Monoamine Oxidase Inhibitors Research Articles

Transporter-dependent uptake and metabolism of myocardial interstitial serotonin in the rat heart

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.

The inhibition of monoamine oxidase by 2H-1,4-benzothiazin-3(4H)-ones

Monoamine oxidase (MAO) plays an important role in psychiatric and neurological disorders, such as depression and Parkinson's disease. As a result, MAO represents a key target for developing drugs to treat these conditions. The present study aimed to synthesise and discover compounds that inhibit the MAO enzymes and which may be relevant to the treatment of neurological disorders. A series of nine 2H-1,4-benzothiazin-3(4H)-ones were synthesised and evaluated as potential in vitro inhibitors of human MAO-A and MAO-B. The benzothiazinones bear structural similarity to a series of 3,4-dihydro-2(1H)-quinolinones that have been shown to be highly potent MAO-B inhibitors. The results show that the benzothiazinones inhibit both MAO isoforms but are more potent MAO-B inhibitors. The most potent inhibitors exhibit IC50 values of 0.0027 (1b), 0.0082 (1c), 0.0096 (1d), and 0.0041 µM (1h) for MAO-B, and 0.714 µM (1d) for MAO-A. These benzothiazinone derivatives exhibit promising MAO inhibition activities and may be developed into clinically useful agents for the treatment of Parkinson’s disease. Interestingly, related 4H-3,1-benzothiazin-4-ones have previously been investigated as dual-target-directed drugs that inhibit MAO-B and antagonize adenosine A2A receptors for the treatment of Parkinson’s disease. Based on an interest in d-amino acid oxidase (DAAO) as a target for the treatment for schizophrenia, the 2H-1,4-benzothiazin-3(4H)-ones were also evaluated as in vitro inhibitors of this enzyme. Among the study compounds, only 7-hydroxy-2H-1,4-benzothiazin-3(4H)-one (IC50 = 4.20 µM) was an active DAAO inhibitor. Finally, molecular docking was employed to gain insight into the binding modes and interactions of the 2H-1,4-benzothiazin-3(4H)-ones with MAO.

Evolution of ideas about the risk of tyramine syndrome developing during therapy with irreversible non-selective monoamine oxidase inhibitors (to the 70th anniversary of the first use of this group of antidepressants)

We describe the history of studying of the problem of tyramine syndrome during the treatment with antidepressants, irreversible non-selective monoamine oxidase inhibitors. Data on clinical observations are presented. Early hypotheses of pathogenesis are considered. The period of discovery of the relationship between increased blood pressure and the use of foods containing tyramine is outlined. The transformation of terminology is demonstrated. The events associated with the restriction of the use of therapy are characterized. The formation of the opinion about the exaggeration of the risk of developing tyramine syndrome is analyzed. Data on the involvement in the discussion of the problem of tyramine syndrome of society as a whole are given.

THE INFLUENCE OF PHARMACOGENETICS IN THE CLINICAL USE OF ANTIDEPRESSANTS

The interest on personalized medicine encourages researches on pharmacogenetics. The promotion of new analytical combinations in extensive drug development and also with the progression in the technologies for human gene cloning resulted in a great interest for pharmacogenetics. In last years the development on genetical sciences also influenced pharmacogenetics. Personalized medicine also includes areas such as stratified medicine and precision medicine and these terms are closely related with pharmacogenetics. Moderate response rates and the difference in drug effect on individuals focus pharmacogenetics on psychopharmacology area and antidepressants. It is considered that genetic factors may contribute %50 of antidepressant drug response. Additionally the genetical properties of the patient may effect the pharmacokinetics and pharmacodynamics of the antidepressants therefore the change in the effect and an increase in the side effects may be seen. The genes which codes serotonin transporter, 5-HTTLPR and SLC6A4 are commonly investigated and they are thought to be the main reasons of the difference in antidepressant drug responses. Also the difference in the activities of CYP 2D6 and CYP 2C19 may change the pharmacokinetics of the antidepressants and therefore the stable concentration of antidepressant leves in the plasma. These variations in the factors contributing to the drug levels may lead to a difference in the response rates of antidepressants. In this review, we focused on the pharmacogenetics of different classes of antidepressant drugs such as selective serotonine reuptake inhibitors, serotonin-noradrenaline reuptake inhibitors, tricyclic antidepressants and mono-amine oxidase inhibitors. We have compiled pharmacogenetic studies on antidepressants and effect of genetic variations on the drug responses.

