Monoamine Oxidase B Activity Research Articles

Identification of Sarmentosin as a Key Bioactive from Blackcurrants (Ribes nigrum) for Inhibiting Platelet Monoamine Oxidase in Humans.

Previous clinical studies indicate that monoamine oxidase-B (MAO-B) inhibition by blackcurrants must be predominantly attributed to bioactives other than anthocyanins. In this natural products discovery study, MAO-A/B inhibitory phytochemicals were isolated from blackcurrants, and a double-blind crossover study investigated the efficacy of freeze-dried whole-fruit blackcurrant powder in inhibiting MAO-B compared with blackcurrant juice in healthy adults. Platelet MAO-B inhibition was comparable between powder (89% ± 6) and juice (91% ± 4), and it was positively correlated with MAO-modulated plasma catecholamines, subjective alertness, and reduced mental fatigue, assessed using the Bond-Lader questionnaire. Sarmentosin, a nitrile glycoside, and its hydroxycinnamoyl esters were identified as novel MAO-A/B inhibitors from blackcurrant in vitro, and sarmentosin was demonstrated to inhibit platelet MAO-B activity in vivo. These findings confirm sarmentosin as the primary bioactive for MAO-A/B inhibition in blackcurrants, as well as its bioavailability and stability during freeze-drying, and suggest that consuming blackcurrant powder and juice may positively affect mood in healthy adults.

Evaluation of monoamine oxidase B fluctuation in liver fibrosis cell and mice models via a specificity fluorescent probe

Liver fibrosis can result in cirrhosis and cancer, leading to damage to liver function and even endangering life. Early diagnosis of fibrosis is essential for optimizing the therapeutic schedule and improving the cure rates. Recent researches have shown that monoamine oxidase B (MAO-B) could be used as the marker for the early diacrisis of liver fibrosis. However, there still lacked strategies for accurate in situ monitoring of MAO-B. In this work, we developed a fluorescence probe YXHcy-NH2 for detecting MAO-B activity in living cells and in vivo. MAO-B activates the probe within 100 minutes and emits bright fluorescence at the fluorescence emission peak. The results displayed that the fluorescence intensity of fibrotic LX-2 cells was ten times that of normal cells, and the fluorescence brightness of liver tissues in liver fibrotic mice was five times higher than that of normal mice, so our probe could successfully distinguish between fibrotic cells and normal cells, as well as liver fibrotic mice and normal mice. Our study provides an easy, rapid, and high sensitive method for in situ in vivo imaging of MAO-B. It may become an effective mean for early diagnosis of liver fibrosis.

Baicalin and baicalein from Scutellaria baicalensis Georgi alleviate aberrant neuronal suppression mediated by GABA from reactive astrocytes.

γ-aminobutyric acid (GABA) from reactive astrocytes is critical for the dysregulation of neuronal activity in various neuroinflammatory conditions. While Scutellaria baicalensis Georgi (S. baicalensis) is known for its efficacy in addressing neurological symptoms, its potential to reduce GABA synthesis in reactive astrocytes and the associated neuronal suppression remains unclear. This study focuses on the inhibitory action of monoamine oxidase B (MAO-B), the key enzyme for astrocytic GABA synthesis. Using a lipopolysaccharide (LPS)-induced neuroinflammation mouse model, we conducted immunohistochemistry to assess the effect of S. baicalensis on astrocyte reactivity and its GABA synthesis. High-performance liquid chromatography was performed to reveal the major compounds of S. baicalensis, the effects of which on MAO-B inhibition, astrocyte reactivity, and tonic inhibition in hippocampal neurons were validated by MAO-B activity assay, qRT-PCR, and whole-cell patch-clamp. The ethanolic extract of S. baicalensis ameliorated astrocyte reactivity and reduced excessive astrocytic GABA content in the CA1 hippocampus. Baicalin and baicalein exhibited significant MAO-B inhibition potential. These two compounds downregulate the mRNA levels of genes associated with reactive astrogliosis or astrocytic GABA synthesis. Additionally, LPS-induced aberrant tonic inhibition was reversed by both S. baicalensis extract and its key compounds. In summary, baicalin and baicalein isolated from S. baicalensis reduce astrocyte reactivity and alleviate aberrant tonic inhibition of hippocampal neurons during neuroinflammation.

