The effects of moclobemide on damaged ovarian tissue induced by ischemia- reperfusion and damaged contralateral ovarian tissue were investigated in rats, biochemically and histologically.

Though there are several classes of antidepressant drugs available on the pharmaceutical market, depression that affects globally over 320 million people is still undertreated. Scientists have made attempts to develop novel therapeutical strategies to maximize effectiveness of therapy and minimize undesired reactions. One of the ideas is use of either dual-action agents or combined administration of two substances that affect diverse neurotransmissions. Thus, we investigated whether the selected CB receptor ligands (oleamide, AM251, JWH133, and AM630) can have an impact on the activity of bupropion and moclobemide. Bupropion belongs to the dual acting drugs, whereas moclobemide is an inhibitor of monoamine oxidase.

Metastatic burden and aggressive behavior determine severity stratification and guide treatment decisions in prostate cancer (PCa). Monoamine oxidase A (MAOA) may promote tumor burden and drug/castration resistance in PCa. A positive association will pave the way for MAOA inhibitors such as moclobemide for PCa therapy.

Even with many antidepressant and anxiolytic drugs available on the market, there are still patients who do not respond well to the standard first or second line treatments for affective or anxiety disorders. The antidepressant agomelatine has been used in Europe for several years. Agomelatine, an agonist at melatonin receptors and an antagonist at serotonin receptors, can be particularly useful in patients suffering from a major depressive disorder associated with insomnia. Some clinical data have shown a limited effect for agomelatine in a subset of patients with major depression. A number of case reports published in 2011-2016 describe the effect of agomelatine in combination with an established antidepressant, such as escitalopram, venlafaxine, duloxetine, moclobemide or bupropion. A successful combination of agomelatine was reported after adjunctive use of agomelatine combined with clomipramine, escitalopram, and venlafaxine in patients with major depression or obsessive-compulsive disorder. Moreover, bupropion or moclobemide augmentation with agomelatine in patients with major depressive disorder led to a significant improvement. Other supportive data have been published, such as analysis of the VIVALDI study, although it should be noted that the study was supported by the manufacturer of agomelatine. In this study, agomelatine in combination with other antidepressants was shown to be effective and well tolerated in practice, although the most effective antidepressant treatment in the study consisted of agomelatine alone and not in combination with other antidepressants. There have also been two published case reports about the concomitant use of duloxetine and agomelatine which were not efficacious. The positive results of agomelatine augmentation with other antidepressants should be confirmed through randomized, double-blind clinical trials.

Ethyl and phenyl carbamate derivatives of pyrazoline (3a-3h) were synthesized and tested for their MAO inhibitory activity. All the compounds were found to be selective towards MAO-A. Phenyl carbamates (3e-3h) were better than ethyl carbamates (3a-3d) and displayed the best selectivity index. Compound 3f (KiMAO-A; 4.96 ± 0.21 nM) was found to be equally potent as that of standard drug, Moclobemide (KiMAO-A; 5.01 ± 0.13 nM) but with best selectivity index (8.86 × 10(-5)). Molecular docking studies with R &S conformer of 3f revealed S-enantiomer is better than R-enantiomer as reported earlier by other groups. It is proposed that VdW's radii of the substitution (bulkiness) in ring B determine the potency of phenyl carbamates.

In the present work, a hit molecule obtained from zinc 'clean drug-like database' by systematically performed computational studies was modified chemically to obtain different derivatives (VS1-VS25). Structures of synthesized derivatives were confirmed by IR, 1H-NMR, 13C-NMR, 13C-DEPT, MS, and elemental analysis. All the synthesized compounds were biologically evaluated for their antidepressant activity by using tail suspension test and forced swimming test in albino mice. All these derivatives showed moderate to good antidepressant activity. The most potent compound (VS25) among the synthesized compounds showed better antidepressant potential than the standard drugs moclobemide, imipramine, and fluoxetine. To understand the time-dependent interactions of this most active compound with MAO-A molecular dynamics was carried out and reported here. Additionally, acute oral toxicity was performed for the most active compound as per OECD guidelines.