Green Spectrophotometric Platforms for Resolving Overlapped Spectral Signals of Recently Approved Antiparkinsonian Drug (Safinamide) in the Presence of Its Synthetic Precursor (4-Hydroxybenzaldehyde): Applying Ecological Appraisal and Comparative Statistical Studies.

Safinamide, a highly specific inhibitor of monoamine oxidase B, is a new approved prodigious therapy used to cure Parkinson's disease (PD). Before marketing and selling a medicine, manufacturers must guarantee that the manufacturing process is consistent by monitoring levels of process-related chemicals and drug contaminants. Therefore, five precise, fast, and accurate spectrophotometric techniques were employed and evaluated for the simultaneous measurement of safinamide and its synthetic precursor, 4-hydroxybenzaldehyde. The first derivative, derivative ratio, ratio difference, dual wavelength, and Fourier self-deconvolution methods worked well to resolve spectral overlap of safinamide and its synthetic precursor, 4-hydroxybenzaldehyde. Safinamide detection limits ranged from 0.598 to 1.315 µg/mL, whereas the 4-hydroxybenzaldehyde detection limit was found to be as low as 0.327 µg/mL. According to International Council for Harmonisation (ICH) criteria, all procedures were verified and confirmed to be accurate, robust, repeatable, and precise within reasonable range. No considerable variation was found when comparing the outcomes of the suggested approaches to the findings of previously published methods. The ecological value of established methods was measured: the national environmental methods index (NEMI), the analytical eco-scale, the analytical greenness metric (AGREE), and the green analytical process index (GAPI) were used. This is the first spectrophotometric determination of safinamide drug in the presence of its synthetic precursor. Five simple and efficient spectrophotometric approaches were employed to determine a newly approved antiparkinsonian drug in the presence of its synthetic precursor simultaneously. Ecological appraisal was performed for the developed methods using four assessment tools.

Biomimetic Adsorptive Composites for Redox Remediation of Organic Pollutants

Conductive hydrogels have gained interest as responsive materials for pollutant sensing and degradation in a variety of applications such as wastewater and soil remediation. There has been a significant increase in both commercial and domestic wastewater, which is output into ground sources, acting as a leading contaminant for surrounding communities. Specifically, cationic organic textile dyes such as methylene blue, methyl red, and methyl violet which are known monoamine oxidase inhibitors are prevalent pollutants. To improve remediation, this work employs a biopolymeric (i.e. polysaccharide) matrix to aid in non-covalent adsorption of pollutants to the network. Additionally, modification of the polysaccharide backbone with a conductive polymer can promote electron transfer throughout the matrix. This work employs the photoinitiation of a metal-polysaccharide complex to directly polymerize polyaniline (PANI) on the polysaccharide backbone. The PANI-functionalized composite can be utilized as a reducing substrate for the adsorptive redox remediation of the organic pollutants that occur in contaminated soils or water supplies.

Computational Insights into β-Carboline Inhibition of Monoamine Oxidase A.

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.

Effectiveness and safety of safinamide in routine clinical practice in a Belgian Parkinson’s disease population: an open-label, levodopa add-on study

BackgroundSafinamide is a recent multimodal antiparkinsonian drug that inhibits monoamine oxidase B and modulates the glutamatergic system with positive effects on motor and nonmotor symptoms of Parkinson’s disease (PD). This post-hoc analysis of the European SYNAPSES study provides first-time data on the use of safinamide in routine clinical practice in Belgium.ObjectiveTo describe the efficacy and safety of safinamide in Belgian PD patients in real-life conditions.MethodsPost-hoc analysis of the Belgian cohort from the European SYNAPSES trial, which was an observational, multicenter, retrospective-prospective cohort study. Patients were followed up to 12 months. Analyses were performed in the overall population and according to different criteria such as the age limit (> 75 years), presence or absence of relevant comorbidities, presence or absence of psychiatric conditions such as depression and anxiety, patients on levodopa monotherapy or levodopa in combination with other treatments, patients on rasagiline before inclusion or not.ResultsOf the 172 patients included, 29.2% were > 75 years, 58.9% had relevant comorbidities and 32.7% had psychiatric conditions. Almost all the patients reported motor (98.8%) or non-motor (86.3%) symptoms. During the study, 36.3% of patients reported drug-related reactions. The adverse drug reactions were those already described in the patients’ information leaflet. The majority were mild or moderate and completely resolved and no differences were detected between the subgroups of patients. Almost 35% of the patients demonstrated a clinically significant improvement in the UPDRS and 50% of the patients with wearing-off at baseline, did not report wearing-off anymore after one year of treatment. Patients under levodopa monotherapy compared to patients receiving levodopa combined with other antiparkinsonian treatments benefit more from safinamide treatment. Patients switched from rasagiline to safinamide seemed also to benefit more from safinamide treatment.ConclusionThe study confirms the excellent safety and efficacy profile of safinamide, particularly in more vulnerable groups of patients such as the elderly and patients with significant comorbidities or psychiatric conditions such as depression or anxiety.

