Monoamine Oxidase Inhibitors Research Articles

The effect of mixed tobacco monoamine oxidase inhibitors in animal models relevant to tobacco dependence

The effect of mixed tobacco monoamine oxidase inhibitors in animal models relevant to tobacco dependence

Monoamine oxidase inhibition by thiazole derivatives substituted with the benzenesulfonamide moiety

Monoamine oxidase inhibition by thiazole derivatives substituted with the benzenesulfonamide moiety

Design, synthesis and evaluation of benzothiazole-derived phenyl thioacetamides as dual inhibitors of monoamine oxidases and cholinesterases.

A series of rationally designed benzothiazole-derived thioacetamides was synthesized and investigated for monoamine oxidases (MAO-A and MAO-B) and cholinesterases (AChE and BChE) inhibition properties. The tested compounds 18-31 inhibited MAO-A and MAO-B in the micromolar to nanomolar range and AChE in the submicromolar range. Compound 28 was identified as the most potent MAO-A inhibitor with an IC50 = 0.030 ± 0.008 µM, whereas compound 30 showed the highest potency towards MAO-B and AChE with IC50 values of 0.015 ± 0.007 µM and 0.114 ± 0.003 µM, respectively. Further, compound 30 inhibited BChE at an IC50 value of 4.125 ± 0.143 µM. Among all screened molecules, compound 30 emerged as the lead dual MAO-B and AChE inhibitor that blocked these enzymes in a competitive-reversible and mixed-reversible mode, respectively. Selected compounds have displayed iron-chelation and antioxidant properties. Further, computational assessment of ligand binding affinity and pharmacokinetic parameters of all new compounds and molecular dynamic simulation of compound 30 with MAO-B and AChE were carried out to understand ligand efficiency, pharmacokinetic, and virtual molecular interaction profile, respectively. The in silico ADMET prediction studies revealed a few undesired pharmacokinetic attributes of our compounds. The attempted virtual lead-based library synthesis and subsequent biological investigation produced a new benzothiazole-bearing dual MAO-B and AChE inhibitor as a prospective MTDL candidate for treating neurological disorders.

Parkinson's Disease: Unravelling the Medicinal Perspectives and Recent Developments of Heterocyclic Monoamine Oxidase-B Inhibitors.

Parkinson's disease is a neurodegenerative condition characterized by slow movement (bradykinesia), tremors, and muscle stiffness. These symptoms occur due to the degeneration of dopamine- producing neurons in the substantia nigra region of the brain, leading to reduced dopamine levels. The development of Parkinson's Disease (PD) involves a combination of genetic and environmental factors. PD is associated with abnormal regulation of the monoamine oxidase (MAO) enzyme. Monoamine oxidase inhibitors (MAOIs) are an important class of drugs used to treat PD and other neurological disorders. In the early stages of PD, monotherapy with MAO-B inhibitors has been shown to be both safe and effective. These inhibitors are also commonly used as adjuncts in long-term disease management, as they can improve both motor and non-motor symptoms, reduce "OFF" periods, and potentially slow disease progression. However, current MAO-B inhibitors come with side effects like dizziness, nausea, vomiting, light-headedness, and fainting. Therefore, accelerating the development of new MAO-B inhibitors with fewer side effects is crucial. This review explores natural compounds that may inhibit monoamine oxidase B (MAO-B), focusing on key findings from the past seven years. It highlights the most effective heterocyclic compounds against MAO-B, including thiazolyl hydrazone, pyridoxine-resveratrol, pyridazine, isoxazole, oxadiazole, benzothiazole, benzoxazole, coumarin, caffeine, pyrazoline, piperazine, piperidine, pyrrolidine, and morpholine derivatives. The review covers in vitro, in silico, and in vivo data, along with the structure- activity relationship of these compounds. These findings offer valuable insights for the development of more effective MAO-B inhibitors and advancements in Parkinson's disease research.

