Monoamine Oxidase B Inhibitor Research Articles

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.

Screening of monoamine oxidase B inhibitors in Tibetan strawberry by ligand fishing based on enzyme functionalized cellulose filter paper

Tibetan strawberry (Fragaria nubicola) is a wild medicinal and edible plant in Tibet possessing various health benefits such as neuroprotection and anti-oxidation. However, there has been little study reported on its chemical constituents. To investigate the inhibitors of monoamine oxidase B (MAO-B) in Tibetan strawberry, we immobilized the enzyme onto cellulose filter paper for the first time to develop a new screening method. Two known glycosides (compounds 1 and 2) and one new iridoid glucoside (Compound 3) were fished out by this method, which was found to effectively inhibit MAO-B with IC50 values of 16.95 ± 0.93, 24.69 ± 0.20, and 46.77 ± 0.78 μM, respectively. Molecular docking and kinetic analysis were performed to reveal the inhibition mechanism of these compounds. Furthermore, compound 1 exhibited neuroprotective effects against 6-OHDA-induced injury on PC12 cells. The developed method exhibits the advantages of rapidness and effectiveness in screening of MAO-B inhibitors from complex herbal extracts.

Effect of particle size versus surface charge on the brain targeting behavior of elastic nanovesicles: In-vitro characterization, comparison between I-optimal and D-optimal statistical optimization and in-vivo pharmacokinetic evaluation

Rasagiline mesylate (RM) is a potent monoamine oxidase-B inhibitor that suffers from extensive hepatic metabolism, low bioavailability, and low brain distribution. Thus, this study aimed to formulate an intranasal nanovesicular system with high RM encapsulation (EE%) and enhanced delivery to the brain tissues. In this perspective, negatively and positively charged RM-transfersomal vesicles were prepared, characterized and the formulation parameters were statistically optimized as per two different response surface methodologies namely, I-optimal and D-optimal design. Although both statistical designs acted almost similarly in terms of experimental response analysis; the I-optimal design might be functioning better in terms of formulations’ optimization and response prediction with higher desirability factors. Consequently, the optimized negative transfersomes (particle size: 213 nm, EE%:62.55 %) and positive transfersomes (particle size: 515 nm, EE%:70.9 %) suggested by the I-optimal design were furtherly formulated, characterized for their in-vitro release, elasticity, transmission electron microscope and pH. Finally, both systems were administered intranasally and compared to an intravenous RM solution where the optimized positive transfersomes has shown significantly higher brain targeting efficiency, positive direct transfer percentage values and longer brain mean residence time. These results suggested that the surface charge of the formulated vesicles could be more effective factor -than the particle size-in enhancing the brain bioavailability of the administered drugs.

Iron-catalysed C–H ortho-arylation of edaravone, a promising monoamine oxidase-B inhibitor

Edaravone is a neuroactive drug that is currently used in the treatment of stroke patients and shows promise against a range of neurodegenerative processes including amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease. We show that iron-catalysed C–H functionalisation of edaravone and its derivatives can be exploited to generate a small library of 21 arylated edaravones, while the results of a preliminary computational binding study of these derivatives predicts that they should all bind more strongly in the active site of monoamine oxidase-B than edaravone.

A decision support system based on recurrent neural networks to predict medication dosage for patients with Parkinson's disease

Using deep learning has demonstrated significant potential in making informed decisions based on clinical evidence. In this study, we deal with optimizing medication and quantitatively present the role of deep learning in predicting the medication dosage for patients with Parkinson's disease (PD). The proposed method is based on recurrent neural networks (RNNs) and tries to predict the dosage of five critical medication types for PD, including levodopa, dopamine agonists, monoamine oxidase-B inhibitors, catechol-O-methyltransferase inhibitors, and amantadine. Recurrent neural networks have memory blocks that retain crucial information from previous patient visits. This feature is helpful for patients with PD, as the neurologist can refer to the patient's previous state and the prescribed medication to make informed decisions. We employed data from the Parkinson's Progression Markers Initiative. The dataset included information on the Unified Parkinson's Disease Rating Scale, Activities of Daily Living, Hoehn and Yahr scale, demographic details, and medication use logs for each patient. We evaluated several models, such as multi-layer perceptron (MLP), Simple-RNN, long short-term memory (LSTM), and gated recurrent units (GRU). Our analysis found that recurrent neural networks (LSTM and GRU) performed the best. More specifically, when using LSTM, we were able to predict levodopa and dopamine agonist dosage with a mean squared error of 0.009 and 0.003, mean absolute error of 0.062 and 0.030, root mean square error of 0.099 and 0.053, and R-squared of 0.514 and 0.711, respectively.

