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Based on the multitarget-directed ligands (MTDLs) strategy, a series of chromone-hydroxypyridinone hybrids were designed, synthesised, and evaluated as potential multimodal anti-AD ligands. Prospective iron-chelating effects and favourable monoamine oxidase B (MAO-B) inhibitory activities were observed for most of the compounds. Pharmacological assays led to the identification of compound 17d, which exhibited favourable iron-chelating potential (pFe3+ = 18.52) and selective hMAO-B inhibitory activity (IC50 = 67.02 ± 4.3 nM, SI = 11). Docking simulation showed that 17d occupied both the substrate and the entrance cavity of MAO-B, and established several key interactions with the pocket residues. Moreover, 17d was determined to cross the blood–brain barrier (BBB), and can significantly ameliorate scopolamine-induced cognitive impairment in AD mice. Despite its undesired pharmacokinetic property, 17d remains a promising multifaceted agent that is worth further investigation. [ABSTRACT FROM AUTHOR]

There is a group of enzymes called monoamine oxidase(s) (MAOs) that help with the oxidation of amines found in both our diet and our bodies. Currently, monoamine oxidase inhibitors (MAO-Is) are utilized to manage conditions like depression, Parkinson's disease, and other psychiatric disorders. Rheumatoid arthritis (RA) is an auto-immune disease that has been linked to negative changes in mental health, such as depression. When depression co-occurs with RA, it can further worsen the outcome of the disease. Inhibiting monoamine oxidases could potentially treat RA by improving its pathological markers. Using existing pre-clinical and clinical data on safety and toxicity makes drug re-purposing advantageous. Hence, the pre-clinical validation of MAO-I's effectiveness in managing RA requires urgent regulatory intervention to commence clinical trials. Back in 1983, a clinical case report put forward the idea of repurposing MAO-I for RA treatment. Although MAO-I had been used for depression, it was observed to have a significant reduction in joint pain and stiffness. However, no significant clinical research has been conducted on this matter since then. In this commentary article, we provide a summary of the pre-clinical data that is currently available. The main focus of our discussion is on the significance of clinical trials for MAO-I, repurposing it for RA, and using it for the simultaneous management of depression and RA. [ABSTRACT FROM AUTHOR]

The article focuses on treatment-resistant depression (TRD) in a patient, Ms. B, with a history of major depressive disorder (MDD) and migraines. Topics include Ms. B's extensive medication history, the definition of TRD, and the consideration of monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) as potential treatment options.

Monoamine oxidase inhibitors (MAOIs) prevent the breakdown of tyramine in the body, and can cause a sudden increase in blood pressure with significant tyramine build up. This phenomenon, when it occurs, is known as tyramine pressor response. It is unknown if tyrosine administered in parenteral nutrition (PN) leads to tyramine build-up with concomitant use of MAOIs. It is also unknown if PN patients who are taking MAOI are at risk for the tyramine pressor response. This is a theoretical possibility as tyrosine endogenously undergoes decarboxylation to produce tyramine. We describe our experience with a 67-year-old woman with severe depression who was on the MAOI, transdermal selegiline. Her clinical course was complicated by an inability to take adequate per oral (PO) intake and she met criteria for unspecified severe protein-calorie-malnutrition in the context of social or environmental circumstances. Therefore, she required PN initiation. PlenamineTM (B. Braun, Bethlehem, PA, USA) was used as the amino acid source in the PN, which contains 39 mg of tyrosine per 100 ml of solution. The patient was monitored closely for any signs of hypertensive crisis while on PN and selegiline. She safely tolerated the combined therapy without any side effects. This is the first documented report of co-administration of PN containing tyrosine along with a MAOI. Our findings suggest that the dose of selegiline used in this patient can be co-administered safely in the setting of PN. However, further study is needed to verify our findings beyond this one patient. In conclusion, we recommend initiating PN and increasing it to goal in patients taking MAOIs, gradually, while monitoring for hypertensive crisis given the theoretical possibility of the tyramine pressor response. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases such as Alzheimer’s disease (AD) are multifactorial with several different pathologic mechanisms. Therefore, it is assumed that multitargeted-directed ligands (MTDLs) which interact with different biological targets relevant to the diseases, might offer an improved therapeutic alternative than using the traditional “one-target, one-molecule” approach. Herein, we describe new benzothiazole-based derivatives as a privileged scaffold for histamine H3 receptor ligands (H3R). The most affine compound, the 3-(azepan-1-yl)propyloxy-linked benzothiazole derivative 4b, displayed a Ki value of 0.012 μM. The multitargeting potential of these H3R ligands towards AChE, BuChE and MAO-B enzymes was evaluated to yield compound 3s (pyrrolidin-1-yl-(6-((5-(pyrrolidin-1-yl)pentyl)oxy)benzo[d]thiazol-2-yl)methanone) as the most promising MTDL with a Ki value of 0.036 μM at H3R and IC50 values of 6.7 µM, 2.35 µM, and 1.6 µM towards AChE, BuChE, and MAO-B, respectively. These findings suggest that compound 3s can be a lead structure for developing new multi-targeting anti-AD agents.

Enzymatic metabolism is the key determinant of the overall bioavailability, brain penetration, and efficacy of levodopa in the treatment of Parkinsons disease (PD). Enzyme inhibitors in the form of peripheral dopa‐decarboxylase inhibitors and monoamine oxidase type‐B inhibitors have been successfully employed to maximize the utility of levodopa in both early‐ and late‐stage PD. However, another major pathway of the peripheral metabolism of levodopa through catechol‐O‐methyltransferase (COMT) remains unchecked by those measures. Consequently, this becomes a major factor in determining the extent of delivery to the brain. The introduction of tolcapone as a potent and effective peripheral and central COMT inhibitor was frustrated by the emergence of hepatic toxicity. Only with the subsequent introduction of entacapone as an effective inhibitor of peripheral COMT activity has it become possible to fully control the peripheral metabolism of levodopa and to optimize its delivery to the brain. At a single‐dose level of 200 mg, the efficacy of entacapone in reducing OFF time and increasing ON time has led to its widespread use for the treatment of "wearing off". To maximize the efficacy of entacapone and to time‐lock its pharmacokinetic profile to that of levodopa, a triple combination of levodopa, carbidopa, and entacapone in the form of Stalevo® that allowed for flexibility in levodopa dosing was introduced early in the 21st century. This pioneering development has been successfully used worldwide for the past 20 years. This review considers the role of all three classes of enzyme inhibitors in PD medicine. [ABSTRACT FROM AUTHOR]

This article discusses the potential use of monoamine oxidase inhibitors (MAOIs) as a dual-action therapy for patients with prostate cancer and comorbid depression. Prostate cancer is a leading cause of cancer-related death among men in the United States, and comorbid depression is associated with worse survival outcomes. The article explores the antiproliferative effects of MAOIs on prostate cancer cells and their potential to reduce resistance to treatment. It also discusses the relationship between depression, castration-resistant prostate cancer (CRPC), and the role of the hypothalamic-pituitary-adrenal (HPA) axis. However, further research is needed to fully understand the potential benefits and mechanisms of MAOIs in this context. [Extracted from the article]

