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Whether initial treatment for Parkinson's disease should consist of levodopa, dopamine agonists, or monoamine oxidase type B inhibitors (MAOBI) is uncertain. We aimed to establish which of these three classes of drug, as initial treatment, provides the most effective long-term control of symptoms and best quality of life for people with early Parkinson's disease. In this pragmatic, open-label randomised trial, patients newly diagnosed with Parkinson's disease were randomly assigned (by telephone call to a central office; 1:1:1) between levodopa-sparing therapy (dopamine agonists or MAOBI) and levodopa alone. Patients and investigators were not masked to group assignment. Primary outcomes were the mobility dimension on the 39-item patient-rated Parkinson's disease questionnaire (PDQ-39) quality-of-life scale (range 0–100 with six points defined as the minimally important difference) and cost-effectiveness. Analysis was intention to treat. This trial is registered, number ISRCTN69812316. Between Nov 9, 2000, and Dec 22, 2009, 1620 patients were assigned to study groups (528 to levodopa, 632 to dopamine agonist, 460 to MAOBI). With 3-year median follow-up, PDQ-39 mobility scores averaged 1·8 points (95% CI 0·5–3·0, p=0·005) better in patients randomly assigned to levodopa than those assigned to levodopa-sparing therapy, with no increase or attrition of benefit during 7 years' observation. PDQ-39 mobility scores were 1·4 points (95% CI 0·0–2·9, p=0·05) better in patients allocated MAOBI than in those allocated dopamine agonists. EQ-5D utility scores averaged 0·03 (95% CI 0·01–0·05; p=0·0002) better with levodopa than with levodopa-sparing therapy; rates of dementia (hazard ratio [HR] 0·81, 95% CI 0·61–1·08, p=0·14), admissions to institutions (0·86, 0·63–1·18; p=0·4), and death (0·85, 0·69–1·06, p=0·17) were not significantly different, but the upper CIs precluded any substantial increase with levodopa compared with levodopa-sparing therapy. 179 (28%) of 632 patients allocated dopamine agonists and 104 (23%) of 460 patients allocated MAOBI discontinued allocated treatment because of side-effects compared with 11 (2%) of 528 patients allocated levodopa (p<0·0001). Very small but persistent benefits are shown for patient-rated mobility scores when treatment is initiated with levodopa compared with levodopa-sparing therapy. MAOBI as initial levodopa-sparing therapy was at least as effective as dopamine agonists. UK National Institute for Health Research Health Technology Assessment Programme and UK Department of Health.

Purpose In Alzheimer’s disease (AD), increased metabolism of monoamines by monoamine oxidase type B (MAO-B) leads to the production of toxic reactive oxygen species (ROS), which are thought to contribute to disease pathogenesis. Inhibition of the MAO-B enzyme may restore brain levels of monoaminergic neurotransmitters, reduce the formation of toxic ROS and reduce neuroinflammation (reactive astrocytosis), potentially leading to neuroprotection. Sembragiline (also referred as RO4602522, RG1577 and EVT 302 in previous communications) is a potent, selective and reversible inhibitor of MAO-B developed as a potential treatment for AD. Methods This study assessed the relationship between plasma concentration of sembragiline and brain MAO-B inhibition in patients with AD and in healthy elderly control (EC) subjects. Positron emission tomography (PET) scans using [ 11 C]- L -deprenyl-D 2 radiotracer were performed in ten patients with AD and six EC subjects, who received sembragiline each day for 6–15 days. Results At steady state, the relationship between sembragiline plasma concentration and MAO-B inhibition resulted in an E max of ∼80–90 % across brain regions of interest and in an EC 50 of 1–2 ng/mL. Data in patients with AD and EC subjects showed that near-maximal inhibition of brain MAO-B was achieved with 1 mg sembragiline daily, regardless of the population, whereas lower doses resulted in lower and variable brain MAO-B inhibition. Conclusions This PET study confirmed that daily treatment of at least 1 mg sembragiline resulted in near-maximal inhibition of brain MAO-B enzyme in patients with AD.

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. Monoamine oxidase A (MAO-A) is an outer mitochondrial membrane-bound enzyme best known for its function in the brain, but also linked to cancer progression. Here, the authors show that MAO-A is expressed in tumor associated macrophages, promoting their immunosuppressive properties, and that MAO inhibition suppresses tumor growth in preclinical models.

