Acetylcholinesterase Inhibitors Research Articles

The impact of CYP2D6 on donepezil concentration and its lack of effect on the treatment response and adverse effect in Korean patients with Alzheimer's disease.

Donepezil, an acetylcholinesterase inhibitor, is widely used for managing the symptoms of Alzheimer's disease (AD), yet its clinical response varies widely among individuals. This study aims to investigate the influence of CYP2D6 genetic variants on donepezil concentration, treatment response, and adverse effects in Korean patients with AD dementia. We conducted a longitudinal study involving 76 patients receiving either 5 mg or 10 mg of donepezil. Genetic testing identified 9 CYP2D6 alleles, categorizing patients by metabolizing abilities. Blood sampling for plasma concentrations of donepezil were performed at steady-state. Mini-Mental State Examination (MMSE) were conducted at 12, 24 and 36 months after the initiation of treatment. Adverse events were collected throughout the study period. Donepezil plasma concentrations differed significantly among metabolizer statuses (mean 56.8 ± 27.1 ng/ml in normal metabolizers vs. 69.6 ± 30.1 ng/ml in intermediate metabolizers, p = 0.042), but these differences did not affect cognitive function over three years as assessed by MMSE. Additionally, there was no significant correlation between donepezil plasma concentration and adverse events. Our study is the first to elucidate the associations between CYP2D6 genotype and the concentration, clinical response or adverse events of donepezil in Korean patients with AD dementia. Larger studies are necessary to fully understand the impact of CYP2D6 genetic variants on therapeutic outcomes with donepezil.

Demographics, comorbidities, and comedications in newly diagnosed patients with Alzheimer's disease and related dementias: Findings from United States Medicare claims data.

Medicare claims data enables broad characterization of United States (US) patients with Alzheimer's disease and related dementias (ADRD). Resulting insights can be used as a reference to describe this population and as a benchmark for generalizability of patients with ADRD enrolled in clinical trials. To characterize demographics, comorbidities, comedications, and healthcare resource utilization in US patients with newly diagnosed ADRD, focusing on differences across Medicare fee-for-service (FFS) and Medicare Advantage enrollees. This observational cohort study used complete (100%) Medicare claims data inclusive of both FFS and Medicare Advantage insurance types. Study patients were ≥65-years-old with ≥12 months of continuous pre-index enrollment and Medicare Part D coverage. Two cohorts of patients were selected in calendar year 2019; those newly diagnosed with ADRD and those with a new acetylcholinesterase inhibitor (AChEI) claim. The newly diagnosed ADRD and new AChEI users cohorts included 861,727 and 395,319 patients, respectively. Demographics and comedications were generally similar across the two cohorts, supporting internal validity of the study results. Circulatory system-related comorbidities and mood disorders were common in both cohorts. Differences in race, inpatient claims and long-term care claims were observed between insurance types. The study results provide a reference for describing the ADRD population in the US and emphasize the importance of evaluating new Alzheimer's disease drugs in broad patient populations with comorbidities and concomitant medication use.

Design, Creation, and Biological Screening of Newer Coumarin-Coupled Heterocyclic Hybrids as Acetylcholinesterase Inhibitors that may be Useful in the Treatment of Alzheimer’s Disease

Design, Creation, and Biological Screening of Newer Coumarin-Coupled Heterocyclic Hybrids as Acetylcholinesterase Inhibitors that may be Useful in the Treatment of Alzheimer’s Disease

The phospho-tau cascade, basal forebrain neurodegeneration, and dementia in Alzheimer's disease: Anti-neurodegenerative benefits of acetylcholinesterase inhibitors.

A conundrum in Alzheimer's disease (AD) is why the long-term use of acetylcholinesterase (AChE) inhibitors, intended for treatment of dementia, results in slowing neurodegeneration in the cholinergic basal forebrain, hippocampus, and cortex. The phospho-tau cascade hypothesis presented here attempts to answer that question by unifying three hallmark features of AD into a specific sequence of events. It is proposed that the hyperphosphorylation of tau protein leads to the AD-associated deficit of nerve growth factor (NGF), then to atrophy of the cholinergic basal forebrain and dementia. Because the release of pro-nerve growth factor (pro-NGF) is activity-dependent and is controlled by basal forebrain projections to the hippocampus and cortex, our hypothesis is that AChE inhibitors act by increasing acetylcholine-dependent pro-NGF release and, thus, augmenting the availability of mature NGF and improving basal forebrain survival. If correct, improved central nervous system-selective AChE inhibitor therapy started prophylactically, before AD-associated basal forebrain atrophy and cognitive impairment onset, has the potential to delay not only the onset of dementia but also its rate of advancement. The phospho-tau hypothesis thus suggests that preventing hyperphosphorylation of tau protein, early should be a high priority as a strategy to help reduce dementia and its associated widespread social and economic suffering.