Trends in Brazilian market of antidepressants: A five-year dataset analysis.

Introduction: Depression is an emotional disorder associated with morbidities and disabilities worldwide. The growing use of antidepressants is a concern for health managers because there are still unanswered questions on the effectiveness and safety of these medicines. Drug sales have increased in Brazil in recent years, but investigations on antidepressants sales are not available. We aimed to describe the trends in the antidepressant commerce in Brazil in a five-year period. Materials and Methods: We performed an ecological study on antidepressant sales in Brazil, from November 2014 to October 2019, using data from IQVIA™, a data provider of pharmaceutical sales. Antidepressants were coded by the Anatomical Therapeutic Chemical classification system, and sales were presented in defined daily doses (DDDs) and DDDs per 1,000 inhabitants per day (DIDs). The results were expressed in absolute quantities and growth rates. Results: The analyzed dataset contained 23 active substances in 780 products. The total sales of antidepressants increased from 23.3 DIDs in November 2014 to 38.3 DIDs in October 2019 (p = 0.002). Selective serotonin reuptake inhibitors were the most sold category of drugs (+5.7 million DDDs) in the period. ‘Other’ antidepressants presented the largest growth rate (104.7%). Individually, the most sold active substance was escitalopram (+1.8 million DDDs), and vortioxetine had the largest growth rate (336.2%). Tricyclic sales remained unchanged, and monoamine oxidase inhibitors had low and even decreasing sales (−9.5%). Discussion: The total sales of antidepressants increased in Brazil from November 2014 to October 2019. The higher sale volumes of selective serotonin reuptake inhibitors and higher growth rate of ‘other’ antidepressants, with low sale volume of tricyclics and a decrease of monoamine oxidase inhibitors, suggest the replacement of older drugs by newer ones following a global trend. Therapeutic advances and commercial promotion efforts on new products might explain these findings.

Monoamine Oxidase Inhibitors Prevent Glucose-Dependent Energy Production, Proliferation and Migration of Bladder Carcinoma Cells.

Bladder cancer is the 10th most common cancer in the world and has a high risk of recurrence and metastasis. In order to sustain high energetic needs, cancer cells undergo complex metabolic adaptations, such as a switch toward aerobic glycolysis, that can be exploited therapeutically. Reactive oxygen species (ROS) act as key regulators of cancer metabolic reprogramming and tumorigenesis, but the sources of ROS remain unidentified. Monoamine oxidases (MAOs) are mitochondrial enzymes that generate H2O2 during the breakdown of catecholamines and serotonin. These enzymes are particularly important in neurological disorders, but recently, a new link between MAOs and cancer has been uncovered, involving their production of ROS. At present, the putative role of MAOs in bladder cancer has never been evaluated. We observed that human urothelial tumor explants and the bladder cancer cell line AY27 expressed both MAO-A and MAO-B isoforms. Selective inhibition of MAO-A or MAO-B limited mitochondrial ROS accumulation, cell cycle progression and proliferation of bladder cancer cells, while only MAO-A inhibition prevented cell motility. To test whether ROS contributed to MAO-induced tumorigenesis, we used a mutated form of MAO-A which was unable to produce H2O2. Adenoviral transduction of the WT MAO-A stimulated the proliferation and migration of AY27 cells while the Lys305Met MAO-A mutant was inactive. This was consistent with the fact that the antioxidant Trolox strongly impaired proliferation and cell cycle progression. Most interestingly, AY27 cells were highly dependent on glucose metabolism to sustain their growth, and MAO inhibitors potently reduced glycolysis and oxidative phosphorylation, due to pyruvate depletion. Accordingly, MAO inhibitors decreased the expression of proteins involved in glucose transport (GLUT1) and transformation (HK2). In conclusion, urothelial cancer cells are characterized by a metabolic shift toward glucose-dependent metabolism, which is important for cell growth and is under the regulation of MAO-dependent oxidative stress.

In Vivo Study of Monoamine Oxidases Using Multisite Intracerebral Microdialysis.