Monoamine oxidase B activatable red fluorescence probe for bioimaging in cells and zebrafish

A real-time and specific for the detection of Monoamine Oxidase B (MAO-B) to investigate the MAO-B-relevant disease development and treatment process is urgently desirable. Here, we utilized MAO-B to catalyze the conversion of propylamino groups to aldehyde groups, which was then quickly followed by a β-elimination process to produce fluorescent probes (FNJP) that may be used to detect MAO-B in vitro and in vivo. The FNJP probe possesses unique properties, including favorable reactivity (Km = 10.8 μM), high cell permeability, and NIR characteristics (λem = 610 nm). Moreover, the FNJP probe showed high selectivity for MAO-B and was able to detect endogenous MAO-B levels from a mixed population of NIH-3 T3 and HepG2 cells. MAO-B expression was found to be increased in cells under lipopolysaccharide-stimulated cellular oxidative stress in neuronal-like SH-SY5Y cells. In addition, the visualization of FNJP for MAO-B activity in zebrafish can be an effective tool for exploring the biofunctions of MAO-B. Considering these excellent properties, the FNJP probe may be a powerful tool for detecting MAO-B levels in living organisms and can be used for accurate clinical diagnoses of related diseases.

Platelet Serotonin (5-HT) Concentration, Platelet Monoamine Oxidase B (MAO-B) Activity and HTR2A, HTR2C, and MAOB Gene Polymorphisms in Asthma.

The complex role of the serotonin system in respiratory function and inflammatory diseases such as asthma is unclear. Our study investigated platelet serotonin (5-HT) levels and platelet monoamine oxidase B (MAO-B) activity, as well as associations with HTR2A (rs6314; rs6313), HTR2C (rs3813929; rs518147), and MAOB (rs1799836; rs6651806) gene polymorphisms in 120 healthy individuals and 120 asthma patients of different severity and phenotypes. Platelet 5-HT concentration was significantly lower, while platelet MAO-B activity was considerably higher in asthma patients; however, they did not differ between patients with different asthma severity or phenotypes. Only the healthy subjects, but not the asthma patients, carrying the MAOB rs1799836 TT genotype had significantly lower platelet MAO-B activity than the C allele carriers. No significant differences in the frequency of the genotypes, alleles, or haplotypes for any of the investigated HTR2A, HTR2C and MAOB gene polymorphisms have been observed between asthma patients and healthy subjects or between patients with various asthma phenotypes. However, the carriers of the HTR2C rs518147 CC genotype or C allele were significantly less frequent in severe asthma patients than in the G allele carriers. Further studies are necessary to elucidate the involvement of the serotonergic system in asthma pathophysiology.

Astrocytic scar restricting glioblastoma via glutamate–MAO-B activity in glioblastoma-microglia assembloid

BackgroundGlial scar formation is a reactive glial response confining injured regions in a central nervous system. However, it remains challenging to identify key factors formulating glial scar in response to glioblastoma (GBM) due to complex glia-GBM crosstalk.MethodsHere, we constructed an astrocytic scar enclosing GBM in a human assembloid and a mouse xenograft model. GBM spheroids were preformed and then co-cultured with microglia and astrocytes in 3D Matrigel. For the xenograft model, U87-MG cells were subcutaneously injected to the Balb/C nude female mice.ResultsAdditional glutamate was released from GBM-microglia assembloid by 3.2-folds compared to GBM alone. The glutamate upregulated astrocytic monoamine oxidase-B (MAO-B) activity and chondroitin sulfate proteoglycans (CSPGs) deposition, forming the astrocytic scar and restricting GBM growth. Attenuating scar formation by the glutamate–MAO-B inhibition increased drug penetration into GBM assembloid, while reducing GBM confinement.ConclusionsTaken together, our study suggests that astrocytic scar could be a critical modulator in GBM therapeutics.Graphical

Identification of neurotherapeutic constituents in Ocimum gratissimum with cholinesterase and mono amine oxidase inhibitory activities, using GC-MS analysis, in vitro, and in silico approaches