The decline in the clinical relevance of pilocarpine and physostigmine monitored in pharmacology textbooks from 1878 to 2023: nine take-home messages for future (pharmacology) textbook authors.

In a recent study, using hydrogen cyanide as paradigm, we have shown that pharmacological knowledge evolves non-linearly ( https://pubmed.ncbi.nlm.nih.gov/38900251/ ). The aim of this study was to investigate the changes in the presentation of the drugs pilocarpine and physostigmine in textbooks from 1878 to 2023. The categories of structure, molecular mechanism of action, pharmacokinetics, effects, indications, adverse drug reactions, interactions, and contraindications were evaluated. The pharmacological knowledge on the molecular mechanism, chemical structure, and pharmacokinetics of pilocarpine and physostigmine changed the most during the period of 150 years. Until 1944, textbooks did not mention a molecular mechanism of action of pilocarpine and from 1951 onwards they described the activation of muscarinic acetylcholine receptors as the molecular basis of pilocarpine's effect. Until 1944, most textbooks on physostigmine also did not mention the molecular mechanism of action. From 1951 onwards, the reversible inhibition of acetylcholinesterase is mentioned as the mechanism of action of physostigmine. In contrast, in the categories effects, indications, adverse drug reactions, interactions, and contraindications, the detected changes in the pharmacological knowledge presented were comparatively smaller. Older pharmacology textbooks were better than newer ones at discussing changes in knowledge and scientific errors. We noted substantial differences in the presentation of pilocarpine and physostigmine among German and US pharmacology textbooks. We show a decline of the clinical relevance of both drugs and their presentation in pharmacological textbooks with physostigmine being virtually irrelevant. But modern textbooks still discuss physostigmine substantially, fitting to studies on the obsolete drug reserpine ( https://pubmed.ncbi.nlm.nih.gov/38103060/ ). Thus, textbooks often far lag clinical practice. Google Scholar conveys the incorrect impression that physostigmine is clinically more relevant than it is. An exponential decline in prescription numbers is a robust indicator of clinical obsolescence. From our study, we extract nine easily implementable take-home messages for future (pharmacology) textbook authors to ensure that this traditional teaching format will prevail against the competition of allegedly more "modern" teaching media.

Combinatorial Pattern Response of Bioelectronic Nose for the Detection of Real Nerve Agents.

Nerve agents are toxic organophosphorus chemicals and acetylcholinesterase inhibitors that have been used in terrorist acts. Because they exhibit fatal toxic effects in small amounts, technology is required to detect and identify them early. Research for nerve agent detection using structural simulants of real agents may not function properly for real agents depending on the selectivity of the sensor. For practical sensor applications, experiments were conducted using two toxic nerve agents, sarin and VX, which are used in terrorism and attacks. Herein, human olfactory receptors (ORs) were used as sensing materials with high selectivity and sensitivity to target substances. Through molecular dynamic simulations, the interaction results between ORs and target materials were compared, and an OR combination that could distinguish structurally similar target materials was selected. Four types of OR were combined with a graphene/MoS2-based n-type field-effect transistor platform to create a bioelectronic nose that showed remarkable sensitivity and a stable basal current to convert the biological signals of the OR with target substances into electrical signals. This study developed a nerve agent detection technology using multiple OR sensing signals, advocating combinatorial pattern recognition, which is the core of the human olfactory mechanism. The bioelectronic nose effectively distinguishes structurally similar nerve agents using pattern signals.

Targeting the cholinergic anti-inflammatory pathway for type 2 diabetes prevention: A retrospective cohort study.