CGRP causes anxiety via HP1γ–KLF11–MAOB pathway and dopamine in the dorsal hippocampus

Calcitonin gene-related peptide (CGRP) is a neuropeptide that causes anxiety behavior; however, the underlying mechanisms remain unclear. We found that CGRP modulates anxiety behavior by epigenetically regulating the HP1γ-KLF-11-MAOB pathway and depleting dopamine in the dorsal hippocampus. Intracerebroventricular administration of CGRP (0.5 nmol) elicited anxiety-like behaviors in open field, hole-board, and plus-maze tests. Additionally, we observed an increase in monoamine oxidase B (MAOB) levels and a concurrent decrease in dopamine levels in the dorsal hippocampus of mice following CGRP administration. Moreover, CGRP increased abundance the transcriptional regulator of MAOB, Krüppel-like factor 11 (KLF11), and increased levels of phosphorylated heterochromatin protein (p-HP1γ), which is involved in gene silencing, by methylating histone H3 in the dorsal hippocampus. Chromatin immunoprecipitation assay showed that HP1γ was recruited to the Klf11 enhancer by CGRP. Furthermore, infusion of CGRP (1 nmol) into the dorsal hippocampus significantly increased MAOB expression as well as anxiety-like behaviors, which were suppressed by the pharmacological inhibition or knockdown of MAOB. Together, these findings suggest that CGRP reduces dopamine levels and induces anxiety-like behavior through epigenetic regulation in the dorsal hippocampus.

Probing the inhibition of MAO-B by chalcones: an integrated approach combining molecular docking, ADME analysis, MD simulation, and MM-PBSA calculations.

Monoamine oxidase B (MAO-B), an enzyme of significant relevance in the realm of neurodegenerative disorders, has garnered considerable attention as a potential target for therapeutic intervention. Natural compounds known as chalcones have shown potential as MAO-B inhibitors. In this particular study, we employed a multimodal computational method to evaluate the inhibitory effects of chalcones on MAO-B. Molecular docking methods were used to study and assess the complicated binding interactions that occur between chalcones and MAO-B. This extensive analysis provided a valuable and deep understanding of possible binding methods as well as the key residues implicated in the inhibition process. Furthermore, the ADME investigation gave valuable insights into the pharmacokinetic properties of chalcones. This allowed them to be assessed in terms of drug-like attributes. The use of MD simulations has benefited in the research of ligand-protein interactions' dynamic behaviour and temporal stability. MM-PBSA calculations were also done to estimate the binding free energies and acquire a better knowledge and understanding of the binding affinity between chalcones and MAO-B. Our thorough method gives a thorough knowledge of chalcones' potential as MAO-B inhibitors, which will be useful for future experimental validation and drug development efforts in the context of neurodegenerative illnesses.

Dual Inhibitors of Brain Carbonic Anhydrases and Monoamine Oxidase-B Efficiently Protect against Amyloid-β-Induced Neuronal Toxicity, Oxidative Stress, and Mitochondrial Dysfunction.

We report here the first dual inhibitors of brain carbonic anhydrases (CAs) and monoamine oxidase-B (MAO-B) for the management of Alzheimer's disease. Classical CA inhibitors (CAIs) such as methazolamide prevent amyloid-β-peptide (Aβ)-induced overproduction of reactive oxygen species (ROS) and mitochondrial dysfunction. MAO-B is also implicated in ROS production, cholinergic system disruption, and amyloid plaque formation. In this work, we combined a reversible MAO-B inhibitor of the coumarin and chromone type with benzenesulfonamide fragments as highly effective CAIs. A hit-to-lead optimization led to a significant set of derivatives showing potent low nanomolar inhibition of the target brain CAs (KIs in the range of 0.1-90.0 nM) and MAO-B (IC50 in the range of 6.7-32.6 nM). Computational studies were conducted to elucidate the structure-activity relationship and predict ADMET properties. The most effective multitarget compounds totally prevented Aβ-related toxicity, reverted ROS formation, and restored the mitochondrial functionality in an SH-SY5Y cell model surpassing the efficacy of single-target drugs.

