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European Neuropsychopharmacology : the... Aug 2017It has been over 50 years since a review has focused exclusively on the monoamine oxidase (MAO) inhibitor tranylcypromine (TCP). A new review has therefore been... (Meta-Analysis)
Meta-Analysis Review
It has been over 50 years since a review has focused exclusively on the monoamine oxidase (MAO) inhibitor tranylcypromine (TCP). A new review has therefore been conducted for TCP in two parts which are written to be read preferably in close conjunction: part I - pharmacodynamics, pharmacokinetics, drug interactions, toxicology; and part II - clinical studies with meta-analysis of controlled studies in depression, practice of TCP treatment, place in therapy. The irreversible and nonselective MAO-A/B inhibitor TCP has been confirmed as an efficacious and safe antidepressant drug. For the first time, a meta-analysis of controlled clinical trials in depression demonstrated that TCP is superior to placebo (pooled logOR=0.509, 95%CI=0.026 to 0.993, 4 studies) and equal to other antidepressants (pooled logOR=0.208, 95%CI=-0.128 to 0.544, 10 studies). In treatment resistant depression (TRD) after tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), TCP was superior to placebo (logOR=2.826, 95%CI=1.494 to 4.158, one study) and non-established antidepressants (pooled logOR=1.976, 95%CI=0.907 to 3.045, 4 studies), and was equal to other MAO inhibitors and an antidepressant combination (pooled logOR=-0.366, 95%CI=-0.869 to 0.137, 4 studies). Controlled studies revealed that TCP might provide a special advantage in the treatment of atypical depression, which was supported by a recent PET study of MAO-A activity in brain. However, TCP treatment remains beset with the need for a mandatory tyramine-restricted diet and is therefore limited to use as a third-line antidepressant according to recent treatment algorithms and guidelines for depression treatment. On the other hand, the effort needed to maintain a tyramine-restricted diet may have been overestimated in the perception of both doctors and patients, which may have led to relative underuse of TCP. Interaction with serotonergic drugs bears the risk of severe serotonin toxicity (SST) and combination with indirect sympathomimetic drugs may result in hypertensive crisis which both adds to the risks of TCP. At the same time, TCP has low to no risks of central anticholinergic, sedative, cardiac conduction, body weight, hemostatic effects, or pharmacokinetic drug interactions. Neuroprotection by MAO inhibitors due to reduced oxidative stress is becoming increasingly studied. Taken together, TCP is being increasingly recognized as an important option in systematic treatment approaches for patients suffering from severe courses of depression, such as TRD and atypical depression, by offering a MAO-related pathophysiological rationale.
Topics: Animals; Antidepressive Agents; Depression; Humans; Monoamine Oxidase; Pharmacology, Clinical; Tranylcypromine
PubMed: 28579071
DOI: 10.1016/j.euroneuro.2017.04.003 -
Sheng Li Xue Bao : [Acta Physiologica... Jun 2020Dopamine (DA), as a catecholamine neurotransmitter widely distributed in the central nervous system and the peripheral tissues, has attracted a lot of attention.... (Review)
Review
Dopamine (DA), as a catecholamine neurotransmitter widely distributed in the central nervous system and the peripheral tissues, has attracted a lot of attention. Especially in recent years, DA has been found to regulate the function of the immune system, and the involvement of DA in the intestinal mucosal inflammation-related diseases has become a hot research topic. The digestive tract is an important source of peripheral DA, and DA is not only produced in the enteric nervous system and gastrointestinal epithelium, but also produced by intestinal microorganisms. In addition to the synthetases of DA, the DA contents in body tissues are also affected by the two kinds of metabolic enzymes, monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). This article reviewed the sources, metabolism, and functions of DA in digestive tract, especially focusing on the distribution and function of MAO and COMT, the enzymes degrading DA.
Topics: Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Dopamine; Gastrointestinal Tract; Monoamine Oxidase; Monoamine Oxidase Inhibitors
PubMed: 32572431
DOI: No ID Found -
Frontiers in Pharmacology 2021Mucosal epithelial cell integrity is an important component of innate immunity and it protects the host from an environment rich in microorganisms. Virulence factors...