Neuroprotective activities of various extracts of Ocimum gratissimum (OG), have been reported, but there is paucity of information on its neurotherapeutic constituents. This study is aimed at identifying the neurotherapeutic constituents in OG leaves using in vitro assays, GC-MS chemical investigation and in silico studies including molecular docking, ensemble-based docking, molecular dynamics (MD) simulation, clustering and ADMET filtering analysis. Methanol extract of O gratissimum (MEOG) and solvent-partition (n-hexane, ethylacetate, and methanol residue fraction) of MEOG were investigated for in vitro acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and monoamine oxidase B (MAO-B) inhibition at concentration of 0.65, 12.5, 2.5, 5, and 10 mg/mL, using donepezil, phenazine methosulfate and selegiline as reference inhibitors for AChE, BChE and MAO B respectively. n-hexane solvent partition fraction was further investigated using GC-MS analysis. Identified compounds were screened against human AChE, BChE and MAO-B activities using molecular docking and molecular dynamics. The lead phytochemicals were further analysed for ADMET in silico analysis. MEOG and the 3 fractions (n-hexane, ethylacetate, and methanol residue fraction) inhibited the activities of AChE, BChE and MAO-B in a concentration-dependent manner with AChE (IC50 = 2.380, 2.022, 2.066 and 1.079 mg/mL respectively), BChE (IC50 = 2.261, 2.126, 2.630 and 1.465 mg/mL respectively) and MAO-B (IC50 = 2.345, 1.584, 2.933 and 2.935 mg/mL respectively). From the 38 GC-MS identified compounds, 7 hit compounds were further subjected to ensemble-docking, the lead phytochemicals (LP): cholestane and 3-methoxy-morphanin presented highest multiple binding tendencies to the three enzymes. Cholestane had the highest binding energies of −9.9, −9.0 and −11 kcal/mol, while 3-methoxy-morphanin presented the second-best binding energies of −9.3, −8.2 and −10.1 kcal/mol respectively. When compared with the binding pattern of reference inhibitors of the enzyme, lead phytochemicals were orientated in the catalytic sites of the enzyme and interacted with important catalytic residues. The LP-enzyme complexes were stable during the MD simulation analysis. Cholestane and 3-methoxy-morphanin presented favorable ADMET properties over several molecular descriptors and filters, with druggable properties and ability to cross the blood-brain barrier. Hence, cholestane and 3-methoxy-morphanin, in part, or in synergy with other hit phytochemicals, may be responsible for the neurotherapeutic activities of MEOG leaves.

Vanillin attenuates oxidative stress and neurochemical balance in MPTP-induced Parkinson's disease mice by regulating the TLR-4 inflammatory pathway.

This study investigated the protective effect of vanillin against Parkinson's disease (PD). 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 30 mg/kg) was administered s.c. for 6 consecutive days to induce PD and mice were treated with vanillin (100 and 200 mg/kg, p.o.) for 15 days. Cognitive, motor and non-motor functions were assessed to evaluate the effect of vanillin in PD mice. Levels of dopamine and glutamate and activity of monoamine oxidaseB (MAO-B) were estimated in vanillin-treated PD mice. The effect of vanillin on the level of lipid peroxidation and superoxide dismutase in brain tissue of PD mice was estimated. Data of the study revealed that vanillin reversed the altered cognitive, motor and non-motor function in PD mice. Activity of MAO-B and neurochemical level were attenuated with vanillin in PD mice. Inflammatory cytokines, nuclear factor kappa B (NF-kB) and Toll-like receptor 4 (TLR-4) levels were lower in the vanillin-treated group compared to the PD group of mice. Data of the study suggest that vanillin protects against neuronal injury and recovers the altered behaviour in PD mice by regulating neurochemical balance and the TLR-4/NF-kB pathway.

The SARS-CoV-2 spike glycoprotein interacts with MAO-B and impairs mitochondrial energetics