Pharmacologic Management of Parkinsonism and Other Movement Disorders

Parkinsonism and other movement disorders constitute a diverse group of neurodegenerative conditions characterized by disturbances in motor control. This abstract provides an overview of the pharmacologic management strategies employed in the treatment of these disorders. Parkinson's disease, the most prevalent form of Parkinsonism, is primarily managed through dopaminergic therapies aimed at replenishing dopamine levels or enhancing its effects in the central nervous system. Levodopa, a precursor of dopamine, remains the gold standard, often combined with dopaminergic agonists or monoamine oxidase-B inhibitors for optimal efficacy.In addition to Parkinson's disease, other movement disorders such as essential tremor, dystonia, and chorea pose unique challenges. Beta-blockers and anticonvulsants, like primidone, are commonly prescribed for essential tremor, while dystonia may respond to anticholinergic agents or botulinum toxin injections. Huntington's disease, characterized by chorea, is managed through dopamine-depleting agents, tetrabenazine being a notable example.Recent advances in pharmacotherapy include the development of adenosine A2A receptor antagonists and glutamate receptor modulators, providing promising alternatives and adjuncts to traditional therapies. However, challenges such as medication-induced side effects, disease progression, and the need for personalized treatment plans persist.This abstract underscore the evolving landscape of pharmacologic interventions for managing Parkinsonism and other movement disorders. A comprehensive understanding of the underlying pathophysiology, coupled with ongoing research efforts, promises to enhance therapeutic options and improve the quality of life for individuals affected by these debilitating conditions.

Efficacy and safety of adjunctive oral therapy in Parkinson’s disease with motor complications: a systematic review and network meta-analysis

BackgroundThe aim of this manuscript is to review the evidence and compare the efficacy and safety of catechol-O-methyltransferase inhibitors (COMT-Is), dopamine receptor agonists (DRAs) and monoamine-oxidase B inhibitors (MAOB-Is) as...

In silico and in vitro profiling of coumarins and flavonoids for anti-Alzheimer and antioxidant activity

Abstract In this study, we examined the potential anti-Alzheimer’s and antioxidant activities of 12 analogs of coumarin and flavone compounds. Notably, nitro coumarins 6 and 7 demonstrated noteworthy activity against acetylcholinesterase, although they did not exhibit antioxidant properties. Among the tested compounds, four flavones and one coumarin displayed dual activity as both inhibitors of acetylcholinesterase and antioxidants. Particularly, flavone 9 exhibited exceptional antioxidant activity as well as substantial anti-cholinesterase activity. Molecular docking techniques were employed to investigate the relationship between the anti-Alzheimer’s and antioxidant potential of the compounds. Intriguingly, compound 9 displayed the strongest binding energy values with both monoamine oxidase-B (MAO-B) enzyme (−15.70 kcal/mol) and acetylcholinesterase enzyme (−21.70 kcal/mol), indicating that its antioxidant activity may be attributed to MAO-B inhibition. The pharmacokinetic and safety profiles of five compounds (5, 6, 7, 8, and 9) were examined using pkCSM server, revealing varying characteristics in absorption, CYP enzyme interactions, and toxicity. Compound 8 displays high absorption and lower toxicity, while Compound 6 emerges as a promising candidate due to favorable overall attributes. Nonetheless, comprehensive evaluation, including clinical studies, is crucial for determining their suitability for human use.

