MAO-B Research Articles

Chemical space navigation by machine learning models for discovering selective MAO-B enzyme inhibitors for Parkinson’s disease

Monoamine Oxidase-B (MAO-B) is a key neuroprotective target that breaks neurotransmitters such as dopamine and releases highly reactive free radicals as the by-product. Its over-expression in the brain observed due to ageing and neurodegenerative diseases contributes to worsening neuronal degeneration. Being the primary enzyme for dopamine metabolism in the substantia nigra of the brain and due to the lack of efficient drug candidates, MAO-B selective, reversible inhibition is hot topic of research in Parkinson’s disease (PD). This study developed machine learning (ML) models that predict the activity of experimentally tested indole and indazole derivatives against MAO-B using linear genetic function approximation (GFA) and two non-linear support vector machine (SVM) and artificial neural network (ANN) techniques. ANN model with an R2 of 0.9704 for the training dataset, q2of 0.9436 for cross-validation and r2of 0.9025 for the test dataset were identified as the best-performing ML model with the seven significant molecular descriptors CATS2D_04_DA, CATS2D_05_DA, CATS3D_06_LL, Mor04u, Mor25m, P_VSA_v_2 and nO. The robust ML model was then employed to design novel MAO-B inhibitors with similar core scaffolds and their biological activity prediction. ANN model was further employed in the virtual screening of 4356 molecules from the ChEMBL database. Applicability domain analysis and pharmacokinetic and toxicity profiles predicted three newly designed molecules (22 N, 23 N and 24 N) and two virtually screened best ChEMBL molecules as potential drug candidates using the ANN ML model. Molecular docking studies of the best-identified compounds were performed to understand the molecular mechanism of interactions having high binding energy and selectivity with the MAO-B enzyme. The current study shortlisted 5 potential lead compounds as potent and selective MAO-B inhibitors, which could further be carried forward for in vitro and in vivo studies to discover small molecules against neurodegenerative disease.

Pharmacological and Non-Pharmacological Treatments for Depression in Parkinson's Disease: An Updated Review.

Depression represents one of the most common non-motor disorders in Parkinson's disease (PD) and it has been related to worse life quality, higher levels of disability, and cognitive impairment, thereby majorly affecting not only the patients but also their caregivers. Available pharmacological therapeutic options for depression in PD mainly include selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, and tricyclic antidepressants; meanwhile, agents acting on dopaminergic pathways used for motor symptoms, such as levodopa, dopaminergic agonists, and monoamine oxidase B (MAO-B) inhibitors, may also provide beneficial antidepressant effects. Recently, there is a growing interest in non-pharmacological interventions, including cognitive behavioral therapy; physical exercise, including dance and mind-body exercises, such as yoga, tai chi, and qigong; acupuncture; therapeutic massage; music therapy; active therapy; repetitive transcranial magnetic stimulation (rTMS); and electroconvulsive therapy (ECT) for refractory cases. However, the optimal treatment approach for PD depression is uncertain, its management may be challenging, and definite guidelines are also lacking. It is still unclear which of these interventions is the most appropriate and for which PD stage under which circumstances. Herein, we aim to provide an updated comprehensive review of both pharmacological and non-pharmacological treatments for depression in PD, focusing on recent clinical trials, systematic reviews, and meta-analyses. Finally, we discuss the pharmacological agents that are currently under investigation at a clinical level, as well as future approaches based on the pathophysiological mechanisms underlying the onset of depression in PD.