The activity of monoamine oxidases (MAOs) in the brain is often associated with neurodegenerative diseases. The study of MAOs in vivo or ex vivo is generally performed using MAO inhibitors and rarely using substrates. We present a pharmacological approach using intracerebral microdialysis to study the activity of MAO in the striatum and the prefrontal cortex of rats. It consists of applying ascending concentrations of 3-methoxytyramine (3-MT) as a substrate via the probes and measuring the indirect product homovanillic acid generated by MAO activity. We present herein the methodologies comprising our in-house stereotaxic procedures in rats, the microdialysis perfusion system and the substrate application, and the neurochemical analysis of the samples.

Assay of MAO Inhibition by Chromatographic Techniques (HPLC/HPLC-MS).

Monoamine oxidase (MAO) enzymes (MAO A and B) catalyze the oxidative deamination of biogenic amines, neurotransmitters, and xenobiotic amines and contribute to the regulation of the contentof these activesubstances in mammalian organisms. The oxidation of biogenic amines by MAO produces hydrogen peroxide (H2O2) and aldehydes that represent risk factors for oxidative injury.The inhibitorsof MAO are useful as antidepressants and neuroprotective agents. Usually, the assays of MAO determine amine deamination products or measure the H2O2 released by using direct spectrophotometric or fluorimetric methods. Direct methods are more prone to interferences and can afford inaccurate results. Those limitations can beavoided by using chromatographic techniques. This work describesa chromatographic method to assay MAO A and MAOB activity by using kynuramine as a nonselective substrate and the subsequentanalysis of 4-hydroxyquinoline by RP-HPLC-DAD-fluorescence and mass spectrometry(MS). Alternatively, the assay uses the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin as a substrate of MAO that is oxidized (bioactivated) to neurotoxic pyridinium cations which areanalyzed by HPLC. These methods are applied to assess the inhibition of MAO by bioactive β-carboline alkaloids occurring in foods, plants, and biological systems.

Does prescribing SSRI alone effective to prevent relapse in panic disorder?

Psychological and pharmacological modalities have been proposed by studies to be adapted for treatment of panic disorder. Selective Serotonin Receptor Inhibitors (SSRI), a group of antidepressant is the first-line drug recommended by National Institute for Health and Care Excellence (NICE) and the British Association for Psychopharmacology for their more desired profile of adverse effect over other classes of antidepressants such as tricyclic antidepressants (TCAs) and Monoamine Oxidase Inhibitors (MAOIs). However, the efficacy of SSRI as a monotherapy to prevent relapse in panic disorder has not being widely studied, hence, this review.

Isatoic anhydrides as novel inhibitors of monoamine oxidase

The monoamine oxidase (MAO) enzymes metabolise neurotransmitter amines in the central and peripheral tissues, and thereby contribute to the regulation of neurotransmission. Inhibitors of MAO modulate the levels of neurotransmitters in the central nervous system, and have been used for several decades for the treatment of depression and Parkinson’s disease, while potential new therapeutic applications in other diseases such as prostate cancer and heart failure may exist. In the interest of discovering new classes of chemical compounds that potently inhibit the MAOs, the present study synthesises a series of ten isatoic anhydrides and evaluates their potential as in vitro inhibitors of human MAO-A and MAO-B. The isatoic anhydrides bear structural similarity to a series of 3,4-dihydro-2(1H)-quinolinones as well as to series of isatins and phthalimides that have been reported to act as potent MAO-B inhibitors. The results document that the isatoic anhydrides inhibit both MAO isoforms with the most potent inhibitors exhibiting IC50 values of 0.010 µM (1b and 1h) and 0.0047 µM (1j) for MAO-A and MAO-B, respectively. Molecular docking suggests that isatoic anhydrides exhibit similar binding modes and interactions with MAO-A and MAO-B, which may explain their potent inhibition of both isoforms. It may be concluded that the isatoic anhydrides represent a new class of MAO inhibitors, while it is interesting to note that very few studies on the pharmacological actions of isatoic anhydrides have been reported. As a secondary aim, the isatoic anhydrides were also evaluated as potential inhibitors of d-amino acid oxidase (DAAO), acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE).

