities of the endogenous catecholamines to enzymatic oxidation by MAO-A and MAO-B have not been studied systematically. MAOs catalyze the conversion of catecholamines to catecholaldehydes-3,4-dihydroxyphenylacetaldehyde (DOPAL) from DA and 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL) from NE and EPI. In this study we exploited the technical ability to assay DOPAL and DOPEGAL simultaneously with the substrate catecholamines to compare DA, NE, and EPI in their metabolism by MAO-A and MAO-B. For both MAO isoforms, DA was the better substrate compared to NE or EPI, which were metabolized equally. Since catecholaminergic neurons express mainly MAO-A, the finding that MAO-A is more efficient than MAO-B in metabolizing endogenous catecholamines reinforces the view that the predominant route of intraneuronal enzymatic oxidation of catecholamines is via MAO-A. The results have implications for clinical neurochemistry, experimental therapeutics, and computational models of catecholaminergic neurodegeneration. For instance, the greater susceptibility of DA than the other catecholamines to both MAO isoforms can help explain relatively high concentrations of the deaminated DA metabolite 3,4-dihydroxyphenylacetic acid than of the NE metabolite 3,4-dihydroxyphenylglycol in human plasma and urine. SIGNIFICANCE STATEMENT: Endogenous catecholamines are metabolized by monoamine oxidase (MAO)-A and -B, yielding the catecholaldehydes 3,4-dihydroxyphenylacetaldehyde (DOPAL) from dopamine (DA) and 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL) from norepinephrine (NE) and epinephrine (EPI). Based on measurements of DOPAL and DOPEGAL production, DA is a better substrate than NE or EPI for both MAO isoforms, and MAO-A is more efficient than MAO-B in metabolizing DA, NE, and EPI. MAO-A is the main route of intraneuronal metabolism of endogenous catecholamines.
Topics: Catecholamines; Dopamine; Epinephrine; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Norepinephrine
PubMed: 34503991
DOI: 10.1124/jpet.121.000826 -
Medicines (Basel, Switzerland) Jan 2019Two classes of amine oxidases are found in mammals: those with a flavin adenine dinucleotide as a cofactor, such as monoamine oxidases (MAO) and lysine-specific... (Review)
Review
Two classes of amine oxidases are found in mammals: those with a flavin adenine dinucleotide as a cofactor, such as monoamine oxidases (MAO) and lysine-specific demethylases (LSD), and those with copper as a cofactor, including copper-containing amine oxidases (AOC) and lysyl oxidases (LOX). All are expressed in adipose tissue, including a semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1) strongly present on the adipocyte surface. Previously, irreversible MAO inhibitors have been reported to limit food intake and/or fat extension in rodents; however, their use for the treatment of depressed patients has not revealed a clear anti-obesity action. Semicarbazide and other molecules inhibiting SSAO/VAP-1 also reduce adiposity in obese rodents. Recently, a LOX inhibitor and a subtype-selective MAO inhibitor have been shown to limit fattening in high-fat diet-fed rats. Phenelzine, which inhibits MAO and AOC, limits adipogenesis in cultured preadipocytes and impairs lipogenesis in mature adipocytes. When tested in rats or mice, phenelzine reduces food intake and/or fat accumulation without cardiac adverse effects. Novel amine oxidase inhibitors have been recently characterized in a quest for promising anti-inflammatory or anti-cancer approaches; however, their capacity to mitigate obesity has not been studied so far. The present review of the diverse effects of amine oxidase inhibitors impairing adipocyte differentiation or limiting excessive fat accumulation indicates that further studies are needed to reveal their potential anti-obesity properties.
PubMed: 30650583
DOI: 10.3390/medicines6010009 -
Molecules (Basel, Switzerland) Dec 2022Currently, no suitable clinical drugs are available for patients with neurodegenerative diseases complicated by depression. Based on a fusion technique to create...