Evaluation of developmental toxicity of safinamide in zebrafish larvae (Danio rerio)

Monoamine oxidase-B (MAO-B), as a principal metabolizing enzyme, plays important roles in the metabolism of catecholamines and xenobiotics in the central nervous system and peripheral tissues. Safinamide, the third-generation reversible MAO-B inhibitor, has potential to alleviate many neurological diseases such as Parkinson's disease (PD) and depression. Exposure to clinical psychotropic drugs often has adverse effects on fetuses. Currently, a variety of studies of safinamide focus on its curative effect and pharmacological effect, while its side effect of embryonic development is barely studied. In this study, we used zebrafish as a model to evaluate the embryonic developmental toxicity of safinamide. Our results revealed that higher concentrations (30 μM) of safinamide treatment caused a decrease in hatching rate and an increase in malformation and mortality in zebrafish larvae. Meanwhile, we observed that lower safinamide exposure (10 μM) increased the body length of zebrafish larvae and resulted in hyperactivity-like behaviors. In addition, an increased trend in dopamine (DA) level was found in 3.3 μM and 10 μM safinamide-exposed groups. Transcriptome analysis identified that safinamide exposure may disturb a variety of physiological processes such as neuroactive ligand-receptor interaction signaling pathway. In summary, our study reveals that safinamide may cause developmental defects in zebrafish larvae and provides insights into its toxic reactions in early develoment.

Investigation on Novel E/Z 2-Benzylideneindan-1-One-Based Photoswitches with AChE and MAO-B Dual Inhibitory Activity.

The multitarget therapeutic strategy, as opposed to the more traditional 'one disease-one target-one drug', may hold promise in treating multifactorial neurodegenerative syndromes, such as Alzheimer's disease (AD) and related dementias. Recently, combining a photopharmacology approach with the multitarget-directed ligand (MTDL) design strategy, we disclosed a novel donepezil-like compound, namely 2-(4-((diethylamino)methyl)benzylidene)-5-methoxy-2,3-dihydro-1H-inden-1-one (1a), which in the E isomeric form (and about tenfold less in the UV-B photo-induced isomer Z) showed the best activity as dual inhibitor of the AD-related targets acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B). Herein, we investigated further photoisomerizable 2-benzylideneindan-1-one analogs 1b-h with the unconjugated tertiary amino moiety bearing alkyls of different bulkiness and lipophilicity. For each compound, the thermal stable E geometric isomer, along with the E/Z mixture as produced by UV-B light irradiation in the photostationary state (PSS, 75% Z), was investigated for the inhibition of human ChEs and MAOs. The pure E-isomer of the N-benzyl(ethyl)amino analog 1h achieved low nanomolar AChE and high nanomolar MAO-B inhibition potencies (IC50s 39 and 355 nM, respectively), whereas photoisomerization to the Z isomer (75% Z in the PSS mixture) resulted in a decrease (about 30%) of AChE inhibitory potency, and not in the MAO-B one. Molecular docking studies were performed to rationalize the different E/Z selectivity of 1h toward the two target enzymes.

Pharmacological bioactivity of Ceratonia siliqua pulp extract: in vitro screening and molecular docking analysis, implication of Keap-1/Nrf2/NF-ĸB pathway

Inflammation is interfaced with various metabolic disorders. Ceratonia siliqua (CS) has a higher pharmaceutical purpose. The research aimed to investigate the biofunction of CS pulp aqueous extract (CS-PAE) with an emphasis on its integrated computational approaches as opposed to different specific receptors contributing to inflammation. The extract was assessed for its chemical and phenolic components via GC–MS, LC–MS, HPLC, and total phenolic and flavonoid content. In vitro, bioactivities and molecular docking were analyzed. Findings indicate that CS-PAE demonstrated higher scavenging activities of nitric oxide, 1,1-diphenyl-2-picrylhydrazyl radical, superoxide anion, hydrogen peroxide, and anti-lipid peroxidation (IC50 values were 5.29, 3.04, 0.63, 7.35 and 9.6 mg/dl, respectively). The extract revealed potent inhibition of RBCs hemolysis, acetylcholine esterase, monoamine oxidase-B, and α-glucosidase enzymes (IC50 was 13.44, 9.31, 2.45, and 1.5 mg/dl, respectively). The extract exhibited a cytotoxic effect against prostate cancer Pc3, liver cancer HepG2, colon cancer Caco2, and lung cancer A549 cell lines. Moreover, CS-PAE owned higher antiviral activity against virus A and some bacteria. When contrasting data from molecular docking, it was reported that both apigenin-7-glucoside and rutin in CS-PAE have a good affinity toward the Keap-1/Nrf2/ NF-ĸB pathway. In conclusion, CS-PAE showed promise in therapeutic activity in metabolic conditions.