The small molecule, isatin, is a well‐known reversible inhibitor of the monoamine oxidase (MAO) enzymes with IC50 values of 12.3 and 4.86 μM for MAO‐A and MAO‐B, respectively. While the interaction of isatin with MAO‐B has been characterized, only a few studies have explored structure–activity relationships (SARs) of MAO inhibition by isatin analogues. The current study therefore evaluated a series of 14 isatin analogues as in vitro inhibitors of human MAO‐A and MAO‐B. The results indicated good potency MAO inhibition for some isatin analogues with five compounds exhibiting IC50 < 1 μM. 4‐Chloroisatin (1b) and 5‐bromoisatin (1f) were the most potent inhibitors with IC50 values of 0.812 and 0.125 μM for MAO‐A and MAO‐B, respectively. These compounds were also found to be competitive inhibitors of MAO‐A and MAO‐B with Ki values of 0.311 and 0.033 μM, respectively. Among the SARs, it was interesting to note that C5‐substitution was particularly beneficial for MAO‐B inhibition. MAO inhibitors are established drugs for the treatment of neuropsychiatric and neurodegenerative disorders, while potential new roles in prostate cancer and cardiovascular disease are being investigated. [ABSTRACT FROM AUTHOR]

Depression, as a common mental illness that is often accompanied by suicidal and homicidal behaviors, is one of the most important diseases in the medical field that requires urgent attention. The pathogenesis of depression is complex, and the current therapeutic drugs such as tricyclic antidepressants (TCAs), monoamine oxidase inhibitors, and secondary serotonin reuptake inhibitors have certain shortcomings. The inflammatory factor hypothesis, one of the pathogenesis of depression, suggests that inflammatory response is a key factor leading to the occurrence and development of depression, and that overactivation of inflammatory factors such as NLRP3, Toll-like receptor 4, and IDO leads to immune-system dysfunction and depression. The other pathogenic hypothesis, the gut flora hypothesis, has also been the focus of recent research. The gut flora may work together with inflammatory factors to cause depression. The approach to treating depression has been by altering the gut flora through drugs or probiotics. However, effective and clear treatment methods are lacking. In this study, by exploring the involvement of intestinal flora and inflammatory factors in the pathogenesis of depression, we found that improving the intestinal flora can affect inflammatory factors and, therefore, provide research ideas for the development of novel drugs to treat depression. [ABSTRACT FROM AUTHOR]

Dopamine was initially considered as a mere intermediate in the noradrenaline synthesis but was then found to be a neurotransmitter. Its depletion resulted in characteristic symptoms in experimental studies and could be antagonized by DOPA (3,4-dihydroxyphenylalanin), suggesting a similarity to the human disorder Parkinson´s disease (PD) and a therapeutic potential which was successfully exploited from the 1970s on. This was due to the pioneering work of Arvid Carlsson and clinicians around the world who first worked on the breakthrough of L-DOPA therapy and then on its amendment and modification and on alternative therapies for PD patients. All these developments led to the establishment of PD therapy as we know it today. It is characterized by the availability of many different compounds which are mostly employed in combination and by different methods: orally, intravenously, transdermally, subcutaneously, or duodenally. Here, we present without claim of completeness some personal reflections about causal drug developments for PD patients and reflect on some personal interactions with leading clinicians and basic researchers who cooperated with us. Such interactions are crucial for the creation, sometimes serendipitously, of fresh ideas and to further develop existing concepts to make therapeutical progress. [ABSTRACT FROM AUTHOR]

Background: Betahistine was registered in Europe in the 1970s and approved in more than 80 countries as a first-line treatment for Menière's disease. It has been administered to more than 150 million patients. However, according toa Cochrane systematic review of betahistine and recent meta-analyses, there is insufficient evidence to say whether betahistine has any effect in the currently approved dosages of up to 48 mg/d. A combination with the monoamine oxidase B (MAO-B) inhibitor, selegiline, may increase the bioavailability of betahistine to levels similar to the well-established combination of L-DOPA with carbidopa or benserazide in the treatment of Parkinson's disease. We investigated the effect of selegiline on betahistine pharmacokinetics and the safety of the combination in humans. Methods: In an investigator-initiated prospective, non-randomized, single-sequence, two-period titration, open label single-center phase 1 study, 15 healthy volunteers received three single oral dosages of betahistine (24, 48, and 96 mg in this sequence with at least 2 days' washout period) without and with selegiline (5 mg/d with a loading period of 7 days). Betahistine serum concentrations were measured over a period of 240 min at eight time points (area under the curve, AUC0-240 min). This trial is registered with EudraCT (2019-002610-39) and ClinicalTrials.gov. Findings: In all three single betahistine dosages, selegiline increased the betahistine bioavailability about 80- to 100-fold. For instance, the mean (±SD) of the area under curve for betahistine 48 mg alone was 0.64 (+/-0.47) h*ng/mL and for betahistine plus selegiline 53.28 (+/-37.49) h*ng/mL. The half-life time of around 30 min was largely unaffected, except for the 24 mg betahistine dosage. In total, 14 mild adverse events were documented. Interpretation: This phase 1 trial shows that the MAO-B inhibitor selegiline increases betahistine bioavailability by a factor of about 80 to 100. No safety concerns were detected. Whether the increased bioavailability has an impact on the preventive treatment of Menière's disease, acute vestibular syndrome, or post-BPPV residual dizziness has to be evaluated in placebo-controlled trials. Clinical trial registration: https://clinicaltrials.gov/study/NCT05938517?intr= betahistine%20and%20selegiline&rank=l, identifier: NCT05938517. [ABSTRACT FROM AUTHOR]

Introduction: Among treatment-resistant depression (TRD), we identified anergic-anhedonic clinical presentations (TRAD) as putatively responsive to pro-dopaminergic strategies. Based on the literature, non-selective monoamine oxidase inhibitors (MAOI) and dopamine D2 receptor agonists (D2RAG) were sequentially introduced, frequently under the coverage of a mood stabilizer. This two-step therapeutic strategy will be referred to as the Dopaminergic Antidepressant Therapy Algorithm (DATA). We describe the short and long-term outcomes of TRAD managed according to DATA guidelines. Method: Out of 52 outpatients with TRAD treated with DATA in a single expert center, 48 were included in the analysis [severity -- QIDS (Quick Inventory of Depressive Symptomatology) = 16 ± 3; episode duration = 4.1 ± 2.7 years; Thase and Rush resistance stage = 2.9 ± 0.6; functioning -- GAF (Global Assessment of Functioning) = 41 ± 8]. These were followed-up for a median (1st - 3rd quartile) of 4 (1-9) months before being prescribed the first dopaminergic treatment and remitters were followed up 21 (11-33) months after remission. Results: At the end of DATA step 1, 25 patients were in remission (QIDS <6; 52% [38-66%]). After DATA step 2, 37 patients were in remission (77% [65--89%]) to whom 5 patients with a QIDS score = 6 could be added (88% [78-97%]). Many of these patients felt subjectively remitted (GAF = 74 ± 10). There was a significant benefit to combining MAOI with D2RAG which was maintained for at least 18 months in 30 patients (79% [62-95%]). Conclusion: These results support TRAD sensitivity to pro-dopaminergic interventions. However, some clinical heterogeneities remain in our sample and suggest some improvement in the description of dopamine-sensitive form(s). [ABSTRACT FROM AUTHOR]