The Lasting Legacy of Charles Fisher (1908-1988), Pioneering Sleep Laboratory Scientist and Sleep Medicine Psychiatrist

Abstract Charles Fisher is a pioneering historical figure in sleep laboratory research and sleep medicine who distinguished himself in nine areas: i) The first documentation of nocturnal sleep-onset REM sleep periods in narcoleptic patients; ii) He published the first case of polysomnography (PSG) documented acute REM sleep behavior disorder (RBD) that was triggered by sudden withdrawal from a monoamine oxidase inhibitor (MAOI) in 1978, 8 years before the formal identification of RBD; iii) He worked with Roffwarg and Dement on the early delineation of the ontogeny of the human sleep cycle; iv) He first demonstrated that benzodiazepine (diazepam) therapy was effective in controlling night terrors together with suppression of Stage 4 NREM sleep, and he was also an early investigator of night terrors as phenomena emerging from Stage 4 NREM sleep, without dreaming, as had been traditionally assumed; v) He collaborated with another pioneering sleep medicine physician, William C. Dement on studies focused on REM sleep deprivation and dreaming at Fisher’s Mt. Sinai Hospital sleep laboratory; vi) He published the first PSG-documented case of Sleep Related (Psychogenic) Dissociative Disorder (SRDD) in 1976; vii) He first documented that typical nightmares (“anxiety dreams”) occurred during REM sleep; viii) He conducted some of the earliest research, beginning in 1965, that documented cycles of nocturnal penile tumescence emerging in conjunction with REM sleep cycles; ix) He conducted similar early studies of female sexual arousal during sleep that occurred predominantly in REM sleep.

In silico and in vivo evaluations of fisetin and fisetin-loaded nanosuspension on monoamine oxidase inhibition in Aβ(25-35) induced dementia in mice model

BackgroundAmyloid beta (Aβ) plaques on the extracellular matrix and intracellular neurofibrillary tangles comprise the key indicative pathology of Alzheimer's disease (AD). Fisetin, an antioxidant bioactive compound having pharmacotherapeutic effects is applied by traditional Chinese medicine (TCM) such as Toxicodendron vernicifum (Chinese lacquer tree), Cotinus coggygria Scop, Gan Shuang granulates and formula of Acacia catechu-Scutellariae Radix. Nevertheless, fisetin has constraints such as low oral bioavailability, insignificant aqueous solubility and high hepatic metabolisms. ObjectiveThis investigation aimed to envisage the effects of fisetin and its optimised nanoformulation on Aβ(25-35) desirous neurotoxicity in mice through deciphering inhibitory actions against monoamine oxidase A and B (MAO-A and B) enzymes following molecular docking. MethodsMolecular docking with MAO-A and B enzymes were accomplished by AMDock's integrated AutoDock Tools (ADT) scripts. For in vivo studies, fisetin nanosuspension was prepared by nanoprecipitation method and evaluated for standard characterization. 10 and 20 mg/kg of fisetin and 10 mg/kg of fisetin nanosuspension were given once daily to mice for 21 days. On the 15th day, the mice were challenged with Aβ(25–35) by intracerebroventricular injection (ICV) and behavioural tests (open field and elevated plus maze) were performed on the 20th day. Biochemical and histology were examined in brain tissues. ResultsFisetin docked to the catalytic positions of MAO-A and B, unveiling good binding scores and molecular interactions with amino acid residues for inhibition activities. Fisetin nanosuspension has average particle size (225.4 ± 2.95 nm) with low polydispersity index (0.19) and standard zeta potential (-19.13 ± 1.17 mV). Findings showed that fisetin increased locomotor activity and reduced anxiety-like behaviour. Fisetin and its nanosuspension significantly reduced the concentration of MAO-A (P < 0.01) and MAO-B enzymes suggesting a potential neuroprotection effect in Aβ peptide-induced amnesia in mice. ConclusionFisetin with optimized bioavailability, effectively exhibits neuroprotection through molecular interactions of MAO enzymes. Further investigations affidavits the neuroprotection through bidirectional pathways related to biogenic amines and their deamination on Aβ stress conditions.