The actions of many drugs involve enzyme inhibition. This is exemplified by the inhibitors of monoamine oxidases (MAO) and the cholinsterases (ChE) that have been used for several pharmacological purposes. This review describes key principles and approaches for the reliable determination of enzyme activities and inhibition as well as some of the methods that are in current use for such studies with these two enzymes. Their applicability and potential pitfalls arising from their inappropriate use are discussed. Since inhibitor potency is frequently assessed in terms of the quantity necessary to give 50% inhibition (the IC50 value), the relationships between this and the mode of inhibition is also considered, in terms of the misleading information that it may provide. Incorporation of more than one functionality into the same molecule to give a multi-target-directed ligands (MTDLs) requires careful assessment to ensure that the specific target effects are not significantly altered and that the kinetic behavior remains as favourable with the MTDL as it does with the individual components. Such factors will be considered in terms of recently developed MTDLs that combine MAO and ChE inhibitory functions.

Previously synthesized novel chalcone oxime ethers (COEs) were evaluated for inhibitory activities against monoamine oxidases (MAOs) and acetylcholinesterase (AChE). Twenty-two of the 24 COEs synthesized, except COE-17 and COE-24, had potent and/or significant selective inhibitory effects on MAO-B. COE-6 potently inhibited MAO-B with an IC50 value of 0.018 µM, which was 105, 2.3, and 1.1 times more potent than clorgyline, lazabemide, and pargyline (reference drugs), respectively. COE-7, and COE-22 were also active against MAO-B, both had an IC50 value of 0.028 µM, which was 67 and 1.5 times lower than those of clorgyline and lazabemide, respectively. Most of the COEs exhibited weak inhibitory effects on MAO-A and AChE. COE-13 most potently inhibited MAO-A (IC50 = 0.88 µM) and also significantly inhibited MAO-B (IC50 = 0.13 µM), and it could be considered as a potential nonselective MAO inhibitor. COE-19 and COE-22 inhibited AChE with IC50 values of 5.35 and 4.39 µM, respectively. The selectivity index (SI) of COE-22 for MAO-B was higher than that of COE-6 (SI = 778.6 vs. 222.2), but the IC50 value (0.028 µM) was slightly lower than that of COE-6 (0.018 µM). In reversibility experiments, inhibitions of MAO-B by COE-6 and COE-22 were recovered to the levels of reference reversible inhibitors and both competitively inhibited MAO-B, with Ki values of 0.0075 and 0.010 µM, respectively. Our results show that COE-6 and COE-22 are potent, selective MAO-B inhibitors, and COE-22 is a candidate of dual-targeting molecule for MAO-B and AChE.

Key Points Monoamine oxidase (MAO) inhibitors were among the first antidepressants to be discovered and introduced into the clinic. Early forms have almost disappeared from use as a consequence of their side effects, which include the 'cheese reaction' — that is, stimulation of cardiovascular sympathetic nervous system activity due to a build-up of dietary amines. The identification of two forms of MAO, known as MAOA and MAOB, and their respective selective inhibitors has contributed to a better understanding of their physiological roles, regulation of neurotransmitter metabolism and the mechanism of the 'cheese reaction', and has led to the development of selective inhibitors that avoid this side effect. The two enzymes differ structurally in their substrate–inhibitor recognition sites, but not in their active sites, which contain a covalently bound flavin moiety. Knowledge of the three-dimensional structures of MAOA and MAOB has provided new insights into the way in which MAO interacts with substrates and inhibitors, and has revealed intriguing species differences for MAOA. The discovery that the synthetic compound MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a substrate of MAOB, which converts this compound to the neurotoxin MPP + (1-methyl-4-phenylpyridinium), causing a parkinsonism syndrome in some mouse strains and primates including humans, provided a basis for our understanding of the participation of MAO in dopaminergic neurodegeneration, and MAOB inhibitors as neuroprotective drugs with disease-modifying activity. The propargylamine irreversible MAOB inhibitors, including l -deprenyl (Selegiline) and rasagiline, have shown efficacy in the treatment of Parkinson's disease. These drugs exert a neuroprotective activity not related to MAO inhibition, as shown in cultured neurons and in vivo models of neurodegeneration. The molecular mechanism of this neuroprotective activity involves regulation of B-cell lymphoma/leukaemia 2 (BCL2) family proteins and protein kinase-dependent signalling pathways as well as interactions with glyceraldehyde-3-phosphate dehydrogenase and induction of some antioxidant enzymes. Although considerable advances have been made in our understanding of the structure of MAO, its neurobiology and the mechanisms of action of its selective inhibitors in neuropsychiatric disorders, much remains to be learnt about MAO and its interactions with both substrates and inhibitors. Youdim and colleagues describe how the recent solving of the crystal structures of monoamine oxidase enzymes has increased our understanding of the action of their inhibitors, some of which are now showing therapeutic value in the treatment of neurodegenerative conditions. Monoamine oxidase inhibitors were among the first antidepressants to be discovered and have long been used as such. It now seems that many of these agents might have therapeutic value in several common neurodegenerative conditions, independently of their inhibition of monoamine oxidase activity. However, many claims and some counter-claims have been made about the physiological importance of these enzymes and the potential of their inhibitors. We evaluate these arguments in the light of what we know, and still have to learn, of the structure, function and genetics of the monoamine oxidases and the disparate actions of their inhibitors.