Chronic inflammation is a key factor in type 2 diabetes mellitus (T2DM) development. The cholinergic anti-inflammatory pathway (CAP) reduces inflammation by activating α7 nicotinic acetylcholine receptors (α7nAChRs) on macrophages, suppressing proinflammatory cytokines. Acetylcholinesterase inhibitors (AChEis), primarily used for Alzheimer's disease (AD), may exert anti-inflammatory effects through the CAP. One AChEi, galantamine, also directly agonizes α7nAChRs, potentially enhancing its anti-inflammatory properties. This study aimed to investigate the association between AChEi use, particularly galantamine, and T2DM risk in AD patients. We conducted a retrospective analysis of Veterans Health Administration (VA) data, examining early- and late-onset AD patients receiving galantamine or other AD medications. Propensity score matching was used to balance groups and minimize confounding. Cox proportional hazard models assessed T2DM risk for galantamine, other AChEis and memantine. A total of 40 065 AD patients were included in the study. Among early-onset AD patients, galantamine use significantly reduced T2DM risk (hazard ratio [HR] = 0.80, 95% confidence interval [CI]: 0.66-0.98). Memantine also showed a protective effect (HR = 0.82, 95% CI: 0.69-1) in this group. Neither galantamine nor memantine influenced T2DM risk in late-onset AD. Other AD medications showed no association with T2DM risk. Galantamine use was associated with a lower risk of T2DM in early-onset AD patients, potentially due to enhanced anti-inflammatory effects through both AChE inhibition and direct α7nAChR agonism. Memantine also demonstrated a protective effect. These findings suggest potential new applications for existing AD medications in T2DM prevention, particularly in early-onset AD patients. Further research, including randomized controlled trials with diverse populations, is needed to confirm these results and the underlying mechanisms.

Assessing the effects of cadmium on antioxidant enzymes and histological structures in rainbow trout liver and kidney

Cadmium contamination in aquatic environments poses severe risks to aquatic organisms, particularly fish, where cadmium accumulation in tissues can lead to compromised organ functionality and reproductive issues. The present study aimed to assess the effects of cadmium (Cd) exposure on key biomarkers of oxidative stress, DNA damage, apoptosis, and enzyme activity in the liver and kidney tissues of rainbow trout (Oncorhynchus mykiss). Specifically, the study measured 8-hydroxy-2-deoxyguanosine (8-OHdG) levels, caspase-3 activation, acetylcholinesterase (AChE) activity, and oxidative stress indicators (ONOO−, MDA, GSH, SOD, and CAT) following exposure to three Cd concentrations (1, 3, and 5 mg/L) over three time points (24, 48, and 96 h). Tissue samples were collected post-exposure, and the analysis revealed a significant decrease in MDA levels in both tissues. GSH concentrations declined with prolonged exposure, while SOD activity increased, indicating a response to oxidative stress, contrasted by a reduction in CAT activity. An initial increase in ONOO− levels was observed at 24 h, followed by a subsequent decrease at the 48 and 96 h marks. These results suggest that cadmium induces oxidative stress in the liver and kidney tissues of fish. Cadmium exposure also significantly elevated 8-OHdG levels, signaling DNA damage, and increased caspase-3 activity, indicative of apoptosis, across all doses and time points (p < 0.05). The histological examination of liver and kidney showed tissue injury. Additionally, a negative correlation between AChE activity and exposure duration was noted, with prolonged exposure resulting in substantial AChE inhibition. Given the role of AChE in behavior regulation, these findings underscore the importance of exploring time-dependent, tissue-specific changes in AChE activity to further elucidate the mechanisms underlying cadmium-induced behavioral abnormalities.

Design, synthesis and evaluation of benzothiazole-derived phenyl thioacetamides as dual inhibitors of monoamine oxidases and cholinesterases.