Currently, no suitable clinical drugs are available for patients with neurodegenerative diseases complicated by depression. Based on a fusion technique to create effective multi-target-directed ligands (MTDLs), we synthesized a series of ()--(benzo[d]thiazol-2-yl)-2-(1-phenyl-3,4-dihydroisoquinolin-2(1)-yl) acetamides with substituted benzothiazoles and (-1-phenyl-1,2,3,4-tetrahydroisoquinoline. All compounds were tested for their inhibitory potency against monoamine oxidase (MAO) and cholinesterase (ChE) by in vitro enzyme activity assays, and further tested for their specific inhibitory potency against monoamine oxidase B (MAO-B) and butyrylcholinesterase (BuChE). Among them, six compounds (-, , and ) displayed excellent activity. The classical antidepressant forced swim test (FST) was used to verify the in vitro results, revealing that six compounds reduced the immobility time significantly, especially compound . The cytotoxicity of the compounds was assessed by the MTT method and Acridine Orange (AO) staining, with cell viability found to be above 90% at effective compound concentrations, and not toxic to L929 cells reversibility, kinetics and molecular docking studies were also performed using compound , which showed the highest MAO-B and BuChE inhibitory activities. The results of these studies showed that compound binds to the primary interaction sites of both enzymes and has good blood-brain barrier (BBB) penetration. This study provides new strategies for future research on neurodegenerative diseases complicated by depression.
Topics: Humans; Monoamine Oxidase Inhibitors; Structure-Activity Relationship; Molecular Docking Simulation; Butyrylcholinesterase; Monoamine Oxidase; Benzothiazoles; Isoquinolines; Cholinesterase Inhibitors; Molecular Structure
PubMed: 36558194
DOI: 10.3390/molecules27249062 -
Molecular Diversity Feb 2021Monoamine oxidase (MAO) is of much clinical relevance, and inhibitors of this enzyme are used in the treatment for neuropsychiatric and neurodegenerative disorders such...
Monoamine oxidase (MAO) is of much clinical relevance, and inhibitors of this enzyme are used in the treatment for neuropsychiatric and neurodegenerative disorders such as depression and Parkinson's disease. The present study synthesises and evaluates the MAO inhibition properties of a series of 33 1-tetralone and 4-chromanone derivatives in an attempt to discover high-potency compounds and to expand on the structure-activity relationships of MAO inhibition by these classes. Among these series, eight submicromolar MAO-A inhibitors and 28 submicromolar MAO-B inhibitors are reported, with all compounds acting as specific inhibitors of the MAO-B isoform. The most potent inhibitor was a 1-tetralone derivative (1h) with IC values of 0.036 and 0.0011 µM for MAO-A and MAO-B, respectively. Interestingly, with the reduction of 1-tetralones to the corresponding alcohols, a decrease in MAO inhibition potency is observed. Among these 1-tetralol derivatives, 1p (IC = 0.785 μM) and 1o (IC = 0.0075 μM) were identified as particularly potent inhibitors of MAO-A and MAO-B, respectively. Potent compounds such as those reported here may act as leads for the future development of MAO-B specific inhibitors. The present study describes the MAO inhibitory activities of a series of 1-tetralone and 4-chromanone derivatives. Numerous high-potency MAO-B specific inhibitors were identified.
Topics: Chromones; Humans; Inhibitory Concentration 50; Kinetics; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Recombinant Proteins; Tetralones
PubMed: 32970293
DOI: 10.1007/s11030-020-10143-w -
Neural Regeneration Research Jan 2024Type-B monoamine oxidase inhibitors, encompassing selegiline, rasagiline, and safinamide, are available to treat Parkinson's disease. These drugs ameliorate motor... (Review)
Review
Type-B monoamine oxidase inhibitors, encompassing selegiline, rasagiline, and safinamide, are available to treat Parkinson's disease. These drugs ameliorate motor symptoms and improve motor fluctuation in the advanced stages of the disease. There is also evidence supporting the benefit of type-B monoamine oxidase inhibitors on non-motor symptoms of Parkinson's disease, such as mood deflection, cognitive impairment, sleep disturbances, and fatigue. Preclinical studies indicate that type-B monoamine oxidase inhibitors hold a strong neuroprotective potential in Parkinson's disease and other neurodegenerative diseases for reducing oxidative stress and stimulating the production and release of neurotrophic factors, particularly glial cell line-derived neurotrophic factor, which support dopaminergic neurons. Besides, safinamide may interfere with neurodegenerative mechanisms, counteracting excessive glutamate overdrive in basal ganglia motor circuit and reducing death from excitotoxicity. Due to the dual mechanism of action, the new generation of type-B monoamine oxidase inhibitors, including safinamide, is gaining interest in other neurological pathologies, and many supporting preclinical studies are now available. The potential fields of application concern epilepsy, Duchenne muscular dystrophy, multiple sclerosis, and above all, ischemic brain injury. The purpose of this review is to investigate the preclinical and clinical pharmacology of selegiline, rasagiline, and safinamide in Parkinson's disease and beyond, focusing on possible future therapeutic applications.
PubMed: 37488838
DOI: 10.4103/1673-5374.375299