Parkinson's Disease: A Progressive Neurodegenerative Disorder and Structure-Activity Relationship of MAO Inhibitor Scaffolds as an Important Therapeutic Regimen.

Parkinson's disease is considered an advancing neurodegenerative disorder with unknown causes, and its association with some risk factors, including aging, family history, and exposure to chemicals, makes it the second most common occurring neurodegenerative disorder throughout the world with increasing prevalence. Parkinson's disease is associated with slow movement, rigidity, tremors, imbalance, depression, anxiety, cognitive impairment, orthostasis, hyperhidrosis, sleep disorders, pain, and sensory disturbances. In recent decades, there has been a rise in research on the development of effective and potential therapies for the treatment of Parkinson's disease. An important target for neuroprotection is Monoamine Oxidases (MAO), which hydrolyze neurotransmitters like dopamine and produce very reactive free radicals as a by-product. Aging and neurodegenerative illnesses cause overexpression in the brain, which exacerbates neuronal loss. The treatment of Parkinson's disease with MAO inhibitors has shown promising outcomes. Herein, we reported characteristic features of Parkinson's disease, various treatment strategies, and the SAR of potential drugs that can be explored further as lead for the development of newer molecules with improved pharmacological profiles.

Design, Synthesis, Molecular Docking, Pharmacokinetic Properties, and Molecular Dynamics Simulation of Sulfonyl Derivatives of Benzimidazole against Parkinson's Disease.

The disability and mortality related to Parkinson's disease (PD), a neurodegenerative disease, are increasing globally at a faster rate than other neurological disorders. With no permanent cure for PD, there is an urgent need to develop novel and effective anti-PD drugs. Targeting monoamine oxidases (MAO), which catalyze the breakdown of neurotransmitters, is one way to treat neurodegenerative diseases. In this context, an initial molecular docking of twenty designed sulfonyl derivatives of benzimidazole against monoamine oxidase B (MAO-B) associated with PD was conducted using AutoDock Vina. The results were compared with those of the conventional inhibitors, selegiline and rasagiline. Based on the docking score, the in-silico pharmacokinetic properties (ADME), drug-likeness, and toxicity profiles of the newly synthesized molecules were examined using SwissADME, PreADMET, ProTox-3.0, vNN, and ADMETlab web tools. Then, twelve potential derivatives were synthesized and characterized by IR, 1H-NMR, 13C-NMR, 19F-NMR (for some compounds), and mass spectrometry. Derivatives 2cj and 1bj were the two molecules having the best binding affinity of -11.9 and -11.8 kcal/mol, respectively, against MAOB, exhibiting a higher binding affinity compared to that of some commercially available drugs. A 50 ns MD simulation run was performed to observe the stability of the top two docked complexes, MAO-B-2cj and MAO-B-1bj, in order to further validate the efficacy of those two substances. Moreover, the MM-PBSA method was used to calculate the final, binding free energy of the simulated (MAO-B-2cj) complex. This study indicates that the binding affinity of most of the hits was superior to that of known MAO inhibitors; therefore, these newly synthesized benzimidazole derivatives may be developed into essential drug candidates for the treatment of PD.

Target Fisher: A Consensus Structure-Based Target Prediction Tool, and its Application in the Discovery of Selective MAO-B Inhibitors.

In this work we introduce Target Fisher, a consensus structure-based target prediction tool that integrates molecular docking and machine learning with the aim to aid in the identification of potential biological targets and the optimization of the use of bioassays. Target Fisher uses per-residue energy decomposition profiles extracted from docking poses as fingerprints to train target-specific machine learning models. It provides predictions for a curated set of 37 protein targets, covering a diverse range of biological entities, and offers a user-friendly interface accessible via a web server (https://gqc.quimica.unlp.edu.ar/targetfisher/). In this sense, Target Fisher is a valuable tool to aid organic and medicinal chemistry groups in target identification, drug discovery and drug repurposing. As a case study, we demonstrate the efficacy of Target Fisher by screening a small library of assorted natural products for targets relevant to neurodegenerative diseases, which resulted in the identification and experimental validation of selective inhibitors of monoamine oxidase B (MAO-B).