The catalytic activity of monoamine oxidase A (MAO-A) has been linked to tumorigenesis due to the production of reactive oxygen species (ROS) and the resulting oxidative stress. MAO-A inhibition revealed a beneficial role in prostate and lung cancer treatment. This study is aimed at evaluating the effect of different monoamine oxidase A inhibitors (MAO-AIs) on the proliferation and progression of breast cancer cell lines. The cell viability assay was used to evaluate the antiproliferative and combined effects of MAO-AIs. Cell migration was evaluated using wound healing, invasion, and colony formation assays. The underlying mechanism of cell death was studied using flow cytometry. The real-time polymerase chain reaction was used to determine the relative gene expression. Finally, MAO-A activity in breast cancer cells was evaluated using an MAO-A activity assay. According to the results, the examined MAO-AIs significantly inhibited the proliferation of breast cancer cells in a dose-dependent manner. In breast cancer cells, the combination of anticancer drugs (doxorubicin or raloxifene) with MAO-AIs resulted in a synergistic effect. MAO-AIs significantly reduced wound closure and invasion ability in breast cancer cells. Also, MAO-AIs reduced the colony count and size of breast cancer cells. MAO-AIs resulted in significant proapoptotic activity in breast cancer cells. Finally, the MAO-AIs suppressed MAO-A, Bcl-2, and VEGF gene expressions in breast cancer cells relative to untreated cells. This study provides solid evidence supporting the anticancer effect of MAO-A inhibitors in breast cancer cells. [ABSTRACT FROM AUTHOR]

Monoamine oxidase (MAO) enzymes over see the concentration of neurotransmitters and intracellular amines in the brain and peripheral tissues by catalysing their oxidative deamination and represents a crucial target in drug designing for the management of neurological and psychiatric disorders. Present study is an effort to present an economical fast high throughput screening easy method to identify indole analogues as potent MAO inhibitors, using different computational techniques. CoMSIA field-based 3D-QSAR models have been developed by applying the partial least squares regression algorithm that exhibit satisfactory predictive and descriptive capability with statistical parameters R² (0.9557) and Q² (0.8529). Generated model (s) helped in explaining the key descriptors firmly related with MAO inhibitory activity and are used to generate library of 1853 indole derivatives. Library is evaluated and has resulted in the identification of 30 indole derivatives with high docking scores (−9.978 to −7.136) in comparison to the antidepressant standard drug Isocarboxazid (−7.125). Further, these compounds have been scrutinized through drug-likeliness profiles and Desmond's molecular dynamics simulations studies for 100 ns. Further in vitro and in vivo studies on these molecules might provide us with new drug candidate for the treatment of depression with high therapeutic index. [ABSTRACT FROM AUTHOR]

Depression is characterized by a feeling of sadness and a lack of pleasure, with impaired daily functioning and poor quality of life. The neurobiology and the pathogenesis of depression are not fully understood yet. Several hypotheses have been discussed including, monoamine theory, neurotransmission, oxidation, inflammation, glutamatergic transmission, neurotrophic factors, and others. Reviewing three decades of randomized controlled trials of antidepressants revealed that the antidepressants response rate is about 54% compared to a placebo response rate of 37%. Treatment-resistant depression (TRD) could be defined as an inadequate response to two different of antidepressants. In TRD, a combination strategy of using two FDA-approved antidepressants is used, which may predispose patients to adverse effects. Therefore, there is a compelling need to explore the potential "out of the box" adjuvants to antidepressants to provide higher and consistent response rates with high tolerability. These adjuvants could be medications available for other indications, food supplements, or even experimental drugs. This review will highlight potentially beneficial adjuvants to antidepressants such as nitric oxide modulators, NMDA antagonists, anti-inflammatory, antioxidants, mitochondrial modulators, insulin sensitizers, opioids, probiotics, and GABA agonists. [ABSTRACT FROM AUTHOR]

Mistletoe infests common plant trees of great medicinal values such as Moringa and Almond. According to folklore, mistletoe leaves have been found to have application as food and medicine in the alleviation of various degenerative diseases. Host–parasite relationship may possibly influence the phytochemical and biological activities of mistletoe leaves. Hence, we examined the polyphenol contents, antioxidant properties, α-amylase, α-glucosidase, acetylcholinesterase (AChE) and monoamine oxidase (MAO) inhibitory activities of African mistletoe leaves obtained from Moringa and Almond host plants in fruit fly in vitro. The phenolic constituents of the leaves were evaluated using HPLC system. The antioxidant activities were determined through the ABTS, DPPH and OH free radicals scavenging properties, ferric (Fe3+) and malondialdehyde (MDA) reducing abilities and Fe2+ chelation. The inhibitory effects of the leaves aqueous extracts on α-amylase, α-glucosidase, AChE and MAO activities were also assessed. The HPLC characterization of the leaves revealed that host plants caused marked variation in their phenolic composition, however, Almond mistletoe leaves had significantly (p<0.05) greater amounts of phenolic constituents. Both Moringa and Almond mistletoe leaves reduced Fe3+ and MDA levels, scavenged free radicals, chelated Fe2+ and inhibited α-amylase, α-glucosidase, AChE and MAO activities with the Almond mistletoe leaves having significantly (p<0.05) higher antioxidant properties and enzyme inhibitory activities. This present study indicated that host plants could positively modulate the phenolic profile of mistletoe leaves and this probably brought about the vivid noticeable changes in their antioxidant abilities, cholinergic, monoaminergic and carbohydrate hydrolyzing enzymes inhibitory activities. [ABSTRACT FROM AUTHOR]

Monoamine oxidase (MAO) is a membrane‐bound mitochondrial enzyme that maintains the steady state of neurotransmitters and other biogenic amines in biological systems through catalytic oxidation and deamination. MAO dysfunction is closely related to human neurological and psychiatric diseases and cancers. However, little is known about the relationship between MAO and viral infections in humans. This review summarises current research on how viral infections participate in the occurrence and development of human diseases through MAO. The viruses discussed in this review include hepatitis C virus, dengue virus, severe acute respiratory syndrome coronavirus 2, human immunodeficiency virus, Japanese encephalitis virus, Epstein‐Barr virus, and human papillomavirus. This review also describes the effects of MAO inhibitors such as phenelzine, clorgyline, selegiline, M‐30, and isatin on viral infectious diseases. This information will not only help us to better understand the role of MAO in the pathogenesis of viruses but will also provide new insights into the treatment and diagnosis of these viral diseases. [ABSTRACT FROM AUTHOR]