Importance of time to ON versus wearing OFF in total daily OFF time experienced by patients with Parkinson's disease

Most patients with Parkinson's disease (PD) receiving levodopa (LD)/DOPA decarboxylase inhibitors develop motor fluctuations with an increasing amount of OFF time, negatively impacting patient quality of life. Herein, we review the evidence supporting the substantial, yet underappreciated contribution of delays in time to ON (including delayed ON and no ON) to total daily OFF time. Most clinical studies use patient diaries that do not capture time to ON and wearing OFF separately as related to LD dosing, and consequently, most OFF time has generally been attributed to wearing OFF. Hence, most treatment regimens focus on reducing wearing OFF by changing LD dosing/formulations and/or using “ON-extenders” (eg, catechol-o-methyltransferase inhibitors, monoamine oxidase-B inhibitors, extended-release amantadine, and adenosine A2A receptor antagonists). However, the literature describing approved treatments for PD that has focused on delays in time to ON is sparse and suggests this type of OFF may comprise more than twice the amount of total daily OFF time as wearing OFF. Here, we advocate for the importance of measuring and adequately addressing delays in time to ON and build support for the consistent inclusion of the time to ON measurement in future clinical trials.

NLRP3–GABA signaling pathway contributes to the pathogenesis of impulsive-like behaviors and cognitive deficits in aged mice

BackgroundPerioperative neurocognitive disorders (PND), such as delirium and cognitive impairment, are commonly encountered complications in aged patients. The inhibitory neurotransmitter γ-aminobutyric acid (GABA) is aberrantly synthesized from reactive astrocytes following inflammatory stimulation and is implicated in the pathophysiology of neurodegenerative diseases. Additionally, the activation of NOD-like receptor protein 3 (NLRP3) inflammasome is involved in PND. Herein, we aimed to investigate whether the NLRP3–GABA signaling pathway contributes to the pathogenesis of aging mice’s PND.Methods24-month-old C57BL/6 and astrocyte-specific NLRP3 knockout male mice were used to establish a PND model via tibial fracture surgery. The monoamine oxidase-B (MAOB) inhibitor selegiline (1 mg/kg) was intraperitoneally administered once a day for 7 days after the surgery. PND, including impulsive-like behaviors and cognitive impairment, was evaluated by open field test, elevated plus maze, and fear conditioning. Thereafter, pathological changes of neurodegeneration were explored by western blot and immunofluorescence assays.ResultsSelegiline administration significantly ameliorated TF-induced impulsive-like behaviors and reduced excessive GABA production in reactive hippocampal astrocytes. Moreover, astrocyte-specific NLRP3 knockout mice reversed TF-induced impulsive-like and cognitive impairment behaviors, decreased GABA levels in reactive astrocytes, ameliorated NLRP3-associated inflammatory responses during the early stage, and restored neuronal degeneration in the hippocampus.ConclusionsOur findings suggest that anesthesia and surgical procedures trigger neuroinflammation and cognitive deficits, which may be due to NLRP3–GABA activation in the hippocampus of aged mice.

Xanthine-Dopamine Hybrid Molecules as Multitarget Drugs with Potential for the Treatment of Neurodegenerative Diseases.