Comments on "Expert Opinion on Anesthetic Considerations For Patients Receiving a Classic Monoamine Oxidase Inhibitor".

Comments on "Expert Opinion on Anesthetic Considerations For Patients Receiving a Classic Monoamine Oxidase Inhibitor".

Chemical Composition and Biological Activity of Hypericum Species-H. hirsutum, H. barbatum, H. rochelii.

St. John's wort (Hypericum perforatum, Hypericaceae) is the most well-known species in the genus Hypericum, which comprises several hundred species. This study investigates the biological and phytochemical potential of the under-researched Hypericum species, H. hirsutum, H. barbatum, and H. rochelii. A high level of similarity between the chemical profiles of H. hirsutum and H. barbatum and the official source of the herbal drug (H. perforatum) was shown, but a higher content of quercetin and rutin was also found in all three evaluated species (116-230 µg/g dry herb). The highest amount of phenolics (195 mg GAE/g) was recorded in H. hirsutum extract, while the highest amount of flavonoids (47 mg QE/g) was recorded in H. barbatum extract. The evaluated species were excellent scavengers of DPPH, OH, and NO radicals, as well as strong ferric ion reducers in the FRAP test. Prominent monoamine oxidase A and α-glucosidase inhibition was observed, compared to modest inhibition of monoamine oxidase B, α-amylase, and acetylcholinesterase. High activity against Gram-positive MRSA S. aureus was demonstrated for the tested species, with MIC/MBC values recorded at 12.5 µg/mL. Antifungal activity against Candida strains was not observed. The obtained results emphasize the need for further investigation of species of the genus Hypericum to discover potentially new sources of biologically active compounds.

Perception of the Capixaba population regarding the use and benefits of antidepressants and anxiolytics

Depression is a routine disorder characterized by at least two weeks of loss of pleasure, mood, and interest in basic daily activities. Treatment involves psychotherapy, lifestyle changes, and medication therapy with antidepressants. These medications increase the availability of neurotransmitters in the central nervous system through different mechanisms of action, such as Monoamine Oxidase Inhibitors, Tricyclic Antidepressants, Selective Serotonin Reuptake Inhibitors, and Atypicals. Studies indicate that, after the pandemic, mental health issues such as anxiety and depression became more frequent in society, leading to greater use of antidepressants, especially clonazepam, sertraline, and amitriptyline. This project aims to investigate this usage, focusing on the benefits and drawbacks from the user’s perspective. To this end, it was submitted to the Ethics and Human Research Council of UNESC, with a bibliographic review conducted in the PubMed, Lilacs, and Scielo databases during the approval period. After approval, the research was conducted through structured questionnaires, made available online to the Capixaba society. The study evaluated the rate of use of these psychotropic drugs in the region, the benefits, risks, and behaviors regarding the use of antidepressants and anxiolytics from the perspective of patients. The use of psychotropic drugs by the population can be satisfactory for treating mental disorders, but it is essential that these medications are used with caution and under the guidance of a healthcare professional. Regular monitoring helps to manage adverse effects, ensure the medication is working properly, and prevent long-term medication-related problems.

Tilianin obtained from Agastache mexicana inhibits monoamine oxidase and modifies depressive behavior in rats.

Agastache mexicana is used in traditional medicine to treat anxiety, insomnia, pain, among others. In a previous study, the methanolic extract exerted anxiolytic and sedative effects, as observed behaviorally, associated with one of its major components, tilianin. To assess the effect produced by the extracts and tilianin obtained from Agastache mexicana on depressive-induced behavior model and on the activity of monoamine oxidases (MAOs). The depression experimental model consisted of the forced swimming test in rats. MAOs activity was evaluated in cortex and hippocampus from the tilianin and Agastache extracts treated rats using specific inhibitors for each isoform. The quantification of monoamines was carried out using an High Performance Liquid Chromatography method. An increase in the swimming time was observed in rodents treated with doses of 16 (226.6±5.5 seconds) and 50mg/kg (237.8±5.7 seconds) of tilianin, methanolic (260.4±3 seconds), and hydroalcoholic extracts (249.6±2.6 seconds) at 100mg/kg. MAOs activity was significantly decreased in brain tissue from animals treated with 16 and 50mg/kg of tilianin, methanolic, and hydroalcoholic extracts at 100mg/kg. The tilianin effect on monoamine oxidases inhibition is confirmed, suggesting its potential use in the treatment of certain neurological disorders.