Introduction: Drug and Food Interactions (DFI) arise when particular nutrients in food interact with drugs when consumed concurrently, consequently resulting in alterations in the pharmacokinetics, pharmacodynamics, and therapeutic effectiveness of the drug. This study aimed to evaluate the information and understanding of healthcare providers (HCPs) about common DFI.Methods: A cross-sectional study was achieved by a self-administered online-based questionnaire to gather data from HCPs in eastern region of Saudi Arabia between Sep. to Oct. 2022. The questionnaire integrated questions related to HCP demographic features and knowledge of DFI. The DFI section included questions that assessed the general knowledge of DFI and knowledge of specific food and drug interactions.Results: A total of 401 participants completed the study questionnaire; 41.4% were undergraduate students, 37.2% were pharmacists, 10.5% were nurses, and 9.5% were doctors. Unfortunately, HCPs are unable to recognize several food types that may interact with medications, which may lead to undesirable consequences associated with an enormous financial burden. For instance, only 27.9% of the HCPs stated that patients on monoamine oxidase inhibitors should avoid cheese. In addition, only approximately 11% of HCPs knew that patients on levothyroxine should avoid cauliflower, those taking digoxin should avoid wheat bran, those taking lithium should avoid cola, and those on heparin should avoid calcium-rich food. Overall knowledge was significantly higher among pharmacists and others HCPs with more than 5 years of experience.Discussion and Conclusion: This study demonstrated a low level of knowledge regarding specific food and drug interactions among healthcare providers in the eastern region of Saudi Arabia. [ABSTRACT FROM AUTHOR]

Targeting tumor-associated macrophages (TAMs) is a promising strategy to modify the immunosuppressive tumor microenvironment and improve cancer immunotherapy. Monoamine oxidase A (MAO-A) is an enzyme best known for its function in the brain; small molecule MAO inhibitors (MAOIs) are clinically used for treating neurological disorders. Here we observe MAO-A induction in mouse and human TAMs. MAO-A-deficient mice exhibit decreased TAM immunosuppressive functions corresponding with enhanced antitumor immunity. MAOI treatment induces TAM reprogramming and suppresses tumor growth in preclinical mouse syngeneic and human xenograft tumor models. Combining MAOI and anti-PD-1 treatments results in synergistic tumor suppression. Clinical data correlation studies associate high intratumoral MAOA expression with poor patient survival in a broad range of cancers. We further demonstrate that MAO-A promotes TAM immunosuppressive polarization via upregulating oxidative stress. Together, these data identify MAO-A as a critical regulator of TAMs and support repurposing MAOIs for TAM reprogramming to improve cancer immunotherapy.

IntroductionAmong treatment-resistant depression (TRD), we identified anergic-anhedonic clinical presentations (TRAD) as putatively responsive to pro-dopaminergic strategies. Based on the literature, non-selective monoamine oxidase inhibitors (MAOI) and dopamine D2 receptor agonists (D2RAG) were sequentially introduced, frequently under the coverage of a mood stabilizer. This two-step therapeutic strategy will be referred to as the Dopaminergic Antidepressant Therapy Algorithm (DATA). We describe the short and long-term outcomes of TRAD managed according to DATA guidelines.MethodOut of 52 outpatients with TRAD treated with DATA in a single expert center, 48 were included in the analysis [severity – QIDS (Quick Inventory of Depressive Symptomatology) = 16 ± 3; episode duration = 4.1 ± 2.7 years; Thase and Rush resistance stage = 2.9 ± 0.6; functioning – GAF (Global Assessment of Functioning) = 41 ± 8]. These were followed-up for a median (1st – 3rd quartile) of 4 (1–9) months before being prescribed the first dopaminergic treatment and remitters were followed up 21 (11–33) months after remission.ResultsAt the end of DATA step 1, 25 patients were in remission (QIDS

Monoamine oxidase (MAO, EC 1.4.3.4) is responsible for the oxidative breakdown of both endogenous and exogenous amines and exists in MAO-A and MAO-B isomers. Eighteen indole-based phenylallylidene derivatives were synthesized via nucleophilic addition reactions comprising three sub-series, IHC, IHMC, and IHNC, and were developed and examined for their ability to inhibit MAO. Among them, compound IHC3 showed a strong MAO-B inhibitory effect with an IC50 (half-maximal inhibitory concentration) value of 1.672 μM, followed by IHC2 (IC50 = 16.934 μM). Additionally, IHC3 showed the highest selectivity index (SI) value of >23.92. The effectiveness of IHC3 was lower than the reference pargyline (0.14 μM); however, the SI value was higher than pargyline (17.16). Structurally, the IHC (-H in the B-ring) sub-series exhibited relatively stronger MAO-B inhibition than the others. In the IHC series, IHC3 (-F in the A-ring) exhibited stronger MAO-B suppression than the other substituted derivatives in the order -F > -Br > -Cl > -OCH3, -CH3, and -H at the 2-position in the A-ring. In the reversibility and enzyme kinetics experiments, IHC3 was a reversible inhibitor with a Ki value of 0.51 ± 0.15 μM for MAO-B. Further, it was observed that IHC3 greatly decreased the cell death caused by rotenone in SH-SY5Y neuroblastoma cells. A molecular docking study of the lead molecule was also performed to determine hypothetical interactions in the enzyme-binding cavity. These findings suggest that IHC3 is a strong, specific, and reversible MAO-B inhibitor that can be used to treat neurological diseases. [ABSTRACT FROM AUTHOR]

Aggregation of Tau protein into paired helical filaments causing neurofibrillary tangles (NFT) is a neuropathological feature in Alzheimer's disease (AD). This study aimed to develop and evaluate the effectiveness of a novel radioiodinated tracer, 4-[125I]iodo-3-(1H-pyrrolo[2,3-c]pyridine-1-yl)pyridine ([125I]INFT), for binding to Tau protein in postmortem human AD brain. Radiosynthesis of [125I]INFT was carried out using electrophilic destannylation by iodine-125 and purified chromatographically. Computational modeling of INFT binding on Tau fibril was compared with IPPI. In vitro, autoradiography studies were conducted with [125I]INFT for Tau in AD and cognitively normal (CN) brains. [125I]INFT was produced in >95% purity. Molecular modeling of INFT revealed comparable binding energies to IPPI at site-1 of the Tau fibril with an affinity of IC50 = 7.3 × 10−8 M. Binding of [125I]INFT correlated with the presence of Tau in the AD brain, confirmed by anti-Tau immunohistochemistry. The ratio of average grey matter (GM) [125I]INFT in AD versus CN was found to be 5.9, and AD GM/white matter (WM) = 2.5. Specifically bound [125I]INFT to Tau in AD brains was displaced by IPPI (>90%). Monoamine oxidase inhibitor deprenyl had no effect and clorgyline had little effect on [125I]INFT binding. [125I]INFT is a less lipophilic imaging agent for Tau in AD. [ABSTRACT FROM AUTHOR]