Development of morpholine ring-bearing halogenated α,β-unsaturated ketones as selective monoamine oxidase-B inhibitors

Nine morpholine-derived halogenated chalcone derivatives (MHC1-MHC9) were synthesized, and their inhibitory activity against monoamine oxidase (MAO) was evaluated. MHC5 showed the highest inhibitory activity against MAO-B with an IC50 value of 0.065 μM, followed by MHC7 (IC50 = 0.078 μM) and MHC6 (IC50 = 0.082 μM). The para-F substituent MHC4 was also potent (IC50 = 0.095 μM). The selectivity index values of all the compounds were high for MAO-B over MAO-A, and the values for MHC5 and MHC4 were 66.15 and 80.11, respectively. MHC5 and MHC4 were competitive MAO-B inhibitors with Ki values of 0.024 ± 0.00062 and 0.041 ± 0.0028 μM, respectively. In reversibility tests, the changes in residual activity before and after the dialysis of MHC5 and MHC4 were similar to those of safinamide, a reversible MAO-B reference inhibitor. Additionally, molecular docking and dynamic simulations predicted that the lead molecules MHC5 and MHC4 could strongly bind to the MAO-B active site with docking scores of –10.92 ± 0.08 and –10.64 ± 0.14 kcal/mol, respectively. Additionally, MHC4 and MHC5 exhibited favorable ADME features, including blood–brain barrier permeability. The experiments confirmed that MHC5 and MHC4 are reversible and potent selective inhibitors of MAO-B and are promising candidates for the treatment of neurodegenerative diseases (human health).

Neuroprotective Potential of Polydatin in Combating Parkinson’s Disease through the Inhibition of Monoamine Oxidase-B and Catechol-o-Methyl Transferase

Aims: This study aims to deduce the plausible contribution of polydatin in dopamine replenishment and dopaminergic neuroprotection to unveil its potential as a drug candidate for PD. Background: Available therapies for the management of dopaminergic degradation in Parkinson’s disease (PD) provide only symptomatic relief and are associated with various adverse effects. Levodopa (L-DOPA) is an age-old therapy in the treatment paradigm of PD, either used as mono-therapy or in combination with the inhibitors of the dopamine catabolising enzymes monoamine oxidase-B (MAO-B) and catechol O-methyltransferase (COMT) for replenishing the levels of the neurotransmitter. The discovery of plant-based novel drug therapies would help to target multiple pathways underlying the disease pathogenesis and are associated with minimal side effects. Polydatin, the precursor of resveratrol, has been explored recently to possess neuroprotective efficacy, however, the molecular mechanisms that underlie the Parkinsonism-associated neurobehavioral recovery as well as the neurorescue potential of polydatin has not been illustrated yet. Objective: The present study aimed to unveil the role of polydatin in dopamine upregulation in PD, by determining its dual inhibitory potential on the enzymes responsible for its breakdown, MAO-B and COMT. The study further aimed to elucidate the role of this molecule in regulating the enzymatic activity of Cytosolic Phospholipase A2 (cPLA2), the crucial enzyme underlying several pathogenic pathways leading to neurodegeneration. Methods: Molecular docking simulation of polydatin with the dopamine catabolizing enzymes MAO-B and COMT, as well as cPLA2, along with their respective known inhibitors was performed using the Molegro Virtual Docker (MVD) 2.1 package. Results: In-silico analyses revealed that polydatin could significantly inhibit the activities of this dopamine catabolizing enzyme, MAO-B, and COMT with comparable docking scores and more numbers of hydrogen bonds, and weaker interactions as that of their respective available synthetic inhibitors. Moreover, it was found that polydatin could regulate the activity of cPLA2 comparable to its known inhibitors. Conclusion: Polydatin exhibited efficacy as a potent dopamine replenishing agent by inhibiting its metabolizing enzymes as well as found to have efficacy against neuroinflammation, thereby highlighting the significance of designing novel phyto drugs for combating dopamine deficiency in PD.