Molecular Mechanism and Structure-activity Relationship of the Inhibition Effect between Monoamine Oxidase and Selegiline Analogues.

To investigate the inhibition properties and structure-activity relationship between monoamine oxidase (MAO) and selected monoamine oxidase inhibitors (MAOIs, including selegiline, rasagiline and clorgiline). The inhibition effect and molecular mechanism between MAO and MAOIs were identified via the half maximal inhibitory concentration (IC50) and molecular docking technology. It was indicated that selegiline and rasagiline were MAO B inhibitors, but clorgiline was MAO-A inhibitor based on the selectivity index (SI) of MAOIs (0.000264, 0.0197 and 14607.143 for selegiline, rasagiline and clorgiline, respectively). The high-frequency amino acid residues of the MAOIs and MAO were Ser24, Arg51, Tyr69 and Tyr407 for MAO-A and Arg42 and Tyr435 for MAO B. The MAOIs and MAO A/B pharmacophores included the aromatic core, hydrogen bond acceptor, hydrogen bond donor-acceptor and hydrophobic core. This study shows the inhibition effect and molecular mechanism between MAO and MAOIs and provides valuable findings on the design and treatment of Alzheimer's and Parkinson's diseases.

Harnessing Pharmacogenomics in Clinical Research on Psychedelic-Assisted Therapy.

Psychedelics have recently re-emerged as potential treatments for various psychiatric conditions that impose major public health costs and for which current treatment options have limited efficacy. At the same time, personalized medicine is increasingly being implemented in psychiatry to provide individualized drug dosing recommendations based on genetics. This review brings together these topics to explore the utility of pharmacogenomics (a key component of personalized medicine) in psychedelic-assisted therapies. We summarized the literature and explored the potential implications of genetic variability on the pharmacodynamics and pharmacokinetics of psychedelic drugs including lysergic acid diethylamide (LSD), psilocybin, N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), ibogaine and 3,4-methylenedioxymethamphetamine (MDMA). Although existing evidence is limited, particularly concerning pharmacodynamics, studies investigating pharmacokinetics indicate that genetic variants in drug-metabolizing enzymes, such as cytochrome P450, impact the intensity of acute psychedelic effects for LSD and ibogaine, and that a dose reduction for CYP2D6 poor metabolizers may be appropriate. Furthermore, based on the preclinical evidence, it can be hypothesized that CYP2D6 metabolizer status might contribute to altered acute psychedelic experiences with 5-MeO-DMT and psilocybin when combined with monoamine oxidase inhibitors. In conclusion, considering early evidence that genetic factors can influence the effects of certain psychedelics, we suggest that pharmacogenomic testing should be further investigated in clinical research. This is necessary to evaluate its utility in improving the safety and therapeutic profile of psychedelic therapies and a potential future role in personalizing psychedelic-assisted therapies, should these treatments become available.

Prominent Neuroprotective Potential of Indole-2-N-methylpropargylamine: High Affinity and Irreversible Inhibition Efficiency towards Monoamine Oxidase B Revealed by Computational Scaffold Analysis