Mucosal epithelial cell integrity is an important component of innate immunity and it protects the host from an environment rich in microorganisms. Virulence factors from Gram-negative bacteria [e.g. lipopolysaccharide (LPS)] induce significant pro-inflammatory cytokine expression. Monoamine oxidase (MAO) inhibitors reduce cytokine expression in a variety of inflammatory models and may therefore have therapeutic potential for a number of inflammatory diseases. We tested the anti-inflammatory therapeutic potential of a recently developed reversible MAO-B inhibitor (RG0216) with reduced transport across the blood-brain barrier. In an epithelial cell culture model, RG0216 significantly decreased LPS-induced interleukin (IL)-6 and IL-1β gene and protein expression and was as effective as equimolar concentrations of deprenyl (an existing irreversible MAO-B inhibitor). Hydrogen peroxide and modulating dopamine receptor signaling had no effect on cytokine expression. We showed that LPS-induced expression of IL-6 and IL-1β was cAMP dependent, that IL-6 and IL-1β expression were induced by direct cAMP activation (forskolin) and that RG0216 and deprenyl effectively reduced cAMP-mediated cytokine expression. Targeted protein kinase A (PKA) and Exchange Protein Activated by cAMP (EPAC) activation regulated IL-6 and IL-1β expression, albeit in different ways, but both cytokines were effectively decreased with RG0216. RG0216 reduction of LPS-induced cytokine expression occurred by acting downstream of the cAMP-PKA/EPAC signaling cascade. This represents a novel mechanism by which MAO-B selective inhibitors regulate LPS-induced IL-6 and IL-1β expression.
PubMed: 34867348
DOI: 10.3389/fphar.2021.741460 -
Pharmaceuticals (Basel, Switzerland) Sep 2022Two series of dimethoxy-halogenated chalcones (DM1−DM20) were synthesized and tested for their ability to inhibit monoamine oxidase (MAOs). Compound DM2 exhibited the...
Two series of dimethoxy-halogenated chalcones (DM1−DM20) were synthesized and tested for their ability to inhibit monoamine oxidase (MAOs). Compound DM2 exhibited the most significant inhibition against MAO-B with an IC50 value of 0.067 µM, followed by compound DM18 (IC50 = 0.118 µM), with selectivity index (SI) values of 93.88 and >338.98, respectively. However, none of the substances successfully inhibited MAO-A. The MAO-B inhibitors DM2 and DM18 were competitive and reversible, with Ki values of 0.032 ± 0.004 and 0.045 ± 0.001 µM, respectively. DM2 was non-toxic below 100 µg/mL in the cytotoxic test using the Vero epithelial cell line by the MTT method. According to molecular docking studies, DM2 and DM18 formed very similar conformations within the MAO-B binding pocket, with the ortho-chlorine and ortho-fluorine aromatic rings sandwiched between F168 and Y326. These conformations were predicted to show better interactions with the targeted MAO-B than MAO-A. In particular, the induced-fit docking of the dimethoxy phenyl ring of DM2 facing the hydrophobic pocket made up of FAD, Y398, and Y435 had an impact on F168 in the docking pocket. Taken together, DM2 and DM18 may be suitable candidates for treating neurodegenerative conditions such as Parkinson’s disease.
PubMed: 36145373
DOI: 10.3390/ph15091152 -
Iranian Journal of Pharmaceutical... 2016Seven stilbenes and one catechin were bioactivity-guidedly isolated from the rhizomes of . Their structures were identified as piceatannol (1), resveratrol (2), piceid...
Seven stilbenes and one catechin were bioactivity-guidedly isolated from the rhizomes of . Their structures were identified as piceatannol (1), resveratrol (2), piceid (3), rhapontigenin (4), piceatannol-3-O-β-D-glucopyranoside (5), rhaponticin (6), catechin (7) and desoxyrhapontigenin (8). Anti-monoamine oxidase (MAO) activities of compounds 1-8 were tested. Compounds 1 and 8 showed significant MAO inhibitory activities with IC values 16.4 ± 1.5 μM and 11.5 ± 1.1, respectively, when the IC value of iproniazid as a standard was 6.5 ± 0.5 μM. The selectivity of compounds 1-8 against MAO-A and MAO-B were also evaluated. The results showed that compounds 4˴6˴8 preferred to inhibit MAO-A rather than MAO-B with selectivity values ([IC of MAO-B]/ [IC of MAO-A]) of 4.74, 10.01 and 9.42, respectively. The preliminary structure-activity relationships (SARs) of these compounds were discussed and the molecular modeling was also performed to explore the binding mode of inhibitors at the active site of MAO-A and MAO-B.
PubMed: 28243286
DOI: No ID Found -
The Journal of Physiological Sciences :... Oct 2022To investigate the roles of the serotonin (5-HT) transporter (SERT) and plasma membrane monoamine transporter (PMAT) in 5-HT uptake and its metabolism in the heart, we...