A series of rationally designed benzothiazole-derived thioacetamides was synthesized and investigated for monoamine oxidases (MAO-A and MAO-B) and cholinesterases (AChE and BChE) inhibition properties. The tested compounds 18-31 inhibited MAO-A and MAO-B in the micromolar to nanomolar range and AChE in the submicromolar range. Compound 28 was identified as the most potent MAO-A inhibitor with an IC50 = 0.030 ± 0.008 µM, whereas compound 30 showed the highest potency towards MAO-B and AChE with IC50 values of 0.015 ± 0.007 µM and 0.114 ± 0.003 µM, respectively. Further, compound 30 inhibited BChE at an IC50 value of 4.125 ± 0.143 µM. Among all screened molecules, compound 30 emerged as the lead dual MAO-B and AChE inhibitor that blocked these enzymes in a competitive-reversible and mixed-reversible mode, respectively. Selected compounds have displayed iron-chelation and antioxidant properties. Further, computational assessment of ligand binding affinity and pharmacokinetic parameters of all new compounds and molecular dynamic simulation of compound 30 with MAO-B and AChE were carried out to understand ligand efficiency, pharmacokinetic, and virtual molecular interaction profile, respectively. The in silico ADMET prediction studies revealed a few undesired pharmacokinetic attributes of our compounds. The attempted virtual lead-based library synthesis and subsequent biological investigation produced a new benzothiazole-bearing dual MAO-B and AChE inhibitor as a prospective MTDL candidate for treating neurological disorders.

Dammarane-Type Saponins from the Leaves of Vietnamese Ginseng (Panax vietnamensis Ha & Grushv.) and Their Acetylcholinesterase Inhibition In Vitro and In Silico.

Vietnamese ginseng (Panax vietnamensis Ha & Grushv.) represents one of the famous Panax spp. for valuable applications in both traditional and modern medicine; in which, its rhizome part has mainly been used as the medicinal materials based on the bioactive ginsenosides such as ginsenoside Rb1, ginsenoside Rg1, ginsenoside Rd, and majonoside R2. In modern medicine, the development of medicinal materials and utilization of medicinal plants are crucially based on standard bioactive ingredients, so this study to evaluate the leaves of Vietnamese ginseng as source of bioactive ginsenoside led to the identification of seven ginsenosides (1-7). Of them, ginsenoside Rd (2) and pseudoginsenoside RS1 (5) showed inhibitory effects on acetylcholinesterase in vitro with the IC50 values of 47.13 and 79.58 μM and supported by molecular docking analysis, in which ginsenoside Rd (2) and pseudoginsenoside RS1 (5) could play as allosteric inhibitors with high binding affinity (-8.5 and -9.4 kcal/mol) as evidenced by hydrogen bonding and hydrophobic interactions. The findings provided the scientific evidence for using the leaves of Vietnamese ginseng as an alternative source to the roots to enhance memory in traditional medicine as well as for further research on the anti-dementia effects of 2 and 5.

Enzyme Inhibitory Activities and RP-HPLC Analysis of Geranium and Erodium Species.

The genera Geranium and Erodium (Geraniaceae) have been documented to possess diverse ethnopharmacological uses, including diabetes mellitus. Relevant to their ethnopharmacological use, the current study aimed to evaluate the α-glucosidase, α-amylase, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) enzyme inhibitory activity of ethanol extracts from 46 samples belonging to thirty-one species of Geranium (20) and Erodium (11) collected throughout Türkiye. The majority of the extracts displayed a marked α-glucosidase and α-amylase inhibitory activity. Besides, 23 extracts out of 46 exhibited a concentration-dependent inhibitory effect over 50 % towards AChE. The highest AChE inhibition was found in G. subcaulescens collected from Konya with an IC50 value of 4.73±2.96 μg/mL. E. somanum, E. leucanthum, and E. sipthorpianum exhibited the most potent α-glucosidase inhibitory activity, while E. birandianum and E. pelargoniiflorum were the most active extracts against AChE and BChE, respectively. Three extracts that had inhibitory activity over 50 % against four of the enzymes were selected and proceeded to RP-HPLC analysis. Geraniin and ellagic acid were identified as major compounds in the active extracts. Most species screened in the current study were examined for the first time against α-glucosidase, α-amylase, AChE, and BChE.