Multitarget drugs based on a hybrid dopamine-xanthine core were designed as potential drug candidates for the treatment of neurodegenerative diseases. Monoamine oxidase B (MAO-B) inhibitors with significant ancillary A2A adenosine receptor (A2AAR) antagonistic properties were further developed to exhibit additional phosphodiesterase-4 and -10 (PDE4/10) inhibition and/or dopamine D2 receptor (D2R) agonistic activity. While all of the designed compounds showed MAO-B inhibition in the nanomolar range mostly combined with submicromolar A2AAR affinity, significant enhancement of PDE-inhibitory and D2R-agonistic activity was additionally reached for some compounds through various structural modifications. The final multitarget drugs also showed promising antioxidant properties in vitro. In order to evaluate their potential neuroprotective effect, representative ligands were tested in a cellular model of toxin-induced neurotoxicity. As a result, protective effects against oxidative stress in neuroblastoma cells were observed, confirming the utility of the applied strategy. Further evaluation of the newly developed multitarget ligands in preclinical models of Alzheimer's and Parkinson's diseases is warranted.

In Silico Protein-Ligand Interaction Study of Selected Phytochemicals Against Monoamine Oxidase-B

Parkinson’s disease (PD) is a progressive neurodegenerative disease associated with the death of dopaminergic neurons in the substantia nigra pars compacta. Monoamine oxidase B (MAO-B) inhibitors lessen the degree of PD but still present various side effects. Natural products such as morin, piceatannol, resveratrol, and gallic acid are vital phytochemicals from plants with numerous health benefits. This in silico study aimed to identify potent natural MAO-B inhibitors that could serve as better alternatives to the known MAO-B inhibitors (rasagiline and selegiline). The crystal structure of MAO-B (PDB ID: 2C65) was retrieved from the Protein Data Bank (RSCB) and prepared for molecular docking via Discovery Studio 2020 software. Molecular docking between MAO-B and morin, piceatannol, resveratrol, gallic acid, rasagiline, and selegiline utilised the PyRx software. The Discovery Studio 2020 software was used for visualization. The SwissADME server was used to study the physiochemical properties (Lipinski rule of five), pharma-cokinetic parameters, and absorption, distribution, metabolism, elimination, and toxicity (ADMET) profiles of morin. Comparing results with binding affinity indicated that morin (-10.0 kcal/mol) has a superior potency against 2C65 than piceatannol (-9.0 kcal/mol), resveratrol (-807 kcal/mol), dopamine (-6.4 kcal/mol), gallic acid (-6.3 kcal/mol), rasagiline (-8.0 kcal/mol), and selegiline (-7.4 kcal/mol). Drug candidates comply with all five of Lipinski’s drug-likeness rules with appropriate ADMET properties. Overall, the molecular docking results suggest that morin may be considered a suitable therapeutic candidate for PD treatment.

A structural approach to investigate halogen substituted MAO-B inhibitors using QSAR modeling, molecular dynamics, and conceptual DFT analysis

Halogenated inhibitors showed robust, reversible, and selective monoamine oxidase-B (MAO-B) inhibitory efficacy in candidates that were derived from them. Our team has previously synthesized and assessed a panel of halogenated chalcones and coumarin for the study on MAO-B inhibition. The aim of this study was to build GA-MLR based QSAR models and predictive 3D Pharmacophore models, as well as to investigate the relationship between halogenated derivatives and MAO-B inhibitory activity. The robust statistical significance in the parameter (R2 = 0.78 and Q2 = 0.69) was demonstrated. Best Hypo1 contains one hydrophobic and two aromatic rings. The lead molecule for quantum mechanics was performed, and it was revealed that it would bind to proteins and provide stability. To determine the stability of the ligand-enzyme complex, a thorough molecular dynamics analysis of the lead compounds was accomplished.

Molecular Docking and Dynamics Simulation for Searching Anti-Cancer Compounds of Piperlongumine Derivatives that Have Potential as an Inhibitor Against MAO-B (Monoamine Oxidase B)

Molecular Docking and Dynamics Simulation for Searching Anti-Cancer Compounds of Piperlongumine Derivatives that Have Potential as an Inhibitor Against MAO-B (Monoamine Oxidase B)

Preparation and in vitro Evaluation of Rasagiline Mesylate Hybrid Nanoparticles.