Insights of structure-based virtual screening and MPO-based SAR analysis of berberine-benzimidazole derivatives against Parkinson disease

Parkinson's disease (PD) is a progressive neurological condition that causes tremors, rigidity and postural instability. In addition, it can lead to complications such as constipation, orthostatic hypotension, and psychiatric disorders like depression and anxiety. Berberine is a natural alkaloid used in Chinese medicine, extracted from various plants such as Berberis vulgaris and Tinospora cordifolia. The compounds have been reported to possess therapeutic activities, including anti-Alzheimer's, anti-diabetic, anti-inflammatory, antiviral, antibacterial and, in the context of this study, anti-Parkinson's action. This study conducts a structure-based virtual screening of aryl-substituted berberine-benzimidazole derivatives (D1–7). Molecular docking and dynamics simulations are used to predict pharmacodynamics against monoamine oxidase B (MAOB), while multiparametric optimization (MPO) is used to predict pharmacokinetics to the Central Nervous System (CNS). The aim is to propose new alkaloids derived from berberine that can modulate the activity of MAOB receptors in treating PD. The simulations revealed that the D7 compound, which contains a dichlorophenyl group, exhibited a high affinity with MAOB, with an affinity energy of −10 kcal/mol. In contrast, the fluoro- and nitro- substituted compounds showed lower affinity. Structure-activity/property relationship (SAR/SPR) analysis suggest that the chloro‑substituted derivatives are more lipophilic and form essentially hydrophobic interactions with the MAOB. This is corroborated by the dynamics simulations, which show that the MAOB-D7 complex is highly stable and allows for a synergistic effect associated with other anti-Parkinson drugs, further enhancing the inhibition of MAOB. Furthermore, pharmacokinetic predictions indicate that optimal levels of lipophilicity and polarity enhance high passive permeability (Papp = 1.7 × 10−5 cm/s) and metabolic stability of the D7 derivative, leading to increased distribution in the CNS.

Effect of Momordica cochinchinensis extract on locomotor function and brain antioxidant enzyme activity in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated zebrafish Parkinson’s disease model

BACKGROUND: Gac fruit (Momordica cochinchinensis) belongs to the Cucurbitaceae family. The red aril of Gac fruit contains high concentrations of carotenoids, including lycopene and beta-carotene. OBJECTIVE: This study aimed to investigate the effect of Gac fruit aril extract on locomotor activities in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced zebrafish model and measure antioxidant enzyme activities in the zebrafish brain. METHODS: This study used adult male zebrafish (Danio rerio) as an animal model. MPTP was used as a toxin to induce movement dysfunction in zebrafish, while the standard drug selegiline acted as a monoamine oxidase-B inhibitor. Locomotion was recorded on day 7 after MPTP induction using a digital video tracking system, and parameters related to zebrafish swimming, including total distance, velocity, and immobility, were observed. The brain tissue of the zebrafish was collected for antioxidant enzyme activity analysis. RESULTS: The results showed that Gac fruit extract at doses of 200 and 400 mg/kg improved locomotor functions in MPTP-induced Parkinsonism in zebrafish. However, antioxidant enzyme activities, such as catalase and superoxide dismutase activities, in the zebrafish brain showed no significant differences among all groups. CONCLUSIONS: These findings provide insights into the further research of Gac fruit extract as a nutraceutical for preventing Parkinson’s disease.

Real-world evidence on levodopa dose escalation in patients with Parkinson's disease treated with istradefylline.

Istradefylline, a selective adenosine A2A receptor antagonist, is indicated in the US and Japan as adjunctive treatment to levodopa/decarboxylase inhibitors in adults with Parkinson's disease (PD) experiencing OFF time. This study aimed to observe patterns of dose escalation of levodopa over time in patients initiated on istradefylline. Using Japanese electronic health record data, interrupted time series analyses were used to compare levodopa daily dose (LDD, mg/day) gradients in patients before and after initiation of istradefylline. Data were analyzed by period relative to istradefylline initiation (Month 1): pre-istradefylline (Months -72 to 0), early istradefylline (Months 1 to 24), and late istradefylline (Months 25 to 72). Subgroup analyses included LDD before istradefylline initiation (<400, ≥400 to <600, ≥600 mg/day) and treatment with or without monoamine oxidase-B (MAO-B) inhibitors, catechol-O-methyltransferase (COMT) inhibitors, or dopamine agonists before istradefylline initiation. The analysis included 4026 patients; mean (SD) baseline LDD was 419.27 mg (174.19). Patients receiving ≥600 mg/day levodopa or not receiving MAO-B inhibitors or COMT inhibitors demonstrated a significant reduction in LDD increase gradient for pre-istradefylline vs late-phase istradefylline (≥600 mg/day levodopa, -6.259 mg/day each month, p<0.001; no MAO-B inhibitors, -1.819 mg/day each month, p = 0.004; no COMT inhibitors, -1.412 mg/day each month, p = 0.027). This real-world analysis of Japanese prescription data indicated that slowing of LDD escalation was observed in patients initiated on istradefylline, particularly in those receiving ≥600 mg/day levodopa, suggesting istradefylline may slow progressive LDD increases. These findings suggest that initiating istradefylline before other levodopa-adjunctive therapies may mitigate LDD increases, potentially reducing occurrence or severity of levodopa-induced complications in long-term istradefylline treatment.