A study of molecular docking of l-tryptophan ligand as a compound in pineapples and bananas binding with the human serotonin transporter (SERT)

Introduction: Low mood condition is related to a low level of brain serotonin. An early sign of depression with low mood symptoms is generally treated with psychotropic drugs that work as selective serotonin reuptake and monoamine oxidase (MAO) inhibitors (one of which is sertraline), to increase serotonin levels in the brain. There are some concerns regarding side effects available medication like serotonin syndrome, suicidality and aggressive behavior. Thus, development of alternative herbal products made from a combination of pineapple and banana extract with less side effect and its potential affinity with serotonin regulation is important. Aim of the study: To determine potential herbal rich (banana and pineapple) of L-tryptophan and potential active compounds interaction with the human serotonin transporter. Method: In the present study, using in silico molecular docking techniques, the active compound of banana and pineapple and its potential interaction with human serotonin transporter were assed. Docking study explored the bioactive compounds interactions with specific target like catechin, dopamine, epigallocatechin, gallic acid, L-tryptophan, malvidin, norepinephrine, pelargonidin, peonidin, and serotonin. Molecular docking simulations were performed using AutoDock 4.2 software. The docking method was validated first by re-docking sertraline (nature ligand) in a complex with PDB ID: 6AWO against the target receptor (SERT). Result: The molecular docking results had showed that L-tryptophan, peonidin, and catechin could bind to esential amino acid residues in the binding pocket, with binding affinity -5.69, -8.63, -8.24 kcal/mol respectively. Conclusion: L-tryptophan, peonidin, and catechin are the most promising compounds that have good potency as anti-depressant agents through SERT inhibitory activity. This compounds in bananas and pineapples have the potential to affect serotonin transporter receptors that play a role in mood and behavior.

Privileged multi-target directed propargyl-tacrines combining cholinesterase and monoamine oxidase inhibition activities

Twenty-four novel compounds bearing tetrahydroacridine and N-propargyl moieties have been designed, synthesised, and evaluated in vitro for their anti-cholinesterase and anti-monoamine oxidase activities. Propargyltacrine 23 (IC50 = 21 nM) was the most potent acetylcholinesterase (AChE) inhibitor, compound 20 (IC50 = 78 nM) showed the best inhibitory human butyrylcholinesterase (hBChE) profile, and ligand 21 afforded equipotent and significant values on both ChEs (human AChE [hAChE]: IC50 = 0.095 ± 0.001 µM; hBChE: IC50 = 0.093 ± 0.003 µM). Regarding MAO inhibition, compounds 7, 15, and 25 demonstrated the highest inhibitory potential towards hMAO-B (IC50 = 163, 40, and 170 nM, respectively). In all, compounds 7, 15, 20, 21, 23, and 25 exhibiting the most balanced pharmacological profile, were submitted to permeability and cell viability tests. As a result, 7-phenoxy-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydroacridin-9-amine hydrochloride (15) has been identified as a permeable agent that shows a balanced pharmacological profile [IC50 (hAChE) = 1.472 ± 0.024 µM; IC50 (hBChE) = 0.659 ± 0.077 µM; IC50 (hMAO-B) = 40.39 ± 5.98 nM], and consequently, as a new hit-ligand that deserves further investigation, in particular in vivo analyses, as the preliminary cell viability test results reported here suggest that this is a relatively safe therapeutic agent.

Development of Halogenated-Chalcones Bearing with Dimethoxy Phenyl Head as Monoamine Oxidase-B Inhibitors.

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.

Synthesis, biological evaluation and computational investigations of S-benzyl dithiocarbamates as the cholinesterase and monoamine oxidase inhibitors

The current study was aimed to identify the selective and multi-targeted inhibitors of cholinesterase and monoamine oxidase enzymes. For this purpose, a novel class of multi-targeted compounds i.e., S-benzyl dithiocarbamates (1-30) was synthesized via a single pot reaction and the structures were characterized via NMR (1H and 13C), FT-IR and high-resolution mass spectrometry (HRMS). Moreover, the purity of the final products was determined using thin-layer chromatography (TLC). The compounds were evaluated for their inhibitory potential against cholinesterases (ChE) and monoamine oxidases (MAO). Among all derivatives, compound 5 (2-(trifluoromethyl) benzyl azepane-1-carbodithioate) depicted the maximum inhibition of AChE and BChE enzyme with an IC50 value of 4.37±0.94 and 14.9±1.11, respectively. The derivative 11, expressed maximum inhibition of MAO-A and MAO-B with an IC50 value of 1.14±0.03 and 1.01±0.16 µM, respectively. Whereas, compound 16 exhibited maximum inhibitory potential against all four targeted enzymes i.e., AChE, BChE, MAO-A and MAO-B with an IC50 value of 1.39±0.07 µg/ mL, 1.52±0.14 µg/ mL, 44.9±1.54 µM and 2.85±0.21 µM, respectively. The chemical reactivity profile of the potent derivatives were evaluated through density functional theory studies (DFT) where it was found that compound 5, 6 and 11 possessed reactive character due to narrow LUMO/HOMO energy gap. In addition, Molecular docking studies revealed excellent docking scores and produced sable protein-ligand complexes. The stability of protein-ligand complex was affirmed by molecular dynamic simulations which revealed stable and equilibrated trajectories of simulated complexes. The findings of in-vitro and in-silico studies suggested compound 16 as a promising multi-targeted compound that can be act as lead molecule for the treatment of AD.