To investigate the roles of the serotonin (5-HT) transporter (SERT) and plasma membrane monoamine transporter (PMAT) in 5-HT uptake and its metabolism in the heart, we monitored myocardial interstitial levels of 5-HT and 5-HIAA, a metabolite of 5-HT by monoamine oxidase (MAO), in anesthetized rats using a microdialysis technique. Fluoxetine (SERT inhibitor), decynium-22 (PMAT inhibitor), or their mixture was locally administered by reverse-microdialysis for 60 min. Subsequently, pargyline (MAO inhibitor) was co-administered. Fluoxetine rapidly increased dialysate 5-HT concentration, while decynium-22 gradually increased it. The mixture induced a larger increase in dialysate 5-HT concentration compared to fluoxetine or decynium-22 alone. Fluoxetine increased dialysate 5-HIAA concentration, and this increase was abolished by pargyline. Decynium-22 and the mixture did not change dialysate 5-HIAA concentration, which were not affected by pargyline. Both SERT and PMAT regulate myocardial interstitial 5-HT levels by its uptake; however, 5-HT uptake via PMAT leads to 5-HT metabolism by MAO.
Topics: Animals; Rats; Dialysis Solutions; Fluoxetine; Hydroxyindoleacetic Acid; Membrane Transport Proteins; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Pargyline; Serotonin; Heart
PubMed: 36289481
DOI: 10.1186/s12576-022-00852-2 -
Molecules (Basel, Switzerland) May 2020Prostate cancer (PCa) patients commonly experience clinical depression. Recent reports indicated that monoamine oxidase-A (MAO-A) levels elevate in PCa, and...
Prostate cancer (PCa) patients commonly experience clinical depression. Recent reports indicated that monoamine oxidase-A (MAO-A) levels elevate in PCa, and antidepressant MAO-Is show anti-PCa properties. In this work, we aimed to find potential drugs for PCa patients suffering from depression by establishing novel anti-PCa reversible monoamine oxidase-A inhibitors (MAO-AIs/RIMA); with an endeavor to understand their mechanism of action. In this investigation, twenty synthesized flavonoid derivatives, defined as KKR compounds were screened for their inhibitory potentials against human MAO-A and MAO-B isozymes. Meanwhile, the cytotoxic and antiproliferative effects were determined in three human PCa cell lines. MAO-A-kinetics, molecular docking, SAR, cell morphology, and cell migration were investigated for the most potent compounds. The screened KKRs inhibited MAO-A more potently than MAO-B, and non-toxically inhibited LNCaP cell proliferation more than the DU145 and PC3 cell lines, respectively. The results showed that the three top MAO-AI KKRs compounds (KKR11, KKR20, and KKR7 (ICs 0.02-16 μM) overlapped with the top six antiproliferative KKRs against LNCaP (ICs ~9.4 μM). While KKR21 (MAO-AI) and KKR2A (MAO-I) were ineffective against the PCa cells. Furthermore, KKR21 and KKR11 inhibited MAO-A competitively (Ks ≤ 7.4 nM). Molecular docking of the two compounds predicted shared hydrophobic and distinctive hydrophilic interactions-between the KKR molecule and MAO-A amino acid residues-to be responsible for their reversibility. The combined results and SAR observations indicated that the presence of specific active groups-such as chlorine and hydroxyl groups-are essential in certain MAO-AIs with anti-PCa effects. Additionally, MAO-A inhibition was found to be associated more with anti-PCa property than MAO-B. Distinctively, KKR11 [()-3-(3,4-dichlorophenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one] exhibited anti-metastatic effects on the DU145 cell line. The chlorine substitution groups might play vital roles in the KKR11 multiple actions. The obtained results indicated that the flavonoid derivative KKR11 could present a novel candidate for PCa patients with depression, through safe non-selective potent inhibition of MAOs.
Topics: Catalytic Domain; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Depression; Flavonoids; Humans; Hydrophobic and Hydrophilic Interactions; Inhibitory Concentration 50; Kinetics; Male; Molecular Docking Simulation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Prostatic Neoplasms; Structure-Activity Relationship
PubMed: 32403270
DOI: 10.3390/molecules25092257 -
Journal of Neuroinflammation Jul 2023Perioperative neurocognitive disorders (PND), such as delirium and cognitive impairment, are commonly encountered complications in aged patients. The inhibitory...
BACKGROUND
Perioperative neurocognitive disorders (PND), such as delirium and cognitive impairment, are commonly encountered complications in aged patients. The inhibitory neurotransmitter γ-aminobutyric acid (GABA) is aberrantly synthesized from reactive astrocytes following inflammatory stimulation and is implicated in the pathophysiology of neurodegenerative diseases. Additionally, the activation of NOD-like receptor protein 3 (NLRP3) inflammasome is involved in PND. Herein, we aimed to investigate whether the NLRP3-GABA signaling pathway contributes to the pathogenesis of aging mice's PND.