Anhedonia is defined as a diminished ability to experience interest or pleasure, and is a critical psychopathological dimension of major depressive disorder (MDD). The purpose of the current systematic review is to evaluate the therapeutic efficacy of pharmacological treatments on measures of anhedonia in adults with MDD. Electronic databases Cochrane Library (CENTRAL), Ovid MEDLINE, PubMed, PsycINFO, and Google Scholar were searched from inception to June 1, 2018 for longitudinal studies utilizing pharmacotherapy for the treatment of anhedonia in patients with MDD. A total of 17 eligible studies were identified (i.e., evaluated the effects of pharmacotherapy on a measure of anhedonia). Among the identified studies, the efficacy of 14 different pharmacotherapies on measures of anhedonia were evaluated, including melatonergic agents (i.e. agomelatine), monoaminergic agents (i.e. moclobemide, clomipramine, bupropion, venlafaxine, fluoxetine, amitifadine and levomilnacipran, escitalopram, and sertraline), glutamatergic agents (i.e., ketamine and riluzole), stimulants (i.e., methylphenidate), and psychedelics (i.e., psilocybin). Based on the available evidence, most antidepressants demonstrated beneficial effects on measures of anhedonia as well as the other depressive symptoms. Only escitalopram/riluzole combination treatment was ineffective in treating symptoms of anhedonia in MDD. Continued research is warranted to further support the efficacy of mechanistically-distinct antidepressants in treating symptoms of anhedonia in MDD. Future research should also aim to parse out the heterogeneous effects of different pharmacotherapies on anhedonic symptoms.

Dehydrozingerone (DHZ) is an active ingredient of Zingiber officinale and structural half analogue of curcumin. In the present study, DHZ was evaluated for monoamine oxidase (MAO) inhibitory activity in silico and antidepressant activity in vivo.

Cognitive dysfunction is of clinical significance and exerts longstanding implication on patients׳ function. Pharmacological and non-pharmacological treatments of cognitive dysfunction are emerging. This review evaluates pharmacological and non-pharmacological treatments of cognitive impairment primarily in the domains of memory, attention, processing speed and executive function in clinical depression. A total of 35 studies were retrieved from Pubmed, PsycInfo and Scopus after applying inclusion and exclusion criteria. Results show that various classes of antidepressants exert improving effects on cognitive function across several cognitive domains. Specifically, studies suggest that SSRIs, the SSRE tianeptine, the SNRI duloxetine, vortioxetine and other antidepressants such as bupropion and moclobemide may exert certain improving effects on cognitive function in depression, such as in learning and memory and executive function. Class-specific cognitive domains or specific dose-response relationships were not identified yet. The few non-pharmacological studies conducted employing cognitive orientated treatments and cognitive remediation therapy show promising results for the improvement of cognitive impairment in depression. However, several methodological constraints of studies limit generalizability of the results and caution the interpretation. Future direction should consider the development of a neuropsychological consensus cognitive battery to support the discovery, clinical assessment, comparison of studies and registration of new agents in clinical depression.

Monoamine oxidase (MAO) isoenzymes are very important drug targets among neurological disorders. Herein, novel series of thiazolylhydrazine-piperazine derivatives were designed, synthesized and evaluated for their MAO-A and -B inhibitory activity. The structures of the synthesized compounds were assigned using different spectroscopic techniques such as 1H-NMR, 13C-NMR and HRMS. Moreover, the prediction of ADME (Absorption, Distribution, Metabolism, Elimination) parameters for all of the compounds were performed using in silico method. According to the enzyme inhibition results, the synthesized compounds showed the selectivity against MAO-A enzyme inhibition. Compounds 3c, 3d and 3e displayed significant MAO-A inhibition potencies. Among them, compound 3e was found to be the most effective derivative with an IC50 value of 0.057 ± 0.002 µM. Moreover, it was seen that this compound has a more potent inhibition profile than the reference inhibitors moclobemide (IC50 = 6.061 ± 0.262 µM) and clorgiline (IC50 = 0.062 ± 0.002 µM). In addition, the enzyme kinetics were performed for compound 3e and it was determined that this compound had a competitive and reversible inhibition type. Molecular modeling studies aided in the understanding of the interaction modes between this compound and MAO-A. It was found that compound 3e had significant and important binding property.