SARS-CoV-2 infection is associated with both acute and post-acute neurological symptoms. Emerging evidence suggests that SARS-CoV-2 can alter mitochondrial metabolism, suggesting that changes in brain metabolism may contribute to the development of acute and post-acute neurological complications. Monoamine oxidase B (MAO-B) is a flavoenzyme located on the outer mitochondrial membrane that catalyzes the oxidative deamination of monoamine neurotransmitters. Computational analyses have revealed high similarity between the SARS-CoV-2 spike glycoprotein receptor binding domain on the ACE2 receptor and MAO-B, leading to the hypothesis that SARS-CoV-2 spike glycoprotein may alter neurotransmitter metabolism by interacting with MAO-B. Our results empirically establish that the SARS-CoV-2 spike glycoprotein interacts with MAO-B, leading to increased MAO-B activity in SH-SY5Y neuron-like cells. Common to neurodegenerative disease pathophysiological mechanisms, we also demonstrate that the spike glycoprotein impairs mitochondrial bioenergetics, induces oxidative stress, and perturbs the degradation of depolarized aberrant mitochondria through mitophagy. Our findings also demonstrate that SH-SY5Y neuron-like cells expressing the SARS-CoV-2 spike protein were more susceptible to MPTP-induced necrosis, likely necroptosis. Together, these results reveal novel mechanisms that may contribute to SARS-CoV-2-induced neurodegeneration.

Synthesis, Characterization and Biological Evaluation of Benzothiazole-Isoquinoline Derivative.

Currently, no suitable clinical drugs are available for patients with neurodegenerative diseases complicated by depression. Based on a fusion technique to create effective multi-target-directed ligands (MTDLs), we synthesized a series of (R)-N-(benzo[d]thiazol-2-yl)-2-(1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl) acetamides with substituted benzothiazoles and (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline. All compounds were tested for their inhibitory potency against monoamine oxidase (MAO) and cholinesterase (ChE) by in vitro enzyme activity assays, and further tested for their specific inhibitory potency against monoamine oxidase B (MAO-B) and butyrylcholinesterase (BuChE). Among them, six compounds (4b-4d, 4f, 4g and 4i) displayed excellent activity. The classical antidepressant forced swim test (FST) was used to verify the in vitro results, revealing that six compounds reduced the immobility time significantly, especially compound 4g. The cytotoxicity of the compounds was assessed by the MTT method and Acridine Orange (AO) staining, with cell viability found to be above 90% at effective compound concentrations, and not toxic to L929 cells reversibility, kinetics and molecular docking studies were also performed using compound 4g, which showed the highest MAO-B and BuChE inhibitory activities. The results of these studies showed that compound 4g binds to the primary interaction sites of both enzymes and has good blood-brain barrier (BBB) penetration. This study provides new strategies for future research on neurodegenerative diseases complicated by depression.

Gastric Enteric Glial Cells: A New Contributor to the Synucleinopathies in the MPTP-Induced Parkinsonism Mouse.

Accumulating evidence has shown that Parkinson's disease (PD) is a systemic disease other than a mere central nervous system (CNS) disorder. One of the most important peripheral symptoms is gastrointestinal dysfunction. The enteric nervous system (ENS) is regarded as an essential gateway to the environment. The discovery of the prion-like behavior of α-synuclein makes it possible for the neurodegenerative process to start in the ENS and spread via the gut-brain axis to the CNS. We first confirmed that synucleinopathies existed in the stomachs of chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/probenecid (MPTP/p)-induced PD mice, as indicated by the significant increase in abnormal aggregated and nitrated α-synuclein in the TH-positive neurons and enteric glial cells (EGCs) of the gastric myenteric plexus. Next, we attempted to clarify the mechanisms in single MPTP-injected mice. The stomach naturally possesses high monoamine oxidase-B (MAO-B) activity and low superoxide dismutase (SOD) activity, making the stomach susceptible to MPTP-induced oxidative stress, as indicated by the significant increase in reactive oxygen species (ROS) in the stomach and elevated 4-hydroxynonenal (4-HNE) in the EGCs after MPTP exposure for 3 h. Additionally, stomach synucleinopathies appear before those of the nigrostriatal system, as determined by Western blotting 12 h after MPTP injection. Notably, nitrated α-synuclein was considerably increased in the EGCs after 3 h and 12 h of MPTP exposure. Taken together, our work demonstrated that the EGCs could be new contributors to synucleinopathies in the stomach. The early-initiated synucleinopathies might further influence neighboring neurons in the myenteric plexus and the CNS. Our results offer a new experimental clue for interpreting the etiology of PD.

Extended Double Bond Conjugation in the Chalcone Framework Favours MAO-B Inhibition: A Structural Perspective on Molecular Dynamics.