In this study, a series of 1, 4-benzodioxan-substituted thienyl chalcone derivatives were designed, synthesized and evaluated for their inhibitory activities against human MAO-B ( h MAO-B). The structure-activity relationship was investigated and summarized. Among the 22 derivatives, compound 12 showed the most potent inhibitory activity, which exhibited an IC 50 of 0.11 µM with a selectivity index greater than 333. Kinetics and reversibility studies confirmed that compound 12 acted as a competitive and reversible inhibitor of h MAO-B. Molecular docking studies revealed the enzyme-inhibitor interactions and the rationale was provided. Moreover, compound 12 could effectively inhibit the release of nitric oxide, tumor necrosis factor-alpha and interleukin-1 beta in both lipopolysaccharide and amyloid β-protein 1–42 (Aβ 1-42 )-stimulated BV2 cells and attenuate the cytotoxicity induced by Aβ 1-42 in BV2 cells. As compound 12 exhibited low neurotoxicity, we believe the hit compound which combines the activities of MAO-B inhibiting and anti-neuroinflammation could be further investigated as a novel potential lead for future studies.

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.

Monoamine oxidases (MAOs) regulate local levels of neurotransmitters such as dopamine, norepinephrine, and serotonin and thus have been targeted by drugs for the treatment of certain CNS disorders. However, recent studies have shown that these enzymes are upregulated with age in nervous and cardiac tissues and may be involved in degeneration of these tissues, since their metabolic mechanism releases hydrogen peroxide leading to oxidative stress. Thus, targeting these enzymes may be a potential anti-aging strategy. The purpose of this study was to compare the MAO inhibition and selectivity of selected dietary phenolic compounds, using a previously validated assay that would avoid interference from the compounds. Kynuramine metabolism by human recombinant MAO-A and MAO-B leads to formation of 4-hydroxyquinoline, with Vmax values of 10.2±0.2 and 7.35±0.69 nmol/mg/min, respectively, and Km values of 23.1±0.8 μM and 18.0±2.3 μM, respectively. For oral dosing and interactions with the gastrointestinal tract, curcumin, guaiacol, isoeugenol, pterostilbene, resveratrol, and zingerone were tested at their highest expected luminal concentrations from an oral dose. Each of these significantly inhibited both enzymes except for zingerone, which only inhibited MAO-A. The IC50 values were determined, and selectivity indices (MAO-A/MAO-B IC50 ratios) were calculated. Resveratrol and isoeugenol were selective for MAO-A, with IC50 values of 0.313±0.008 and 3.72±0.20 μM and selectivity indices of 50.5 and 27.4, respectively. Pterostilbene was selective for MAO-B, with IC50 of 0.138±0.013 μM and selectivity index of 0.0103. The inhibition of resveratrol (MAO-A) and pterostilbene (MAO-B) was consistent with competitive time-independent mechanisms. Resveratrol 4’-glucoside was the only compound which inhibited MAO-A, but itself, resveratrol 3-glucoside, and pterostilbene 4’-glucoside failed to inhibit MAO-B. Additional studies are needed to establish the effects of these compounds on MAO-A and/or MAO-B in humans.

This double-blind trial was designed to determine whether rasagiline slows the progression of Parkinson's disease. As compared with delayed treatment, early treatment with rasagiline at a dose of 1 mg per day achieved benefits consistent with a disease-modifying effect, but 2 mg per day did not result in similar benefits. As compared with delayed treatment, early treatment with rasagiline at a dose of 1 mg per day achieved benefits consistent with a disease-modifying effect, but 2 mg per day did not result in similar benefits. A neuroprotective therapy that slows or stops disease progression is the major unmet medical need in Parkinson's disease. 1 Although current therapies provide beneficial effects on symptoms that help control the classic motor features of the disease (i.e., tremor, rigidity, and bradykinesia), intolerable disability eventually develops in most patients. 2 Numerous agents have neuroprotective effects in laboratory models, but none have been shown to have disease-modifying effects in patients with Parkinson's disease. 3 A limiting factor is the requirement for a clinical end point that reliably measures disease progression and is not confounded by the study intervention's effects on symptoms. The delayed-start design . . .