Background: Monoamine oxidases (MAO) are flavoenzymes that metabolize a range of brain neurotransmitters, whose dysregulation is closely associated with the development of various neurological disorders. This is why MAOs have been the central target in pharmacological interventions for neurodegeneration for more than 60 years. Still, existing drugs only address symptoms and not the cause of the disease, which underlines the need to develop more efficient inhibitors without adverse effects. Methods: Our drug design strategy relied on docking 25 organic scaffolds to MAO-B, which were extracted from the ChEMBL20 database with the highest cumulative counts of unique member compounds and bioactivity assays. The most promising candidates were substituted with the inactivating propargylamine group, while further affinity adjustment was made by its N-methylation. A total of 46 propargylamines were submitted to the docking and molecular dynamics simulations, while the best binders underwent mechanistic DFT analysis that confirmed the hydride abstraction mechanism of the covalent inhibition reaction. Results: We identified indole-2-propargylamine 4fH and indole-2-N-methylpropargylamine 4fMe as superior MAO-B binders over the clinical drugs rasagiline and selegiline. DFT calculations highlighted 4fMe as more potent over selegiline, evident in a reduced kinetic requirement (ΔΔG‡ = −2.5 kcal mol−1) and an improved reaction exergonicity (ΔΔGR = −4.3 kcal mol−1), together with its higher binding affinity, consistently determined by docking (ΔΔGBIND = −0.1 kcal mol−1) and MM-PBSA analysis (ΔΔGBIND = −1.5 kcal mol−1). Conclusions: Our findings strongly advocate 4fMe as an excellent drug candidate, whose synthesis and biological evaluation are highly recommended. Also, our results reveal the structural determinants that influenced the affinity and inhibition rates that should cooperate when designing further MAO inhibitors, which are of utmost significance and urgency with the increasing prevalence of brain diseases.

Drug-Drug Interactions of Selective Serotonin Reuptake Inhibitors: A Pharmacovigilance Study on Real-World Evidence from the EudraVigilance Database.

As the most common psychiatric symptom, depression represents a subject of high interest for the medical community. Background/Objectives: International guidelines consider selective serotonin reuptake inhibitors (SSRIs) the first-line treatment of depression. Although having better efficacy and tolerability in comparison to tricyclic antidepressants or monoamine oxidase inhibitors, the diversity and potential severity of adverse effects and interactions manifested by SSRIs, combined with the frequency of prescriptions, lead to the necessity of evaluating real-world data. The aim of this study was to identify and evaluate the drug interactions reported in EudraVigilance (EV) for the six SSRIs representatives that are authorized in Europe: fluoxetine (FXT), fluvoxamine (FVM), citalopram (CIT), escitalopram (ESC), paroxetine (PAR) and sertraline (SER). The entire class of SSRIs was examined as a comparator to identify whether one of the representatives was more prone to reporting. Methods: Descriptive analysis and disproportionality analysis were conducted on data extracted from the EV database. Results: A total of 326,450 adverse reactions (ADRs) were reported for the SSRIs group. Approximately a quarter of these (n = 83,201; 25.46%) were reported for SER and 22.37% (n = 73,131) for PAR. Of the total ADRs reported, 2.12% (n = 6925) represent preferred terms related to drug-drug interactions (DDIs): SER (n = 1474; 22.37%), CIT (n = 1272, 19.86), and FXT (n = 1309, 19.83%). Specific ADRs related to inhibitory activity represent 0.98%, and for potentiating activity, 1.89%. Conclusions: Although representing a small value of the total ADRs, DDIs may be related to severe outcomes. Awareness should be raised for this category of ADRs that can be reduced by the joined efforts of physicians and pharmacists.

Monoamine Oxidase Contributes to Valvular Oxidative Stress: A Prospective Observational Pilot Study in Patients with Severe Mitral Regurgitation.