Alzheimer's Disease : Current Landscape and Future Directions

Introduction: Alzheimer's disease (AD) is the most prevalent form of dementia, constituting up to 72% of cases, and poses a significant financial burden on global healthcare. The aging population is expected to triple the cost of dementia to over $600 billion in the US alone by 2050. Dementia, a major cause of dependency and dysfunction, accounted for 11.4% of all reported deaths in Britain and Wales in 2022. Recent studies suggest a potential decline in dementia incidence, especially in males in Occident countries, possibly linked to better management of vascular risk. While 89% of dementia costs are attributed to high-income countries, middle and low-income nations face significant challenges in addressing the epidemiology of dementia. The prevalence of AD in developing nations is estimated at 3.4%, varying widely. Women exhibit a 1.17 times higher age-specific global prevalence compared to men, and their age-normalized death rate is also higher, suggesting factors beyond life expectancy contribute to their vulnerability. AD primarily affects individuals aged 75 or older, with 80% of cases in this age group. Acetylcholinesterase inhibitors are commonly used in all stages of dementia, though their efficacy in mild cognitive impairment and prodromal AD is uncertain. Distinguishing AD from depression symptoms can be challenging. The pathological features of AD involve neurofibrillary tangles (NFTs) and senile plaques, leading to neural and synaptic loss. Multiple mechanisms contribute to AD pathogenesis, including amyloid/tau toxicity and oxidative stress. Diagnosis : traditionally relies on clinical criteria, but biomarkers like CSF Aβ and tau proteins, as well as blood-based biomarkers, have shown promise in early detection. Noveltrearment: Promising treatment options include anti-amyloid monoclonal antibodies like aducanumab, lecanemab, and gantenerumab, with varying degrees of success in clinical trials. Donanemab, targeting a specific type of Aβ, has shown significant slowing of mental degradation in early-stage patients.

Distinct septo-hippocampal cholinergic projections separately mediate stress-induced emotional and cognitive deficits.

Patients suffering from chronic stress develop numerous symptoms, including emotional and cognitive deficits. The precise circuit mechanisms underlying different symptoms remain poorly understood. We identified two distinct basal forebrain cholinergic subpopulations in mice projecting to the dorsal hippocampus (dHPC) or ventral hippocampus (vHPC), which exhibited distinct input organizations, electrophysiological characteristics, transcriptomics, and responses to positive and negative valences of stimuli and were critical for cognitive and emotional modulation, respectively. Moreover, chronic stress induced elevated anxiety levels and cognitive deficits in mice, accompanied by enhanced vHPC but suppressed dHPC cholinergic projections. Chemogenetic activation of dHPC or inhibition of vHPC cholinergic projections alleviated stress-induced aberrant behaviors. Furthermore, we identified that the acetylcholinesterase inhibitor donepezil combined with blockade of muscarinic receptor 1-type muscarinic acetylcholine receptors in the vHPC rescued both stress-induced phenotypes. These data illuminated distinct septo-hippocampal cholinergic circuits mediated specific symptoms independently under stress, which may provide promising strategies for circuit-based treating of stress-related psychiatric disorders.

Exposure to organophosphate insecticides induces behavioral changes and acetylcholinesterase inhibition in Apis mellifera

European honey bee (Apis mellifera L.) is an essential pollinator that contributes significantly to the global ecosystem and agricultural productivity. However, their population has been facing unprecedented threats, primarily due to their exposure to various pesticides, including organophosphates. These pesticides are being widely used in agriculture to control insect pests due to their efficacy, but their non-selective nature raises concerns about their impact on honey bees. Insecticides viz., chlorpyriphos 20 Emulsifiable Concentrate, dimethoate 30 Emulsifiable Concentrate, and profenophos 50 Emulsifiable Concentrate at a range of 0.005–0.09 per cent concentration were evaluated through two modes of application viz., topical and oral. Acetylcholinesterase (AChE) activity was measured at various intervals (1 and 24 hours) to assess enzyme inhibition. Behavioral observations and statistical analyses, including factor analysis with Eigen values, were employed to evaluate the impact of exposure on bee behavior and physiological responses.The results revealed two factors with Eigen value > 0.95 in both topical as well as oral method which accounted for 88.28 and 88.80 per cent of the variation in behaviour, respectively. Insecticides applied to honey bee A. mellifera in both topical as well as oral methods resulted in significant inhibition of the Acetyl choline esterase enzyme (AChE) activity. Studies revealed higher AChE inhibition (%) in oral method as compared to topical method. AChE inhibition percentage increased from 25.15 (1 Hour after treatment) to 58.25 (24 Hours after treatment) with lower concentration (0.005) of chlorpyriphos in topical method while as it reached from 27.66 to 60.94 with same concentration and same time in oral method of application. AChE inhibition percentage increased from 35.81 (1 Hour after treatment) to 78.30 (24 Hours after treatment) with higher concentration (0.06) of chlorpyriphos in topical method while as it reached from 40.35 to 80.18 with same concentration and same time in oral method. Similar trend was observed in dimethoate, and profenophos where AChE inhibition increased from 17.30, 27.15 (1 Hour after treatment) to 57.18, 61.81 (24 Hours after treatment), respectively in topical method and 20.67, 28.80 (1 Hour after treatment) to 59.85 64.04 (24 Hours after treatment), respectively in oral method. Similarly, with higher concentrations of dimethoate (0.07), and profenophos (0.09), per cent inhibition increased from 34.54, 38.60 (1 Hour after treatment) to 75.68, 79.62 (24 Hours after treatment), in topical method and 37.25, 41.23 (1 Hours after treatment) to 77.86, 82.73 (24 Hours after treatment), in oral method, respectively. Thorough risk assessments are vital for evaluating the effects of agrochemicals on Apis mellifera. The findings highlight the necessity for updated pesticide regulations and broadened conservation strategies that take into account the diverse ways pollinators are exposed to agrochemicals in the environment. The study assessed the impact of different insecticides on Apis mellifera by comparing topical and oral exposure methods. The study also aimed to analyze the behavioral effects of insecticide exposure on Apis mellifera, assessing variations in response and enzyme inhibition.The research focused on evaluating Acetylcholinesterase (AChE) inhibition to better understand the risks posed to honeybees in agricultural environments.