Introduction: Tremor is often perceived as severely disabling by patients with idiopathic Parkinson's disease (iPD) and yet ranges among the most difficult symptoms to treat. To date, no comprehensive analysis of non‐lesional therapies to manage tremor in iPD exists to base recommendations upon. We therefore present a systematic literature review and meta‐analysis assessing the efficacy/effectiveness and safety of non‐lesional treatments for tremor in iPD. Methods: Three electronic databases were searched using a combination of title/abstract keywords complemented by hand‐searching of reference lists. A random‐effects meta‐analysis of standardized mean change scores was conducted where appropriate. Results: Some 114 studies met inclusion criteria involving 8045 patients. The meta‐analysis revealed an overall reduction of standardized mean change scores by (−0.93 [CI: −1.42; −0.43], p < 0.001) by 14 different dopaminergic and non‐dopaminergic classes of agents. No significant differences were identified between direct comparisons. Subgroup analysis comparing dopamine receptor agonists resulted in superior effects of pramipexole and rotigotine compared with ropinirole. There was little cumulative evidence to support the use of individual non‐pharmacological interventions for tremor, except for electrical stimulation. Conclusions: The results of this meta‐analysis suggest a large but nonspecific effect of established pharmacological therapies on tremor in iPD. Based on high‐quality studies, there is sufficient evidence to support that levodopa, dopamine receptor agonists, and monoamine oxidase inhibitors provide tremor relief in most patients, while evidence supporting other treatments is less well established. Sufficient evidence to draw conclusions on effects of non‐lesional treatments in cases with refractory tremor is lacking. [ABSTRACT FROM AUTHOR]

The catecholaldehyde hypothesis for the pathogenesis of Parkinson's disease centers on accumulation of 3,4-dihydroxyphenylacetaldehyde (DOPAL) in dopaminergic neurons. To test the hypothesis, it is necessary to reduce DOPAL and assess if this improves locomotor abnormalities. Systemic administration of rotenone to rats reproduces the motor and central neurochemical abnormalities characterizing Parkinson's disease. In this study, we used the monoamine oxidase inhibitor (MAOI) deprenyl to decrease DOPAL production, with or without the antioxidant N-acetylcysteine (NAC). Adult rats received subcutaneous vehicle, rotenone (2 mg/kg/day via a minipump), or rotenone with deprenyl (5 mg/kg/day i.p.) with or without oral NAC (1 mg/kg/day) for 28 days. Motor function tests included measures of open field activity and rearing. Striatal tissue was assayed for contents of dopamine, DOPAL, and other catechols. Compared to vehicle, rotenone reduced locomotor activity (distance, velocity and rearing); increased tissue DOPAL; and decreased dopamine concentrations and inhibited vesicular sequestration of cytoplasmic dopamine and enzymatic breakdown of cytoplasmic DOPAL by aldehyde dehydrogenase (ALDH), as indicated by DA/DOPAL and DOPAC/DOPAL ratios. The addition of deprenyl to rotenone improved all the locomotor indices, increased dopamine and decreased DOPAL contents, and corrected the rotenone-induced vesicular uptake and ALDH abnormalities. The beneficial effects were augmented when NAC was added to deprenyl. Rotenone evokes locomotor and striatal neurochemical abnormalities found in Parkinson's disease, including DOPAL buildup. Administration of an MAOI attenuates these abnormalities, and NAC augments the beneficial effects. The results indicate a pathogenic role of DOPAL in the rotenone model and suggest that treatment with MAOI+NAC might be beneficial for Parkinson's disease treatment. [ABSTRACT FROM AUTHOR]

Eight derivatives of benzyloxy‐derived halogenated chalcones (BB1‐BB8) were synthesized and tested for their ability to inhibit monoamine oxidases (MAOs). MAO‐A was less efficiently inhibited by all compounds than MAO‐B. Additionally, the majority of the compounds displayed significant MAO‐B inhibitory activities at 1 μM with residual activities of less than 50%. With an IC50 value of 0.062 μM, compound BB4 was the most effective in inhibiting MAO‐B, followed by compound BB2 (IC50 = 0.093 μM). The lead molecules showed good activity than the reference MAO‐B inhibitors (Lazabemide IC50 = 0.11 μM and Pargyline Pargyline IC50 = 0.14). The high selectivity index (SI) values for MAO‐B were observed in compounds BB2 and BB4 (430.108 and 645.161, respectively). Kinetics and reversibility experiments revealed that BB2 and BB4 were reversible competitive MAO‐B inhibitors with Ki values of 0.030 ± 0.014 and 0.011 ± 0.005 μM, respectively. Swiss target prediction confirmed the high probability in the targets of MAO‐B for both compounds. Hypothetical binding mode revealed that the BB2 or BB4 is similarly oriented to the binding cavity of MAO‐B. Based on the modelling results, BB4 showed a stable confirmation during the dynamic simulation. From these results, it was concluded that BB2 and BB4 were potent selective reversible MAO‐B inhibitors and they can be considered drug candidates for treating related neurodegenerative diseases such as Parkinson's disease. [ABSTRACT FROM AUTHOR]

Experienced clinicians and academics from the International MAOI Expert Group comment on questions of interest concerning monoamine oxidase inhibitor (MAOI) pharmacotherapy for depression. These comments in this Part Two of the Expert Roundtable Discussion emphasize good pharmacological practice, starting with a low dose and progressing slowly and only changing one element at a time. Issues related to augmentation and drug combinations are also mentioned, including comments about the safety of ketamine. The special ability of MAOIs to improve dopamine function is highlighted, especially in relation to melancholic and psychotic depression. [Psychiatr Ann. 2023;53(8):364–369.] [ABSTRACT FROM AUTHOR]

This article describes and clarifies the two significant interactions encountered with monoamine oxidase inhibitors (MAOIs): serotonin toxicity and the tyramine pressor response. This is important because of the amount of inaccurate and misleading information (including in United States Food and Drug Administration-approved product information sheets and online resource and database systems) promulgated over the last few decades, which continues to cause confusion and undue concern. There are few if any clinically relevant CYP450 interactions with psychotropic drugs and no significant pharmacokinetic interactions. Serotonin toxicity is now well understood and only occurs in a problematic form when MAOIs are given in conjunction with serotonin reuptake inhibitors. Major prolonged elevations of blood pressure from tyramine are now less of a concern because of greatly reduced tyramine levels in foods. Therefore, MAOIs are safer and simpler to use in clinical practice than has usually been stated and should be considered earlier in the treatment algorithm for both atypical and melancholic depression. [Psychiatr Ann. 2023;53(8):353–358.] [ABSTRACT FROM AUTHOR]