Neuroinflammation in Parkinson"s Disease and its Treatment Opportunities

Parkinson’s disease (PD) is a complex, chronic, and progressive neurodegenerative disease that is characterized by irreversible dopaminergic neuronal loss in the substantia nigra. Alpha-synuclein is normally a synaptic protein that plays a key role in PD due to pathological accumulation as oligomers or fibrils. Clustered alpha-synuclein binds to the Toll-like receptors and activates the microglia, which initiates a process that continues with pro-inflammatory cytokine production and secretion. Pro-inflammatory cytokine overproduction and secretion induce cell death and accelerate PD progression. Microglia are found in a resting state in physiological conditions. Microglia became activated by stimulating Toll-like receptors on it under pathological conditions, such as alpha-synuclein aggregation, environmental toxins, or oxidative stress. The interaction between Toll-like receptors and its downstream pathway triggers an activation series, leads to nuclear factor-kappa B activation, initiates the inflammasome formation, and increases cytokine levels. This consecutive inflammatory process leads to dopaminergic cell damage and cell death. Microglia become overactive in response to chronic inflammation, which is observed in PD and causes excessive cytotoxic factor production, such as reactive oxidase, nitric oxide, and tumor necrosis factor-alpha. This inflammatory process contributes to the exacerbation of pathology by triggering neuronal damage or death. Current treatments, such as dopaminergic agonists, anticholinergics, or monoamine oxidase inhibitors alleviate PD symptoms, but they can not stop the disease progression. Finding a radical treatment option or stopping the progression is essential when considering that PD is the second most reported neurodegenerative disorder. Many cytokines are released during inflammation, and they can start the phagocytic process, which caused the degradation of infected cells along with healthy ones. Therefore, targeting the pathological mechanisms, such as microglial activation, mitochondrial dysfunction, and oxidative stress, that should be involved in the treatment program is important. Neuroinflammation is one of the key factors involved in PD pathogenesis as well as alpha-synuclein accumulation, synaptic dysfunction, or dopaminergic neuronal loss, especially in the substantia nigra. Therefore, evaluating the therapeutic efficiency of the mechanisms is important, such as microglial activation and nuclear factor-kappa B pathway or inflammasome formation inhibition, and cytokine release interruption against neuroinflammation may create new treatment possibilities for PD. This study examined the pathological relation between PD and neuroinflammation, and targeting neuroinflammation as an opportunity for PD treatments, such as Toll-like receptor antagonists, NOD-like receptor family pyrin domain containing-3 inflammasome inhibitors, cytokine inhibitors, peroxisome proliferator-activated receptor-γ agonists, reactive oxygen species inhibitors, and nonsteroidal anti-inflammatory drugs.

Molecular Mechanisms of the Neuroprotective Effect of Methylene Blue.

Methylene blue (MB) is the first fully synthetic compound that had found its way into medicine over 120 years ago as a treatment against malaria. MB has been approved for the treatment of methemoglobinemia, but there are premises for its repurposing as a neuroprotective agent based on the efficacy of this compound demonstrated in the models of Alzheimer's, Parkinson's, and Huntington's diseases, traumatic brain injury, amyotrophic lateral sclerosis, depressive disorders, etc. However, the goal of this review was not so much to focus on the therapeutic effects of MB in the treatment of various neurodegeneration diseases, but to delve into the mechanisms of direct or indirect effect of this drug on the signaling pathways. MB can act as an alternative electron carrier in the mitochondrial respiratory chain in the case of dysfunctional electron transport chain. It also displays the anti-inflammatory and anti-apoptotic effects, inhibits monoamine oxidase (MAO) and nitric oxide synthase (NOS), activates signaling pathways involved in the mitochondrial pool renewal (mitochondrial biogenesis and autophagy), and prevents aggregation of misfolded proteins. Comprehensive understanding of all aspects of direct and indirect influence of MB, and not just some of its effects, can help in further research of this compound, including its clinical applications.