The monotropic membrane protein monoamine oxidase B (MAO-B) has been shown to be a crucial drug target for the treatment of neurodegenerative diseases. The design of recent inhibitor therapeutic agents of MAO-B involves conjugation and modification of a chalcone scaffold comprising two aryl or heteroaryl rings connected via a short spacer unit with rotatable bonds. Supported by experimental data, these modifications often result in high potent inhibitor compounds. In this study, we employ molecular dynamics simulations to unravel the impact of extended double bond conjugation in two novel compounds, F1 and MO10, toward the inhibition of the MAO-B protein. It was revealed that extended double bond conjugation induced a unidirectional orientation and motion of F1 and MO10, suggesting a stable binding pocket anchorage favouring high-affinity pocket interactions. Conformational analyses also revealed that the incorporated double bond extension impeded the motion of individual binding pocket residues, which subsequently disrupted the functionality of MAO-B. Real-time structural dynamics also revealed that the extended double bond conjugation mediated peculiar interactions with MAO-B binding pocket residues characterized by π-alkyl, π-π stacking, and π-sulphur interactions which buried both compounds into the hydrophobic core of MAO-B and ultimately induced higher binding affinities of both F1 and MO10. These insights present useful structural perspectives of the extended double bond conjugation associated with the experimentally reported enhanced inhibitory activity of F1 and MO10 against MAO-B.

Development of novel monoamine oxidase B (MAO-B) inhibitors by combined application of docking-based alignment, 3D-QSAR, ADMET prediction, molecular dynamics simulation, and MM_GBSA binding free energy

Unsaturated ketone derivatives are known as inhibitors of monoamine oxidase B (MAO-B), a potential drug target of Parkinson’s disease. Here, docking-based alignment, 3 D-QSAR (three-dimensional quantitative structure-activity relationship) studies, ADMET (absorption, distribution, metabolism, excretion, and toxicity) prediction, molecular dynamics (MD) simulation, and MM_GBSA binding free energy were performed on a novel series of MAO-B inhibitors. The objective is to predict new MAO-B inhibitors with high potency activity. The 3 D-QSAR models were created using comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA). Molecular docking findings indicated that compounds with strong inhibitory efficacy also had a high binding affinity. 3 D-QSAR studies showed the importance of steric, electrostatic, and H-bond acceptor fields on the inhibitory activity of MAO-B. Based on the appropriate 3 D-QSAR model, a new series of MAO-B inhibitors were predicted and their pharmacokinetic characteristics were evaluated using in silico ADMET prediction. All screened compounds show good oral bioavailability without any side effects. Moreover, the dynamic behavior and stability of the most active compounds were evaluated using MD simulations. The results showed that unsaturated ketone derivatives are stable and compact during the 100 ns of MD simulation. Finally, the binding free energy of complexes was determined using the MM_GBSA method; the findings indicated that the T1 compound is more stable (ΔGbinding = −409.506 KJ/mol) than the data set's highest active compound (ΔGbinding = −31.883 KJ/mol). Communicated by Ramaswamy H. Sarma

Effect of diet supplemented with African Star Apple Fruit Pulp on purinergic, cholinergic and monoaminergic enzymes, TNF-α expression and redox imbalance in the brain of hypertensive rats

ABSTRACT Objective This study examined whether diet supplemented with African star apple fruit pulp (FP) can mitigate the effect of high blood pressure on brain neurochemicals, histopathology and expression of genes linked with neuroinflammation. Methods Rats were administered with cyclosporine (25 mg/kg.bw) to induce hypertension and were fed with or without FP supplemented diet. Purinergic (Nucleoside triphosphate diphosphohydrolases [NTPdase] and adenosine deaminase [ADA]) cholinergic (acetylcholinesterase [AChE]) and monoaminergic (monoamine oxidase-B) enzymes were assessed in treated and untreated hypertensive rats’ brains. Oxidative stress biomarkers (catalase, glutathione-S-transferase, thiols, reactive oxygen species [ROS] and malondialdehyde [MDA]), as well as AChE, tumour necrosis factor and receptor (TNF-α and TNF-α-R) expression, were also determined. Results FP supplemented diet significantly reduced NTPdase and ADA activities and increased Na+/K+-ATPase activities in hypertensive rats’ brains compared to the untreated group. Furthermore, FP reduced acetylcholinesterase and monoamine oxidase-B activities compared to the hypertensive group. Redox imbalance was observed in hypertensive rats with inhibition of antioxidant enzymes and high levels of ROS and MDA. However, FP supplemented diet improved antioxidant enzymes, reduced ROS and MDA production in the brain of hypertensive rats. High blood pressure also triggered upregulation of AChE, TNF-α and TNF-α-R while feeding with FP supplemented diet downregulated the genes. Conclusion This study demonstrates the neuroprotective role of FP supplemented diet against alterations in neurochemicals associated with Alzheimer’s disease, oxidative stress-induced neuronal damage and expression of genes linked with neuroinflammation. Moreover, studies on animal behaviour and human subjects are required to confirm these beneficial effects.