Experienced clinicians and academics from the International MAOI (monoamine oxidase inhibitor) Expert Group comment on questions of interest concerning MAOI pharmacotherapy for depression, especially as they pertain to the illustrative case summaries presented in this part one of the Expert Roundtable Discussion. These comments focus on practical therapeutics and aspects of difficult cases that guidelines simply do not, and cannot, address, such as the important fact that psychotic depression may respond rapidly to MAOIs. The ethical and medico-legal issues relating to cost and ongoing availability are also discussed. [Psychiatr Ann. 2023;53(8):359–363.] [ABSTRACT FROM AUTHOR]

Treatment-resistant depression (TRD) remains a significant challenge for clinicians and patients alike, necessitating exploration and understanding of potent but underutilized antidepressant options, such as classic monoamine oxidase inhibitors (MAOIs). This article presents a condensed overview of the fundamental principles outlined in the international consensus guideline on using MAOIs in TRD (the Prescriber's Guide), explicitly focusing on phenelzine and tranylcypromine. These drugs are powerful treatment options for severe depression, including atypical and melancholic subtypes, that have insufficiently responded to first- and second-line treatments. MAOIs are generally indicated before electroconvulsive therapy due to their favorable side-effect profile. However, several contraindications and drug interactions must be considered. This article aims to provide clinicians with a practical, accessible resource for implementing classic MAOIs in the management of TRD. [Psychiatr Ann. 2023;53(8):347–352.] [ABSTRACT FROM AUTHOR]

Background. Monoamine oxidase (MAO) is involved in several biological processes associated with well-being and mental health, and alterations in its function might directly impact various mental disorders. Some mental disorders concomitantly occur in individuals with clinical characteristics, such as substance abuse and diabetes. Objective. To analyze the functional MAOA uVNTR polymorphism genotype frequency in an older adult population with diabetes mellitus/arterial hypertension and associate this frequency with clinical characteristics impacting daily life. Methodology. Older adults diagnosed with diabetes mellitus, systemic arterial hypertension, or both (DM/SAH) were selected and had their MAOA gene genotyped for uVNTR polymorphism. The revised Beck Depression Inventory (BDI) and a questionnaire were also applied to determine their mental health and clinical characteristics. Results. The allelic variants detected among the participants were the 2R, 3R, 4R, and 3R/4R heterozygous genotypes. Genotypes solely containing the 3R allele had patients who marked yes for smoking and alcoholism, and only those with the 3R genotypes (female 3R/3R homozygote or male 3R ∗ hemizygote) were significant. Although not statistically significant, only 3R and 3R/4R genotypes presented cases of severe depression per the revised BDI interpretations. Conclusion. The MAOA uVNTR polymorphism's low-activity 3R allele presence in an older adult population diagnosed with DM/SAH may represent a risk for developing substance use (alcohol and smoking) dependence. [ABSTRACT FROM AUTHOR]

• MAOIs are not available for prescription anymore in most regions. • Oral/transdermal selegiline was appraised for different psychiatric disorders. • Selegiline is effective in depression, especially with atypical features. • Additional studies are needed to appraise selegiline for non-depressive disorders. Selegiline is an irreversible, selective type-B monoamine oxidase inhibitor (MAOI) approved for Parkison's disease—oral and major depressive disorder—transdermal formulation) resulting in non-selective MAOI activity at oral doses≥20 mg/day. The present systematic review and meta-analysis appraises the evidence of different formulations/dosages of selegiline across different psychiatric conditions. We inquired PubMed/MEDLINE/Cochrane-Central/WHO-ICTRP/Clarivate-WebOfScience and the Chinese-Electronic-Journal Database from inception to 10/26/2022 for selegiline trials involving psychiatric patients. Random-effects meta-analyses assessed heterogeneity, publication/risk biases, and confidence in the evidence, followed by sensitivity, subgroup, and meta-regression analyses. Co-primary outcomes were: changes in symptom score (standardized mean difference=SMD) and author-defined response (risk ratios=RRs). RRs of adverse events and all-cause discontinuation were secondary and acceptability outcomes, respectively. Systematic-review included 42 studies; meta-analysis, 23. Selegiline outperformed placebo in depressive symptom reduction (SMD=-0.96, 95%C.I.=-1.78, -0.14, k = 10, n = 1,308), depression (RR=1.61, 95%C.I.=1.20, 2.15, k = 9, n = 1,238) and atypical-depression response (RR=2.23, 95%C.I.=1.35, 3.68, k = 3, n = 136). Selegiline failed to outperform the placebo in negative (k = 4) or positive symptoms of schizophrenia (k = 4), attention-deficit-hyperactivity disorder (ADHD) symptoms reduction (k = 2), and smoking abstinence rate (k = 4). Selegiline did not differ from methylphenidate and ADHD scores (k = 2). No significant difference emerged in acceptability, incident diarrhea, headache, dizziness, and nausea RRs, in contrast to xerostomia (RR=1.58, 95%C.I. =1.03, 2.43, k = 6, n = 1,134), insomnia (RR=1.61, 95%C.I.=1.19, 2.17, k = 10, n = 1,768), and application-site reaction for transdermal formulation (RR=1.81, 95%C.I.=1.40, 2.33, k = 6, n = 1,662). Confidence in findings was low/very-low for most outcomes; moderate for depressive symptoms reduction (transdermal). Selegiline proved effective, safe, and well-tolerated for depressive disorders, yet further evidence is warranted about specific psychiatric disorders. [ABSTRACT FROM AUTHOR]

The antioxidant constituents of ancestral products with ethnobotanical backgrounds are candidates for the study of filtering infusions to aid in pharmacotherapies focused on the treatment of depression and anxiety. Monoamine oxidase A (MAO-A) is an enzyme that regulates the metabolic breakdown of serotonin and noradrenaline in the nervous system. The goal of this study was to evaluate in vitro and in silico the effect of antioxidant constituents of filtering infusions from yerbaniz (Tagetes lucida (Sweet) Voss) and oak (Quercus sideroxyla Bonpl. and Quercus eduardii Trel.) as monoamine oxidase inhibitors. Materials were dried, ground, and mixed according to a simplex–centroid mixture design for obtaining infusions. Differential analysis of the phenolic constituent's ratio in the different infusions indicates that among the main compounds contributing to MAO-A inhibition are the gallic, chlorogenic, quinic, and shikimic acids, quercetin glucuronide and some glycosylated derivatives of ellagic acid and ellagic acid methyl ether. Infusions of Q. sideroxyla Bonpl. leaves, because of their content (99.45 ± 5.17 µg/mg) and synergy between these constituents for MAO-A inhibition (52.82 ± 3.20%), have the potential to treat depression and anxiety. Therefore, future studies with pharmacological approaches are needed to validate them as therapeutic agents with applications in mental health care. [ABSTRACT FROM AUTHOR]