As in other societies, pharmaceutical expenditures in the Netherlands are rising every year. As a consequence, needs for cost control are often expressed. One possible solution for cost control could come through increasing generic substitution by pharmacists. We aim to analyse the extent and nature of substitution in recent years and estimate the likelihood of generic or branded substitution in Dutch pharmacies in relation to various characteristics.

Multiple kinds of monoamine-based antidepressants have been shown prophylactic effects in experimentally induced gastric ulcer. The loss of redox homeostasis plays a principle role in the development of peptic mucosal damage. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases are one of the most important sources of reactive oxygen species within the gastrointestinal tract. It is unclear whether there are some common NADPH oxidases modulated by monoamine-based antidepressants in different gastric mucosal damage models. We explored the effects of selective serotonin-norepinephrine reuptake inhibitor (SNRI) duloxetine on the reactive oxygen species production and antioxidant capacity in the gastric mucosa of water immersion restraint (WIRS) or indomethacin treated rats, and examined the role of NADPH oxidases in the protective effects. Pretreated duloxetine prevented the increase of gastric mucosal NADPH oxidase activity and NADPH oxidase inhibitor apocynin dose-dependently protected gastric mucosa from damage by the two factors. Furthermore, dual oxidase 2 (DUOX2) and NADPH oxidase4 (NOX4) are involved in the protective effects of duloxetine in both models. We then examined NADPH oxidases expression modulated by the other monoamine-based antidepressants including selective serotonin reuptake inhibitor (SSRIs) fluoxetine, tricyclic agent (TCAs) amitriptyline and monoamine oxidase inhibitor (MAOs) moclobemide in the two models, and all the three antidepressants reduced the DUOX2 expression in the gastric mucosa. So DUOX2 was a common modulator in the preventive effects of all the monoamine-based antidepressants on WIRS- and indomethacin-induced gastric lesion. Our work provided a peripheral joint molecular target for monoamine modulatory antidepressants, which may be helpful to reveal the mechanisms of this kind of drugs more than monoamine regulation.

The effect of some antidepressants co-administered with EMD386088 in the modified forced swim test in rats was investigated. Additionally, the pharmacokinetics, metabolic stability, and the effect of EMD386088 on P450 cytochromes were determined. Intraperitoneal (i.p.) coadministration of EMD386088 (2.5 mg/kg) and imipramine (15 mg/kg), reboxetine (5 mg/kg), moclobemide (10 mg/kg), or bupropion (10 mg/kg) evoked significant antidepressant-like activity, whereas no effect was observed after joint administration of EMD386088 with s-citalopram (10 mg/kg). Pharmacokinetic in vivo investigation showed a rapid absorption of EMD386088 (2.5 and 5 mg/kg) with t 1/2 = 67 min (t max = 5 min). Large volume of distribution (V d/F = 102 L/kg) indicated its penetration into peripheral compartments. The most active coadministration of EMD386088 (2.5 mg/kg) with imipramine (15 mg/kg) resulted in slower absorption of the compound (C max = 60 min) and decrease in the volume of distribution (V d/F = 32.2 L/kg). EMD386088 penetrates the blood-brain barrier with a high brain/plasma ratio of about 19 (2.5 mg/kg) and 7.5 for coadministration with imipramine. The in silico and in vitro studies on EMD386088 metabolic stability showed the dehydrogenation of tetrahydropyridine moiety as its main metabolic pathway. EMD386088 did not influence on CYP3A4 activity, and it has been classified as a very weak CYP2D6 inhibitor (IC 50  = 2.25 μM). The results obtained from the forced swim test in rats indicate that an activation of 5HT6 receptor may facilitate antidepressant-like activity of some antidepressants. The pharmacokinetic results suggest that the interaction between EMD386088 and imipramine could not have been pharmacokinetic in nature.