Identification of Cannabidiolic and Cannabigerolic Acids as MTDL AChE, BuChE, and BACE-1 Inhibitors Against Alzheimer's Disease by In Silico, InVitro, and InVivo Studies.

Cannabidiolic (CBDA) and cannabigerolic (CBGA) acids are naturally occurring compounds from Cannabis sativa plant, previously identified by us as dual PPARα/γ agonists. Since the development of multitarget-directed ligands (MTDL) represents a valuable strategy to alleviate and slow down the progression of multifactorial diseases, we evaluated the potential ability of CBDA and CBGA to also inhibit enzymes involved in the modulation of the cholinergic tone and/or β-amyloid production. A multidisciplinary approach based on computational and biochemical studies was pursued on selected enzymes, followed by behavioral and electrophysiological experiments in an AD mouse model. The β-arrestin assay on GPR109A and qPCR on TRPM7 were also carried out. CBDA and CBGA are effective on both acetyl- and butyryl-cholinesterases (AChE/BuChE), as well as on β-secretase-1 (BACE-1) enzymes in a low micromolar range, and they also prevent aggregation of β-amyloid fibrils. Computational studies provided a rationale for the competitive (AChE) vs. noncompetitive (BuChE) inhibitory profile of the two ligands. The repeated treatment with CBDA and CBGA (10 mg/kg, i.p.) improved the cognitive deficit induced by the β-amyloid peptide. A recovery of the long-term potentiation in the hippocampus was observed, where the treatment with CBGA and CBDA also restored the physiological expression level of TRPM7, a receptor channel involved in neurodegenerative diseases. We also showed that these compounds do not stimulate GPR109A in β-arrestin assay. Collectively, these data broaden the pharmacological profile of CBDA and CBGA and suggest their potential use as novel anti-AD MTDLs.

In Silico and In Vitro Evaluation of Quinoline Derivatives as Potential Inhibitors of AChE, BACE1, and GSK3β for Neurodegenerative Diseases Treatment.

Neurodegenerative diseases are characterized by the structural and functional loss of neurons, affecting populations worldwide. Enzymes like acetylcholinesterase (AChE), beta-site APP cleaving enzyme-1 (BACE1), and glycogen synthase kinase 3-beta (GSK3β), contribute to their development. This study explores in silico and in vitro assays of quinoline analogues as potential inhibitors of these enzymes. In silico analyses highlighted derivative SQ6 as the most potent inhibitor for all proteins. In vitro assays confirmed that the quinoline derivatives had a modulating action on the three targets. SQ6 showed a significant AChE inhibition of 94.6%. Regarding the inhibition of GSK3β and BACE1, derivatives SQ6-SQ9, with the quinoline linked to the sulfonamide nitrogen, showed inhibition values above 40%. SQ7 and SQ9 were not considered cytotoxic for cell proliferation in human glioblastoma, and SQ6 did not show cytotoxicity at 7.8 and 3.9 µg mL-1. In murine fibroblasts, SQ6 presented a result similar to that observed for cell proliferation in human glioblastoma, while SQ7 and SQ9 were non-cytotoxic below 62.5 µg mL-1. These findings underscore compound SQ6 as the first potential multitarget enzyme inhibitor for treating neurodegenerative diseases.