METHODS
24-month-old C57BL/6 and astrocyte-specific NLRP3 knockout male mice were used to establish a PND model via tibial fracture surgery. The monoamine oxidase-B (MAOB) inhibitor selegiline (1 mg/kg) was intraperitoneally administered once a day for 7 days after the surgery. PND, including impulsive-like behaviors and cognitive impairment, was evaluated by open field test, elevated plus maze, and fear conditioning. Thereafter, pathological changes of neurodegeneration were explored by western blot and immunofluorescence assays.
RESULTS
Selegiline administration significantly ameliorated TF-induced impulsive-like behaviors and reduced excessive GABA production in reactive hippocampal astrocytes. Moreover, astrocyte-specific NLRP3 knockout mice reversed TF-induced impulsive-like and cognitive impairment behaviors, decreased GABA levels in reactive astrocytes, ameliorated NLRP3-associated inflammatory responses during the early stage, and restored neuronal degeneration in the hippocampus.
CONCLUSIONS
Our findings suggest that anesthesia and surgical procedures trigger neuroinflammation and cognitive deficits, which may be due to NLRP3-GABA activation in the hippocampus of aged mice.
Topics: Male; Animals; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Selegiline; Cognitive Dysfunction; Mice, Knockout; Monoamine Oxidase Inhibitors; NLR Proteins; Signal Transduction; Cognition
PubMed: 37434240
DOI: 10.1186/s12974-023-02845-3 -
Molecules (Basel, Switzerland) Oct 2022Monoamine oxidases (MAOs) are an important group of enzymes involved in the degradation of neurotransmitters and their imbalanced mode of action may lead to the...
Monoamine oxidases (MAOs) are an important group of enzymes involved in the degradation of neurotransmitters and their imbalanced mode of action may lead to the development of various neuropsychiatric or neurodegenerative disorders. In this work, we report the results of an in-depth computational study in which we performed a static and a dynamic analysis of a series of substituted β-carboline natural products, found mainly in roasted coffee and tobacco smoke, that bind to the active site of the MAO-A isoform. By applying molecular docking in conjunction with structure-based pharmacophores and molecular dynamics simulations coupled with dynamic pharmacophores, we extensively investigated the geometric aspects of MAO-A binding. To gain insight into the energetics of binding, we used the linear interaction energy (LIE) method and determined the key anchors that allow productive β-carboline binding to MAO-A. The results presented herein could be applied in the rational structure-based design and optimization of β-carbolines towards preclinical candidates that would target the MAO-A enzyme and would be applicable especially in the treatment of mental disorders such as depression.
Topics: Carbolines; Coffee; Humans; Molecular Docking Simulation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Structure-Activity Relationship; Tobacco Smoke Pollution
PubMed: 36235246
DOI: 10.3390/molecules27196711 -
Annals of Medicine Aug 2017Rasagiline is a second-generation potent selective inhibitor of monoamine oxidase-B. The aim of the study was to analyze the effectiveness of rasagiline in treatment of... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
Rasagiline is a second-generation potent selective inhibitor of monoamine oxidase-B. The aim of the study was to analyze the effectiveness of rasagiline in treatment of Parkinson's disease (PD), both as monotherapy and combination therapy.
METHODS
Medline, Cochrane, EMBASE, and Google Scholar databases were searched until 9 March 2016 using the keywords: Rasagiline, Azilect, Parkinson's disease. Randomized controlled trials of patients with PD who were randomized to treatment with rasagiline or placebo were included. Outcomes were unified Parkinson's disease rating scale (UPDRS) and the three subscales.
RESULTS
Ten studies fulfilled the inclusion criteria and 2709 patients were evaluated. The overall analysis revealed a significant improvement in change of total UPDRS scores in 1 mg/day and 2 mg/day rasagiline groups compared to placebo. Significant improvement in Part I (Mentation) of UPDRS scores was observed in 1 mg/day, but not in 2 mg/day rasagiline treatment group. Part II (ADL) and Part III (Motor) subscales significantly improved with both doses of rasagiline. Both monotherapy and combination therapy significantly improved total UPDRS scores.
CONCLUSIONS
Our results confirm the efficacy of rasagiline in PD. Further studies are required to establish the optimal dose of rasagiline, as well as to determine its effectiveness in different combination therapy protocols. KEY MESSAGES Rasagiline treatment was associated with significant improvement of UPDRS scores and the scores of the subscales. Both monotherapy and combination therapy significantly improved total UPDRS scores. Effect of rasagiline on total UPDRS scores was not dose-dependent.
Topics: Aged; Drug Therapy, Combination; Female; Humans; Indans; Male; Middle Aged; Monoamine Oxidase Inhibitors; Parkinson Disease; Severity of Illness Index; Treatment Outcome
PubMed: 28293967
DOI: 10.1080/07853890.2017.1293285