Monoamine-based antidepressants can prophylactically protect against stress-induced gastric ulcers. Although the central nucleus of amygdala (CeA) has been shown to modulate the severity of stress ulcers, little is known about the molecular mechanisms underlying the gastroprotective effect of this kind of drugs. Here, we first used proton magnetic resonance spectroscopy, a non-invasive tool, to explore the change of neurometabolites of the CeA of rats pretreated with the duloxetine of selective serotonin-norepinephrine reuptake inhibitors during 6 h of water-immersion restraint stress (WIRS). Duloxetine decreased N-acetyl-aspartate/creatine ratio (NAA/creatine) in CeA after WIRS, which was paralleled by the amelioration of gastric lesions. Meanwhile, the gastric ulcer index was negatively correlated with reduced NAA/creatine. Furthermore, the intra-CeA infusion of NAA aggravated WIRS-induced gastric mucosa damage, which suggested the crucial role of reduced NAA. Western blotting was performed to identify the specific enzymes responsible for the change of the contents of NAA at 0.5 h/3 h/6 h after WIRS, considering the preventative gastric protection of duloxetine. The NAA-catabolizing enzyme aspartoacylase (ASPA) was the only enzyme downregulated by 0.5 h WIRS and upregulated by duloxetine. Moreover, overexpressing ASPA in CeA alleviated stress ulcers. Additionally, all of the other three monoamine-based antidepressants, the fluoxetine of selective serotonin reuptake inhibitors, the amitriptyline of tricyclic agents, and the moclobemide of MAOs, increased ASPA expression in CeA. Together, these results indicate that increasing ASPA to hydrolyze NAA in CeA is a common mechanism of gastroprotective effects against stress exerted by monoamine-based antidepressants, and ASPA is a shared target more than monoamine regulation for this kind of drugs.

Background: Monoamine oxidases (MAOs) were discovered nearly a century ago. This article aims to analyze the research literature landscape associated with MAOs as privileged class of neuronal enzymes (neuroenzymes) with key functions in the processes of neurodegeneration, serving as important biological targets in neuroscience. With the accumulating publications on this topic, we aimed to evaluate the publication and citation performance of the contributors, reveal the popular research themes, and identify its historical roots. Methods: The electronic database of Web of Science (WoS) Core Collection was searched to identify publications related to MAOs, which were analyzed according to their publication year, authorship, institutions, countries/regions, journal title, WoS category, total citation count, and publication type. VOSviewer was utilized to visualize the citation patterns of the words appearing in the titles and abstracts, and author keywords. CRExplorer was utilized to identify seminal references cited by the MAO publications. Results: The literature analysis was based on 19,854 publications. Most of them were original articles (n = 15,148, 76.3%) and reviews (n = 2,039, 10.3%). The top five WoS categories of the analyzed MAO publications were Pharmacology/Pharmacy (n = 4,664, 23.5%), Neurosciences (n = 4,416, 22.2%), Psychiatry (n = 2,906, 14.6%), Biochemistry/Molecular Biology (n = 2,691, 13.6%), and Clinical Neurology (n = 1,754, 8.8%). The top 10 institutions are scattered in the United States, UK, France, Sweden, Canada, Israel, and Russia, while the top 10 countries/regions with the most intensive research on the field of MAOs are the United States, followed by European and Asian countries. More highly cited publications generally involved neurotransmitters, such as dopamine (DA), serotonin, and norepinephrine (NE), as well as the MAO-A inhibitors moclobemide and clorgyline, and the irreversible MAO-B inhibitors selegiline and rasagiline. Conclusion: Through decades of research, the literature has accumulated many publications investigating the therapeutic effects of MAO inhibitors (MAOIs) on various neurological conditions, such as Alzheimer's disease (AD), Parkinson's disease (PD), and depression. We envision that MAO literature will continue to grow steadily, with more new therapeutic candidates being tested for better management of neurological conditions, in particular, with the development of multi-target acting drugs against neurodegenerative diseases.