Rasagiline is a selective and irreversible inhibitor of monoamine oxidase B (MAO-B) that is effective in the treatment of Parkinson's disease (PD). It had antioxidant and anti-apoptotic activity in experimental models. Moreover, it has low permeability and its oral bioavailability is weak and highly variable due to extensive first-pass hepatic metabolism (35%). This study aimed to formulate rasagiline mesylate (RM) as a lipid-polymer hybrid nanoparticle in order to enhance its permeation and increase its chance to be absorbed by lymphatic circulation to avoid metabolism and control its release. Successful formulation (PCL-2) was reached by the nanoprecipitation method using polycaprolactone with RM in the organic phase and lecithin in the aqueous phase DSPE-PEG. The lipid:polymer ratio of 24% and DSPE: lecithin of 50% resulted in stable nanoparticles having a particle size of 132±4.58 nm, polydispersity index of 0.273±0.02, zeta potential of -25.6±3.3, entrapment efficiency of 46±3.9%, and drug loading of 51.93±6.5. Results showed that the diffusion was more effective on the release profile than the degradation and resulted in a Fickian diffusion mechanism.

Halogenated class of oximes as a new class of monoamine oxidase-B inhibitors for the treatment of Parkinson’s disease: Synthesis, biochemistry, and molecular dynamics study

Oximes are the promising structural scaffold for inhibiting monoamine oxidase (MAO)-B. Eight chalcone-based oxime derivatives were synthesized by microwave-assisted technique, and their ability to inhibit human MAO (hMAO) enzymes were tested. All compounds showed higher inhibitory activity of hMAO-B than hMAO-A. In the CHBO subseries, CHBO4 most potently inhibited hMAO-B with an IC50 value of 0.031 μM, followed by CHBO3 (IC50 = 0.075 μM). In the CHFO subseries, CHFO4 showed the highest inhibition of hMAO-B with an IC50 value of 0.147 μM. Compound CHBO4 had the highest selectivity index (SI) value of 1290.3. However, CHBO3 and CHFO4 showed relatively low SI values of 27.7 and 19.2, respectively. The -Br substituent in the CHBO subseries at the para-position in the B-ring showed higher hMAO-B inhibition than the -F substituent in the CHFO subseries. In both series, hMAO-B inhibition increased with the substituents at para-position in A-ring (-F > -Br > -Cl > -H in order). Compound CHBO4 (-F in A-ring and -Br in B-ring) was 12.6-times potent than the substituents-reversed compound CHFO3 (-Br in A-ring and -F in B-ring; IC50 = 0.391 μM). In the kinetic study, Ki values of CHBO4 and CHFO4 for hMAO-B were 0.010 ± 0.005 and 0.040 ± 0.007 μM, respectively, with competitive inhibitions. Reversibility experiments showed that CHBO4 and CHFO4 were reversible hMAO-B inhibitors. In the cytotoxicity test using the Vero cells by the MTT technique, CHBO4 had low toxicity with an IC50 value of 128.8 µg/mL. In H2O2-induced cells, CHBO4 significantly reduced cell damage by scavenging reactive oxygen species (ROS). Molecular docking and dynamics showed the stable binding mode of the lead molecule CHBO4 on the active site of hMAO-B. These results suggest that CHBO4 is a potent reversible, competitive, and selective hMAO-B inhibitor and can be used as a treatment agent for neurological disorders.

Inhibition of MAOB Ameliorated High-Fat-Diet-Induced Atherosclerosis by Inhibiting Endothelial Dysfunction and Modulating Gut Microbiota.