Novel compounds with antidepressant activity via monoamine oxidase inhibition are being sought. Among these, derivatives of 3-n-butylphthalide, a neuroprotective lactone from Apiaceae plants, may be prominent candidates. This study aimed to obtain the oxidation products of 3-n-butylphthalide and screen them regarding their activity against the monoamine oxidase A (MAO-A) isoform. Such activity of these compounds has not been previously tested. To obtain the metabolites, we used fungi as biocatalysts because of their high oxidative capacity. Overall, 37 strains were used, among which Penicillium and Botrytis spp. were the most efficient, leading to the obtaining of three main products: 3-n-butyl-10-hydroxyphthalide, 3-n-butylphthalide-11-oic acid, and 3-n-butyl-11-hydroxyphthalide, with a total yield of 0.38–0.82 g per g of the substrate, depending on the biocatalyst used. The precursor–3-n-butylphthalide and abovementioned metabolites inhibited the MAO-A enzyme; the most active was the carboxylic acid derivative of the lactone with inhibitory constant (Ki) < 0.001 µmol/L. The in silico prediction of the drug-likeness of the metabolites matches the assumptions of Lipinski, Ghose, Veber, Egan, and Muegge. All the compounds are within the optimal range for the lipophilicity value, which is connected to adequate permeability and solubility. [ABSTRACT FROM AUTHOR]

Monoamine oxidase inhibitors (MAOIs) are generally only initiated by specialists because of safety concerns, making GPs more wary of these medicines. This article discusses the important side‐effects and interactions of MAOIs and how these can be minimised, and explains why MAOI prescribing may be safer than we are led to believe. [ABSTRACT FROM AUTHOR]

The term 'depression' covers a variety of mental health problems characterised by a loss of interest and enjoyment, low mood and other emotional, cognitive, physical, and behavioural symptoms. Most people experiencing depression are treated in primary care. These treatments include various talking therapies and support to aid physical, psychological and social wellbeing. For people with moderate-to-severe depression, treatment with medication is recommended. This may be prescribed in addition to therapy and support. It is important that the person diagnosed with depression is monitored to assess how they respond to the antidepressants. A different type may need to be offered if response is poor or they have intolerable side effects. Antidepressants need to be prescribed for a given period, the length of which is dependent on whether this is the first or a further episode. [ABSTRACT FROM AUTHOR]

Synthetic cannabinoid receptor agonists (SCRAs) are one of the fastest growing classes of recreational drugs. Despite their growth in use, their vast chemical diversity and rapidly changing landscape of structures make understanding their effects challenging. In particular, the side effects for SCRA use are extremely diverse, but notably include severe outcomes such as cardiac arrest. These side effects appear at odds with the main putative mode of action, as full agonists of cannabinoid receptors. We have hypothesized that SCRAs may act as MAO inhibitors, owing to their structural similarity to known monoamine oxidase inhibitors (MAOI's) as well as matching clinical outcomes (hypertensive crisis) of 'monoaminergic toxicity' for users of MAOIs and some SCRA use. We have studied the potential for SCRA‐mediated inhibition of MAO‐A and MAO‐B via a range of SCRAs used commonly in the UK, as well as structural analogues to prove the atomistic determinants of inhibition. By combining in silico and experimental kinetic studies we demonstrate that SCRAs are MAO‐A‐specific inhibitors and their affinity can vary significantly between SCRAs, most notably affected by the nature of the SCRA 'head' group. Our data allow us to posit a putative mechanism of inhibition. Crucially our data demonstrate that SCRA activity is not limited to just cannabinoid receptor agonism and that alternative interactions might account for some of the diversity of the observed side effects and that these effects can be SCRA‐specific. [ABSTRACT FROM AUTHOR]

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare inherited neurometabolic disorder that can lead to severe physical and developmental impairment. This report includes 16 patients from the Middle East and is the largest series of patients with confirmed AADC deficiency from this region reported to date. The patients displayed a range of signs and symptoms at presentation and almost all failed to reach major motor milestones. Missed and delayed diagnoses were common leading to the late introduction of targeted treatments. Eight unique variants were identified in the DDC gene, including six missense and two intronic variants. A previously undescribed variant was identified: an intronic variant between exons 13 and 14 (c.1243-10A>G). The patients were mostly treated with currently recommended medications, including dopamine agonists, vitamin B6, and monoamine oxidase inhibitors. One patient responded well, but treatment outcomes were otherwise mostly limited to mild symptomatic improvements. Five patients had died by the time of data collection, confirming that the condition is associated with premature mortality. There is an urgent need for earlier diagnosis, particularly given the potential for gene therapy as a transformative treatment for AADC deficiency when provided at an early age. Conclusions: Delays in the diagnosis of AADC deficiency are common. There is an urgent need for earlier diagnosis, particularly given the potential for gene therapy as a transformative treatment for AADC deficiency when provided at an early age. What is Known: • Aromatic L-amino acid decarboxylase deficiency is a rare neurometabolic disorder that can lead to severe physical and developmental impairment. • Currently recommended medications provide mostly mild symptomatic improvements. What is New: • The clinical presentation of sixteen patients with confirmed AADC deficiency varied considerably and almost all failed to reach major motor milestones. • There is an urgent need for earlier diagnosis, given the potential for gene therapy as a transformative treatment for AADC deficiency when provided at an early age. [ABSTRACT FROM AUTHOR]

Objective: This study aims to investigate the anti-inflammatory mechanism of monoamine oxidase inhibitor (MAOI) in carrageenan (CARR) induced inflammation models to reprofile their use. We also aimed to explore the role of monoamine oxidase (MAO)-mediated H2O2–NF–κB–COX-2 pathway in acute inflammation. Methods: In vitro anti-inflammatory activity and hydrogen peroxide (H2O2) scavenging activity were performed according to the established procedure. Inflammation was induced using CARR in BALB/c mice at the foot paw and peritoneal cavity. Hourly measurement of paw swelling was performed. The level of nitric oxide (NO), myeloperoxidase (MPO), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2) and nuclear factor κB (NF-κB) was determined using enzyme-linked immunosorbent assay (ELISA). Peritoneal fluid was collected to investigate total count, differential count of leukocytes, and capillary permeability. Results: In vitro anti-inflammatory evaluations revealed the potential role of MAOI to inhibit heat-induced protein denaturation and human red cell membrane destabilization. H2O2 inhibition activity of MAOI also proved their powerful role as an H2O2 scavenger. Treatment with MAOI in CARR-induced mice significantly reduced paw edema, leukocyte extravasation, and total and differential leukocyte count. The result of ELISA showed MAOI effectively reduce the level of COX-2, PGE2 and NF-κB in inflamed tissue. Conclusions: In short, this study demonstrates that inhibition of H2O2 by MAOI alleviates CARR-induced paw edema possibly by inhibiting the H2O2-mediated NF-κB–COX-2 pathway. The present investigation identifies MAOI might reprofile for the treatment of acute inflammation also, the MAO enzyme may use as a novel therapeutic target to design and develop new class of anti-inflammatory agents. [ABSTRACT FROM AUTHOR]