Non-permitted food colorants induced neurotoxicity in cerebellum of rat brain

Food colorants are important food additives that not only enhance the appearance of food but also appetite. These can be obtained from natural and synthetic sources, but synthetic sources are more popular, efficient, and potential. Non-permitted food colorants (NPFCs) are banned, but their injudicious use in developing countries associated with various adverse health effects. They have potentially toxic effects on the body organs like the brain, liver, kidney, spleen, gut, etc. In view of their toxicity pattern, the present study aims to investigate the effect of three NPFCs (MY: Metanil yellow; MG: Malachite green; SIII: Sudan III) on oxidative stress, mitochondrial complexes, neurochemicals, and histological changes in the cerebellum of rats. Rats treated with MY (430 mg/kg), MG (13.75 mg/kg), SIII (250 mg/kg), and their mixtures (YGR) (MY 143.33 + MG 4.52 + SIII 83.33 mg/kg) p.o. for 60 days showed a significant increase in lipid peroxidation and decreased level of reduced glutathione, superoxide dismutase, and catalase activity as compared to controls. An increase in the activity of acetylcholinesterase (AChE) and a significant decrease in the activity of monoamine oxidase-B (MAO-B) and mitochondrial complex I and II was also observed in NPFCs treated rats as compared to controls. Further, the histological study also revealed the loss of Purkinje neurons in the cerebellum of the rat brain. The results of the present study indicate that NPFCs exposure to rats enhances oxidative stress and alters the activity of neurochemicals and mitochondrial complexes which could further lead to neuronal loss and behavioral dysfunctions.

Inhibition of monoamine oxidase B prevents reactive astrogliosis and scar formation in stab wound injury model.

Reactive astrocytes manifest molecular, structural, and functional alterations under various pathological conditions. We have previously demonstrated that the reactive astrocytes of the stab wound injury model (STAB) display aberrant cellular gamma-aminobutyric acid (GABA) content and tonic GABA release, whereas the active astrocytes under enriched environment (EE) express high levels of proBDNF. However, the role of monoamine oxidase B (MAO-B) in reactive astrogliosis and hypertrophy still remains unknown. Here, we investigate the role of MAO-B, a GABA-producing enzyme, in reactive astrogliosis in STAB. We observed that the genetic removal of MAO-B significantly reduced the hypertrophy, scar formation, and GABA production of reactive astrocytes, whereas the MAO-B overexpression under glial fibrillary acidic protein (GFAP) promoter enhanced the levels of GFAP and GABA. Furthermore, we found that one of the by-products of the MAO-B action, H2 O2 , but not GABA, was sufficient and necessary for the hypertrophy of reactive astrocytes. Notably, we identified two potent pharmacological tools to attenuate scar-forming astrogliosis-the recently developed reversible MAO-B inhibitor, KDS2010, and an H2 O2 scavenger, crisdesalazine (AAD-2004). Our results implicate that inhibiting MAO-B activity has dual beneficial effects in preventing astrogliosis and scar-formation under brain injury, and that the MAO-B/H2 O2 pathway can be a useful therapeutic target with a high clinical potential.

Therapeutic Potential of Multifunctional Derivatives of Cholinesterase Inhibitors.

The aim of this work is to review tacrine analogues from the last three years, which were not included in the latest review work, donepezil and galantamine hybrids from 2015 and rivastigmine derivatives from 2014. In this account, we summarize the efforts toward the development and characterization of non-toxic inhibitors of cholinesterases based on mentioned drugs with various interesting additional properties such as antioxidant, decreasing β-amyloid plaque aggregation, nitric oxide production, pro-inflammatory cytokines release, monoamine oxidase-B activity, cytotoxicity and oxidative stress in vitro and in animal model that classify these hybrids as potential multifunctional therapeutic agents for Alzheimer’s disease. Moreover, herein, we have described the cholinergic hypothesis, mechanisms of neurodegeneration and current pharmacotherapy of Alzheimer’s disease based on the restoration of cholinergic function through blocking enzymes that break down acetylcholine.