In this study, monoamine oxidase B (MAOB) was activated under pathological conditions, and was the novel source of cardiovascular reactive oxygen species (ROS). ROS-induced endothelial dysfunction results in sustained and chronic vascular inflammation, which is central to atherosclerotic diseases. However, whether MAOB regulates endothelial oxidative stress and its related mechanism and whether gut microbiota mediates the anti-atherosclerosis effect of MAOB inhibitor remains unclear. In our study, MAOB expressions were elevated in high-fat diet (HFD) fed mice aortas, but only in vascular endothelial cells (not in smooth muscle cells). MAOB small interfering RNA significantly attenuated the palmitic-acid (PA)-induced endothelial oxidative stress and dysfunction. Furthermore, RNA-sequencing data revealed that MAOB knockdown decreased the levels of proinflammatory and apoptotic gene induced by PA. Microarray analysis and qPCR assay showed that miR-3620-5p was significantly decreased under the HFD condition. The dual-luciferase reporter, Western blot and qPCR assay confirmed that miR-3620-5p directly regulated MAOB by binding to its mRNA 3'UTR. Moreover, inhibition of MAOB by selegiline significantly ameliorated endothelial dysfunction and reduced atherosclerotic burden in HFD-fed ApoE-/- mice. Finally, 16S rRNA sequencing showed that selegiline significantly altered the community compositional structure of gut microbiota. Specifically, selegiline treatment enriched the abundance of Faecalibaculum and Akkermansia, decreased the abundance of unclassified_f__Lachnospiraceae, Desulfovibrio, and Blautia, and these genera were significantly correlated with the serum biochemical indices. Taken together, our findings showed that MAOB controlled endothelial oxidative stress homeostasis, and revealed the anti-atherosclerotic effect of selegiline by ameliorating endothelial dysfunction and modulating the composition and function of gut microbiota.

The effects of safinamide on dysphagia in Parkinson's disease.

Dysphagia is a potentially fatal symptom of Parkinson's disease (PD) and is characterized by frequent silent aspiration, a risk factor for aspiration pneumonia. The transdermal dopamine agonist rotigotine alleviates dysphagia in patients with PD and is more effective than oral levodopa, suggesting the importance of continuous dopaminergic stimulation (CDS) in swallowing. Safinamide is a monoamine oxidase B (MAOB) inhibitor that facilitates CDS. In this retrospective open-label evaluator-blinded research, swallowing functions in nine patients with PD were examined using a video fluoroscopic swallowing study (VFSS) before and after treatment with 50 mg of oral safinamide. The VFSS results showed that safinamide significantly improved some swallowing measures during oral and pharyngeal phases, including oral transit time and pharyngeal transit time, without worsening of any measures. Notably, improvements in lip closure, an oral phase component, seemed to be most attributable to improvements in oral phase scores. In conclusion, a medicine for CDS may effectively improve swallowing functions in patients with PD. This is the first study to show that the MAOB inhibitor safinamide partly but significantly improves swallowing function in patients with PD.

MAO inhibiting phytochemicals from the roots of Glycyrrhiza glabra L.

Glycyrrhizin, a natural compound that is substantially present in Glycyrrhiza glabra L. (Gg) root. Monoamine oxidase B (MAOB) inhibitor is used for the treatment of several important neuropsychological diseases like Parkinson’s disease. Gg is known to possess psychoactive properties which relates to its MAO inhibitory potential. This study sought to determine the MAO inhibition property of glycyrrhizin from Gg root extract. The Aqueous extract containing glycyrrhizin was isolated from the root of Gg and characterized using TLC, HPLC, and LC-MS techniques. In silico docking was conducted using Extra precision Glide 2018, Schrödinger docking suite. In addition, the pharmacokinetic properties of the compounds were predicted using SwissADME. The binding energies of the glycyrrhizin correlated well with their in vitro MAO inhibitory potential. Glycyrrhizin exhibited potent inhibitory activity towards MAOB whereas, an aqueous extract of Gg root inhibits both A and B forms of MAO enzyme. Further, molecular docking and molecular dynamics simulation showed that liquiritigenin and methoxyglabridin showed higher stability than other inhibitor compounds from the Gg root extract. These observations suggest that the phytochemicals from the Gg root extract have potent MAO inhibition properties, which can be exploited for the treatment of neurodegenerative disorders. Communicated by Ramaswamy H. Sarma

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.