The effect of rasagiline on swallowing function in Parkinson's disease

Dysphagia, a potentially fatal symptom of Parkinson's disease, is characterized by frequent silent aspiration, a risk factor for aspiration pneumonia. The transdermal dopamine agonist rotigotine alleviates dysphagia in patients with Parkinson's disease and is more effective than oral levodopa, suggesting the importance of continuous dopaminergic stimulation during swallowing. Rasagiline is a monoamine oxidase B (MAOB) inhibitor that facilitates continuous dopaminergic stimulation. We hypothesized that MAOB inhibition by rasagiline would be effective in improving swallowing function in patients with early- and mid-to late-stage Parkinson's disease. To this end, we performed an analytical observational study to determine the effects of rasagiline (1 mg/day) on swallowing function using videofluoroscopic swallowing study. This open-label, evaluator-blinded study enrolled 32 patients with Parkinson's disease, among whom 19 were drug-naïve and 13 were receiving add-on therapy. Our results showed that rasagiline significantly improved all swallowing measures during the oral and pharyngeal phases, including oral transit time and pharyngeal transit time, in all enrolled patients. Similar results were found in drug-naïve and mid-to late-stage patients, with no intergroup differences. In conclusion, drugs capable of continuous dopaminergic stimulation may effectively improve swallowing function in patients with Parkinson's disease, with similar effects in early- and mid-to late-stage Parkinson's disease. This study has been the first to show that rasagiline significantly improves swallowing function in mid-to late-stage patients receiving add-on therapy.

Development of a New Class of Monoamine Oxidase-B Inhibitors by Fine-Tuning the Halogens on the Acylhydrazones.

A total of 14 acyl hydrazine derivatives (ACH1-ACH14) were developed and examined for their ability to block monoamine oxidase (MAO). Thirteen analogues showed stronger inhibition potency against MAO-B than MAO-A. With a half-maximum inhibitory concentration of 0.14 μM, ACH10 demonstrated the strongest inhibitory activity against MAO-B, followed by ACH14, ACH13, ACH8, and ACH3 (IC50 = 0.15, 0.18, 0.20, and 0.22 μM, respectively). Structure-activity relationships suggested that the inhibition effect on MAO-B resulted from the combination of halogen substituents of the A- and/or B-rings. This series concluded that when -F was substituted to the B-ring, MAO-B inhibitory activities were high, except for ACH6. In the inhibition kinetics study, the compounds ACH10 and ACH14 were identified as competitive inhibitors, with Ki values of 0.097 ± 0.0021 and 0.10 ± 0.038 μM, respectively. In a reversibility experiment using the dialysis methods, ACH10 and ACH14 showed effective recoveries of MAO-B inhibition as much as lazabemide, a reversible reference. These experiments proposed that ACH10 and ACH14 were efficient, reversible competitive MAO-B inhibitors. In addition, the lead molecules showed good blood-brain barrier permeation with the PAMPA method. The molecular docking and molecular dynamics simulation study confirmed that the hit compound ACH10 can form a stable protein-ligand complex by forming a hydrogen bond with the NH atom in the hydrazide group of the compound.

Management of OFF condition in Parkinson disease.