Inhibitors of monoamine oxidase B (MAO-B) and catechol-O-methyltransferase (COMT) are major strategies to reduce levodopa degradation and thus to increase and prolong its effect in striatal dopaminergic neurotransmission in Parkinson's disease patients. While selegiline/rasagiline and tolcapone/entacapone have been available on the market for more than one decade, safinamide and opicapone have been approved in 2015 and 2016, respectively. Meanwhile, comprehensive data from several post-authorization studies have described the use and specific characteristics of the individual substances in clinical practice under real-life conditions. Here, we summarize current knowledge on both medication classes, with a focus on the added clinical value in Parkinson's disease. Furthermore, we outline practical considerations in the treatment of motor fluctuations and provide an outlook on ongoing studies with MAO-B and COMT inhibitors. [ABSTRACT FROM AUTHOR]

Alterations in myelin integrity are involved in many neurological disorders and demyelinating diseases, such as multiple sclerosis (MS). Although magnetic resonance imaging (MRI) is the gold standard method to diagnose and monitor MS patients, clinically available MRI protocols show limited specificity for myelin detection, notably in cerebral grey matter areas. Ultrashort echo time (UTE) MRI has shown great promise for direct imaging of lipids and myelin sheaths, and thus holds potential to improve lesion detection. In this study, we used a sequence combining magnetization transfer (MT) with UTE ("UTE-MT", TE ​= ​76 ​μs) and with short TE ("STE-MT", TE ​= ​3000 ​μs) to evaluate spatial and temporal changes in brain myelin content in the cuprizone mouse model for MS on a clinical 7 ​T scanner. During demyelination, UTE-MT ratio (UTE-MTR) and STE-MT ratio (STE-MTR) values were significantly decreased in most white matter and grey matter regions. However, only UTE-MTR detected cortical changes. After remyelination in subcortical and cortical areas, UTE-MTR values remained lower than baseline values, indicating that UTE-MT, but not STE-MT, imaging detected long-lasting changes following a demyelinating event. Next, we evaluated the potential correlations between imaging values and underlying histopathological markers. The strongest correlation was observed between UTE-MTR and percent coverage of myelin basic protein (MBP) immunostaining (r2 ​= ​0.71). A significant, although lower, correlation was observed between STE-MTR and MBP (r2 ​= ​0.48), and no correlation was found between UTE-MTR or STE-MTR and gliosis immunostaining. Interestingly, correlations varied across brain substructures. Altogether, our results demonstrate that UTE-MTR values significantly correlate with myelin content as measured by histopathology, not only in white matter, but also in subcortical and cortical grey matter regions in the cuprizone mouse model for MS. Readily implemented on a clinical 7 ​T system, this approach thus holds great potential for detecting demyelinating/remyelinating events in both white and grey matter areas in humans. When applied to patients with neurological disorders, including MS patient populations, UTE-MT methods may improve the non-invasive longitudinal monitoring of brain lesions, not only during disease progression but also in response to next generation remyelinating therapies.

Cognitive impairments are key features in multiple sclerosis (MS), a progressive disorder characterized by neuroinflammation-induced demyelination in the central nervous system. To understand the neural substrates that link demyelination to cognitive deficits in MS, we investigated hippocampal neurogenesis and synaptic connectivity of adult-born neurons, which play an essential role in cognitive function. The administration and withdrawal of the combination of cuprizone and rapamycin (Cup/Rap) in C57BL/6J male mice efficiently demyelinated and remyelinated the hippocampus, respectively. In the demyelinated hippocampus, neurogenesis was nearly absent in the dentate gyrus, which was due to inhibited proliferation of neural stem cells (NSCs). Specifically, radial glia-like type 1 NSCs were shifted from a proliferative state to a mitotically-quiescent state in the demyelinated hippocampus. In addition, dendritic spine densities of adult-born neurons were significantly decreased, indicating a reduction in synaptic connections between hippocampal newborn neurons and excitatory input neurons. Concomitant with hippocampal remyelination induced by withdrawal of Cup/Rap, proliferation of type 1 NSCs and dendritic spine densities of adult-born neurons reverted to normal in the hippocampus. Our study shows that proliferation of hippocampal NSCs and synaptic connectivity of adult-born neurons are inversely correlated with the level of demyelination, providing critical insight into hippocampal neurogenesis as a potential therapeutic target to treat cognitive deficits associated with MS.SIGNIFICANCE STATEMENT To identify the neural substrates that mediate cognitive dysfunctions associated with a majority of MS patients, we investigated hippocampal neurogenesis and structural development of adult-born neurons using a Cup/Rap model, which recapitulates the hippocampal demyelination that occurs in MS patients. A shift of NSCs from a proliferatively-active state to mitotically-quiescent state dramatically decreased neurogenesis in the demyelinated hippocampus. Formation of dendritic spines on newborn neurons was also impaired following demyelination. Interestingly, the altered neurogenesis and synaptic connectivity of newborn neurons were reversed to normal levels during remyelination. Thus, our study revealed reversible genesis and synaptic connectivity of adult-born neurons between the demyelinated and remyelinated hippocampus, suggesting hippocampal neurogenesis as a potential target to normalize cognitive impairments in MS patients.

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 article in Acta Psychiatrica Scandinavica discusses the efficacy and tolerability of monoamine oxidase inhibitors (MAOIs) in treating depressive episodes in mood disorders. While the review found similar efficacy between MAOIs and other antidepressants, previous studies suggest potential superiority of MAOIs in certain patient subgroups. The article highlights the need for further research on MAOIs in atypical depression and treatment-resistant depression (TRD), as well as exploring barriers to their use in clinical practice. Overall, the meta-analysis emphasizes the importance of continued research to optimize the use of MAOIs in depression treatment. [Extracted from the article]

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Monoamine oxidase (MAO) is an enzyme involved in neurotransmitter monoamine metabolism through an oxidative deamination reaction that produces a nerve-damaging substance, H2O2. Two isoforms of MAO that are MAO-A, and MAO-B, are known by their specific substrates, serotonin, and dopamine, respectively. Overexpression of MAO-A causes depression and anxiety disorder, whereas MAO-B causes neurodegenerative disorders such as Parkinson's and Alzheimer's. Infections and diseases caused by the activity of these two enzymes are known to affect millions of people worldwide every year. Various drugs for both disorders are available on the market. However, side effects such as dizziness, sore throat, insomnia, obesity, and heart disorder are registered. Therefore, developing new compounds acting as MAO inhibitors with lower side effects but higher selectivity than available drugs is in need. Pyrazolines and amino chalcone derivatives are well known to exhibit inhibition of MAO activity and used as research objects. Virtual screening of molecular docking using DOCK6 of six compounds of each pyrazoline (1a-f) (both R and S configuration) and amino chalcone (2a-f) was conducted to study their inhibition activity to MAO-A (PDB: 2Z5X) and MAO-B (PDB: 6FW0) and selectivity based on comparison of grid score value of Harmin as control positive for MAO-A and E92 ligand for MAO-B. The results showed that the most potent compound as a selective inhibitor of MAO is (R)-3-(4-aminophenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide of pyrazoline derivative and (1-(4-cinnamoyl phenyl) thiourea) of amino chalcone derivative. [ABSTRACT FROM AUTHOR]