Current Pharmacological Treatment for Parkinson's Disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder and its global incidence is on the rise. A well-established dopamine replacement therapy for PD is based on dopamine deficiency, primarily due to dopaminergic neuronal loss in the substantia nigra. Current dopaminergic pharmacotherapy for PD consists of levodopa and other dopaminergic drugs, such as a dopamine agonist (DA) and monoamine oxidase B (MAOB) inhibitor, and patients with PD are administered these mainly according to age, disability of parkinsonism, and tolerance of the drugs. In the advanced stage, patients with PD usually experience motor complications, mainly the wearing-off phenomenon and dyskinesias, resulting in disabled activities of daily life. Many pharmacological options are available against motor fluctuations in patients with advanced PD, including long-acting DAs, MAOB inhibitors, and catechol-O-methyltransferase inhibitors, as adjunct alternatives for dopamine-replacement therapy. Non-dopaminergic pharmacological approaches, including zonisamide and istradefylline, which have been mainly developed in Japan, are also available. Amantadine and anticholinergic drugs may be useful in specific situations. Device-aided therapies, such as deep brain stimulation and levodopa-carbidopa intestinal gel infusion therapy, can be performed at the advanced stage. In this article, we provide an overview of recent pharmacological treatments for PD.

Synthesis and Biological Evaluation of O6-Aminoalkyl-Hispidol Analogs as Multifunctional Monoamine Oxidase-B Inhibitors towards Management of Neurodegenerative Diseases.

Oxidative catabolism of monoamine neurotransmitters by monoamine oxidases (MAOs) produces reactive oxygen species (ROS), which contributes to neuronal cells' death and also lowers monoamine neurotransmitter levels. In addition, acetylcholinesterase activity and neuroinflammation are involved in neurodegenerative diseases. Herein, we aim to achieve a multifunctional agent that inhibits the oxidative catabolism of monoamine neurotransmitters and, hence, the detrimental production of ROS while enhancing neurotransmitter levels. Such a multifunctional agent might also inhibit acetylcholinesterase and neuroinflammation. To meet this end goal, a series of aminoalkyl derivatives of analogs of the natural product hispidol were designed, synthesized, and evaluated against both monoamine oxidase-A (MAO-A) and monoamine oxidase-B (MAO-B). Promising MAO inhibitors were further checked for the inhibition of acetylcholinesterase and neuroinflammation. Among them, compounds 3aa and 3bc were identified as potential multifunctional molecules eliciting submicromolar selective MAO-B inhibition, low-micromolar AChE inhibition, and the inhibition of microglial PGE2 production. An evaluation of their effects on memory and cognitive impairments using a passive avoidance test confirmed the in vivo activity of compound 3bc, which showed comparable activity to donepezil. In silico molecular docking provided insights into the MAO and acetylcholinesterase inhibitory activities of compounds 3aa and 3bc. These findings suggest compound 3bc as a potential lead for the further development of agents against neurodegenerative diseases.

Activatable organic upconversion nanoprobe for bioimaging of monoamine oxidase B in Parkinson’s disease

Monoamine oxidase B (MAO-B) activity has been observed abnormally elevated in Parkinson’s disease patients and can be used as a potential biomarker. Herein, we report an activatable frequency upconversion luminescence (FUCL) MAO-B nano-probe (NIR-MNP) capable of highly specific and real-time MAO-B imaging in biological samples. The turn-on FUCL effect is beneficial to obtaining high-quality imaging and penetrating tissue to achieve in vivo imaging, making it stand out from the existing probes. Moreover, we used NIR-MNP to confirm the role of MAO-B inhibitor in delaying Parkinson’s disease (PD) progression in mouse PD models through bio-imaging technique in vivo. Finally, our study may offer a visual way help researchers to gain further insight into the involvement of MAO-B in PD onset and progression in animals.