Influenza infrastructure systems are crucial for maintaining surveillance operations, and for mitigating and responding to the disease. The role of surveillance is to isolate and identify as rapidly as possible any new influenza strains and collate this information for the preparedness for, and response to, an impending influenza activity in humans. However, sources of surveillance information, particularly in Africa, are meagre. This systematic review will critically evaluate the existing influenza surveillance systems in sub-Saharan Africa.

Stimulation of the amygdala produces pupil dilation in animal and human subjects. The present study examined whether the amygdala is sensitive to variations in the pupil size of others. Male subjects underwent event-related functional magnetic resonance imaging while passively viewing unfamiliar female faces whose pupils were either unaltered (natural variations in large and small pupils) or altered to be larger or smaller than their original size. Results revealed that the right amygdala and left amygdala/substantia innominata were sensitive to the pupil size of others, exhibiting increased activity for faces with relatively large pupils. Upon debrief, no subject reported being aware that the pupils had been manipulated. These results suggest a function for the amygdala in the detection of changes in pupil size, an index of arousal and/or interest on the part of a conspecific, even in the absence of explicit knowledge.

Cellular heterogeneity of aortic valves complicates the mechanistic evaluation of the calcification processes in calcific aortic valve disease (CAVD), and animal disease models are lacking. In this study, we identify a disease-driver population (DDP) within valvular interstitial cells (VICs). Through stepwise single-cell analysis, phenotype-guided omic profiling, and network-based analysis, we characterize the DDP fingerprint as CD44highCD29+CD59+CD73+CD45low and discover potential key regulators of human CAVD. These DDP-VICs demonstrate multi-lineage differentiation and osteogenic properties. Temporal proteomic profiling of DDP-VICs identifies potential targets for therapy, including MAOA and CTHRC1. In vitro loss-of-function experiments confirm our targets. Such a stepwise strategy may be advantageous for therapeutic target discovery in other disease contexts.

Depression emerges as a risk factor for cardiovascular disease, and it is thought that successful antidepressant treatment may reduce such a risk. Therefore, antidepressant treatment embodies a potential preventive measure to reduce cardiovascular events in patients with depression. Accumulating evidence indicates that antidepressants have off-target effects on vascular dysfunction and in the early stages of atherosclerosis, which form the basis for cardiovascular disease (CVD) pathogenesis. In this context, we performed a thorough review of the evidence pertaining to the effects of different classes of antidepressant medications on hemodynamic and early atherosclerosis markers. The preclinical and clinical evidence reviewed revealed a preponderance of studies assessing selective serotonin reuptake inhibitors (SSRI), whereas other classes of antidepressants are less well-studied. Sufficient evidence supports a beneficial effect of SSRIs on vascular inflammation, endothelial function, arterial stiffening, and possibly delaying carotid atherosclerosis. In clinical studies, dissecting the hypothesized direct beneficial antidepressant effect of SSRIs on endothelial health from the global improvement upon remission of depression has proven to be difficult. However, preclinical studies armed with appropriate control groups provide evidence of molecular mechanisms linked to endothelial function that are indeed modulated by antidepressants. This suggests at least a partial direct action on vascular integrity. Further research on endothelial markers should focus on the effect of antidepressants on treatment responders versus non-responders in order to better ascertain the possible beneficial vascular effects of antidepressants, irrespective of the underlying course of depression.