Monoamine oxidases (MAOs), mitochondrial enzymes that constantly produce hydrogen peroxide (H2O2) as a byproduct of their activity, have been recently acknowledged as contributors to oxidative stress in cardiometabolic pathologies. The present study aimed to assess whether MAOs are mediators of valvular oxidative stress and interact in vitro with angiotensin 2 (ANG2) to mimic the activation of the renin-angiotensin system. To this aim, valvular tissue samples were harvested from 30 patients diagnosed with severe primary mitral regurgitation and indication for surgical repair. Their reactive oxygen species (ROS) levels were assessed by means of a ferrous oxidation xylenol orange (FOX) assay, while MAO expression was assessed by immune fluorescence (protein) and qRT-PCR (mRNA). The experiments were performed using native valvular tissue acutely incubated or not with angiotensin 2 (ANG2), MAO inhibitors (MAOI) and the angiotensin receptor blocker, irbesartan (Irb). Correlations between oxidative stress and echocardiographic parameters were also analyzed. Ex vivo incubation with ANG2 increased MAO-A and -B expression and ROS generation. The level of valvular oxidative stress was negatively correlated with the left ventricular ejection fraction. MAOI and Irb reduced valvular H2O2. production. In conclusion, both MAO isoforms are expressed in pathological human mitral valves and contribute to local oxidative stress and ventricular functional impairment and can be modulated by the local renin-angiotensin system.

Functional efficacy of the MAO-B inhibitor safinamide in murine substantia nigra pars compacta dopaminergic neurons in vitro: A comparative study with tranylcypromine

Safinamide (SAF) is currently used to treat Parkinson's disease (PD) symptoms based on its theoretical ability to potentiate the dopamine (DA) signal, blocking monoamine oxidase (MAO) B. The present work aims to highlight the functional relevance of SAF as an enhancer of the DA signal, by evaluating its ability to prolong recovery from DA-mediated firing inhibition of DAergic neurons of the substantia nigra pars compacta (SNpc), compared to another MAO antagonist, tranylcypromine (TCP). Using multielectrode array (MEA) and single electrode extracellular recordings of spontaneous spikes from presumed SNpc DAergic cells in vitro, we show that SAF (30 μM) mildly prolongs the DA-mediated firing inhibition, as opposed to the profound effect of TCP (10 μM). In patch-clamp recordings, we found that SAF (30 μM) significantly reduced the number of spikes evoked by depolarizing currents in SNpc DAergic neurons, in a sulpiride (1 μM) independent manner. According to our results, SAF marginally potentiates the DA signal in SNpc DAergic neurons, while exerting an inhibitory effect on the postsynaptic excitability acting on membrane conductances. Thus, we propose that the therapeutic effects of SAF in PD patients partially depends on MAO inhibition, while other MAO-independent sites of action could be more relevant.

Microdialysis perfusion of COA-Cl enhances dopamine metabolism in the dorsal striatum of freely moving mice.

We performed a microdialysis study to examine the effects of local perfusion of COA‑Cl on the extracellular levels of dopamine (DA) and its metabolites in the dorsal striatum of mice in vivo. The mice were perfused with Ringer's solution (control) and COA‑Cl (0.05, 0.1, or 0.5 mM) into the dorsal striatum. Dialysate samples were collected every 30 min and then analyzed using high‑performance liquid chromatography coupled with an electrochemical detector. We found that local perfusion of COA‑Cl (0.1 or 0.5 mM) into the dorsal striatum of living mice produced a significant and dose‑dependent increase in extracellular levels of DA, 3‑methoxytyramine (3‑MT), and homovanillic acid (HVA), where only 0.5 mM COA‑Cl increased dihydroxyphenylacetic acid (DOPAC) levels. However, 0.05 mM of COA‑Cl did not significantly affect either DA levels or its metabolites. Then, we administered the monoamine oxidase (MAO) inhibitor clorgyline alone or in combination with COA‑Cl (0.1 mM) to test whether COA‑Cl‑induced increases in DOPAC and HVA are mediated by increased MAO activity. Clorgyline alone increased 3‑MT levels and decreased DOPAC and HVA levels but not DA levels. When combined with COA‑Cl, clorgyline increased 3‑MT levels and reversed the decrease in DOPAC and HVA levels caused by clorgyline. The increase in DA metabolism induced by COA‑Cl suggests that some DA was further metabolized into DOPAC, 3‑MT, and HVA. This indicates that COA‑Cl plays a role in DA metabolism via increased DA release and/or activation of MAO, offering new insights into the effects of COA‑Cl on DA metabolism in the brain.