Parkinson disease (PD) impacts nearly 1 million individuals in the United States. Nearly every patient with PD will require therapy with dopamine in the form of levodopa as the disease progresses. In more advanced stages of the disease, patients will experience motor fluctuations and require adjustment to their medication regimens to maintain good control of their symptoms. During the last 10 years, several new therapeutic treatment options have come to the market to treat motor fluctuations and improve patient quality of life. Some of these agents represent additional options to previously available drug classes, such as the catechol-O-methyl transferase (COMT) inhibitor, opicapone, and monoamine-oxidase B-inhibitor (MAO-B inhibitor), safinamide, as well as new dosage forms for available therapeutics. One new agent, istradefylline, has a novel mechanism in the treatment of PD. The place in therapy for these newer therapeutic options will be explored through a series of patient cases. This article focuses on evidence-based recommendations for the use of these newer options in the management of patients experiencing OFF episodes.

Efficacy and Safety of MAO-B Inhibitors Safinamide and Zonisamide in Parkinson's Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

In Parkinson's disease, safinamide and zonisamide are novel monoamine oxidase-B inhibitors with a dual mechanism of action involving the inhibition of sodium and calcium channels and the subsequent release of glutamate. The aim of this systematic review and meta-analysis was to examine the efficacy and safety of both drugs compared with placebo on motor symptoms, cognitive function, and quality of life in patients with Parkinson's disease. We searched MEDLINE, EMBASE, Cochrane Central, Scopus, PsycINFO, and trials registries up to March 2023 for randomized controlled trials of adults with Parkinson's disease administered either safinamide or zonisamide and published in English. We excluded single-arm trials or if neither the efficacy nor safety outcomes of interest were reported. Primary outcomes were the change from baseline in Unified Parkinson's Disease Rating Scale section III (UPDRS-III) and serious adverse events. Secondary outcomes included a change from baseline in OFF-time, Parkinson's Disease Questionnaire 39 to evaluate quality of life, and Mini-Mental State Examination for cognitive function assessment. The meta-analysis was conducted using Review Manager 5.4.1. Random-effect models were used to calculate the pooled mean differences (MDs) and risk ratios with 95% confidence intervals (CIs). Subgroup analyses by medication, doses, Parkinson's disease stage, and risk of bias were conducted. We assessed the risk of bias using the Cochrane's risk of bias tool. Sensitivity analysis was conducted, and publication bias were evaluated. This meta-analysis was not externally funded, and the protocol is available on the Open Science Framework Registration ( https://doi.org/10.17605/OSF.IO/AMNP5 ). Of 3570 screened citations, 16 trials met inclusion criteria (4314 patients with Parkinson's disease). Ten safinamide trials were conducted in several countries. Six zonisamide trials were included, five of which were conducted in Japan and one in India. UPDRS Part III scores were significantly lower with both monoamine oxidase-B inhibitors than with placebo (MD = - 2.18; 95% CI - 2.88 to - 1.49; I 2 =63%; n = 14 studies). A subgroup analysis showed a significant improvement in UPDRS-III in safinamide (MD = - 2.10; 95% CI - 3.09 to - 1.11; I2 = 71%; n = 8 studies) and zonisamide (MD = - 2.31; 95% CI - 3.35 to - 1.27; I2 = 52%; n = 6 studies) compared with placebo. Monoamine oxidase-B inhibitors significantly decreased OFF-time compared with placebo. No significant differences in cognitive function (Mini-Mental State Examination), whereas an improvement in quality of life (Parkinson's Disease Questionnaire 39 scores) was observed. There was no significant difference in incidence rates of serious adverse events among all examined doses of zonisamide and safinamide compared with placebo. Two trials were reported as a high risk of bias and sensitivity analyses confirmed the primary analysis results. Evidence suggests that novel monoamine oxidase-B inhibitors not only improve motor symptoms but also enhance patients' quality of life. The meta-analysis showed that both medications have a similar safety profile to placebo with regard to serious adverse events. The overall findings emphasize the effectiveness of safinamide and zonisamide in the treatment of Parkinson's disease as adjunct therapy. Further long-term studies examining the impact of these medications on motor and non-motor symptoms are necessary.