Association of the MAOB rs1799836 Single Nucleotide Polymorphism and APOE ε4 Allele in Alzheimer’s Disease

The dopaminergic system is functionally compromised in Alzheimer's Disease (AD). The activity of Monoamine Oxidase B (MAOB), the enzyme involved in the degradation of dopamine, is increased during AD. Also, increased expression of MAOB occurs in the postmortem hippocampus and neocortex of patients with AD. The MAOB rs1799836 polymorphism modulates MAOB transcription, consequently influencing protein translation and MAOB activity. We recently showed that cerebrospinal fluid levels of amyloid β1-42 are decreased in patients carrying the A allele in MAOB rs1799836 polymorphism. The present study compares MAOB rs1799836 polymorphism and APOE, the only confirmed genetic risk factor for sporadic AD. We included 253 participants, 127 of whom had AD, 57 had mild cognitive impairment, 11 were healthy controls, and 58 suffered from other primary causes of dementia. MAOB and APOE polymorphisms were determined using TaqMan SNP Genotyping Assays. We observed that the frequency of APOE ε4/ε4 homozygotes and APOE ε4 carriers is significantly increased among patients carrying the AA MAOB rs1799836 genotype. These results indicate that the MAOB rs1799836 polymorphism is a potential genetic biomarker of AD and a potential target for the treatment of decreased dopaminergic transmission and cognitive deterioration in AD.

Metabolomics and computational analysis of the role of monoamine oxidase activity in delirium and SARS-COV-2 infection

Delirium is an acute change in attention and cognition occurring in ~ 65% of severe SARS-CoV-2 cases. It is also common following surgery and an indicator of brain vulnerability and risk for the development of dementia. In this work we analyzed the underlying role of metabolism in delirium-susceptibility in the postoperative setting using metabolomic profiling of cerebrospinal fluid and blood taken from the same patients prior to planned orthopaedic surgery. Distance correlation analysis and Random Forest (RF) feature selection were used to determine changes in metabolic networks. We found significant concentration differences in several amino acids, acylcarnitines and polyamines linking delirium-prone patients to known factors in Alzheimer’s disease such as monoamine oxidase B (MAOB) protein. Subsequent computational structural comparison between MAOB and angiotensin converting enzyme 2 as well as protein–protein docking analysis showed that there potentially is strong binding of SARS-CoV-2 spike protein to MAOB. The possibility that SARS-CoV-2 influences MAOB activity leading to the observed neurological and platelet-based complications of SARS-CoV-2 infection requires further investigation.

Rapid Two-Photon Fluorescence Imaging of Monoamine Oxidase B for Diagnosis of Early-Stage Liver Fibrosis in Mice.

Liver fibrosis could induce cirrhosis and liver cancer, causing serious damages to liver function and even death. Early diagnosis of fibrosis is extremely requisite for optimizing treatment schedule to improve cure rate. In early-stage fibrosis, overexpressed monoamine oxidase B (MAO-B) can serve as a biomarker, which greatly contributes to the diagnosis of early liver fibrosis. However, there is still a lack of desired strategy to precisely monitor MAO-B in situ. In this work, we established a two-photon fluorescence imaging method for in vivo detection of MAO-B activity counting on a simply prepared probe, BiPhAA. The BiPhAA could be activated by MAO-B within 10 min and fluoresced brightly. To our knowledge, this BiPhAA-based imaging platform for MAO-B is more rapid than other current detection methods. Furthermore, BiPhAA allowed the dynamic observation of endogenous MAO-B level changes in hepatic stellate cells (LX-2). Through two-photon fluorescence imaging, we observed six times higher fluorescence brightness in the liver tissue of fibrosis mice than that of normal mice, thus successfully distinguishing mice with liver fibrosis from normal mice. Our work offers a simple, fast, and highly sensitive approach for imaging MAO-B in situ and paves a way to the diagnosis of early liver fibrosis with accuracy.