Inhibitory Potency of Chlorogenic Acid from Apple Cider Vinegar Against Alzheimer’s Disease: Molecular Docking and Dynamics Validation

Objective The primary cause of memory loss is Alzheimer’s disease (AD). Recent studies have shown that natural compounds like apple cider vinegar (ACV) have anti-Alzheimer’s capabilities. Essential components of ACV, such as gallic acid and chlorogenic acid, may be in charge of the drug’s pharmacological effects. Methods Using molecular docking and dynamics (MD), the current work looks at the aspect of ACV that protects against AD. To study the conformational relationships and interaction mechanisms between two biological molecules (such as interactions between proteins and drugs or between proteins), MD simulation is frequently used. MD can help understand molecular structural differences between proteins and small compounds. We used acetylcholinesterase (AChE, PDB ID: 1UT6) to MD chlorogenic and gallic acids, as well as the currently prescribed medication rivastigmine (Standard medication). Furthermore, we determine the binding affinity, which may be responsible for AChE inhibition. MD simulations were performed on docked complexes of chlorogenic acid, gallic acid, and rivastigmine with receptor 1UT6 for a 300 ns trajectory to ensure the stability of docked ligand-protein complexes. Results The results showed that chlorogenic acid has the highest binding affinity and stability for AChE inhibition. In the docking and dynamics analysis, both techniques have predicted chlorogenic acid to be a potential constituent of ACV which shows a similar activity when compared to rivastigmine by virtue of binding affinity. Conclusion These findings identify chlorogenic acid as the key component of ACV that protects against AD-related cognitive and behavioral impairments. This finding will be critical in the development of ACV-based drugs for Alzheimer’s disease treatment.

Non-adherence to antidementia medications and associated factors: a study of Spanish population-based registry data

IntroductionWith an increasing prevalence, dementia is one of the most disabling diseases among the elderly. Impaired cognitive function and behavioral and psychological symptoms predispose patients to medication non-adherence, resulting in increased morbidity, mortality, and healthcare costs. The aim of this study was to estimate the prevalence of non-adherence to antidementia medications and to identify the main predictors.MethodsA population-based registry study was conducted in 2022 in Castile and Leon, Spain. A total of 17,563 patients with dementia were included. The medication possession ratio (MPR) was used as an indirect method to measure adherence. The cut-off point for determining that a patient was nonadherent was 80% of MPR. Multivariate logistic regression was used to identify predictors of nonadherence based on sociodemographic and health-related variables.ResultsIn 2022, 6.2% of the population over 80 years old used antidementia medications. Of these patients, 70% were women, 28.15% were institutionalized, and over 90% were polymedicated and had multiple prescribers. The most used medicines were donepezil (43.49%), rivastigmine (36.84%), and memantine (30.7%). The combined use of an acetylcholinesterase inhibitor plus memantine was relevant (13.33%). Men were less adherent than women, and the prevalence of non-adherence decreased with age. The medication associated with the highest prevalence of non-adherence was rivastigmine (19%), followed by donepezil (17%) and memantine (13.23%). Institutionalized patients (13%) and patients on combination therapy (13.29%) had the lowest prevalence of non-adherence. Protective factors against non-adherence include institutionalization, polymedication, use of memantine or combination therapy, and comorbid mental illness.ConclusionsIn Castile and Leon, one in six patients were non-adherent to antidementia medications. Younger male patients with cardiometabolic disease are more likely to be non-adherent to antidementia medications. On the other hand, institutionalization is a protective factor against non-adherence, but still 10% of nursing home patients are non-adherent to antidementia medications.

Investigation of Algerian Crataegus monogyna Jacq Phenolic Compounds (Using LC-ESI-MS/MS Analysis, Antioxidant Activity, and Enzyme Inhibition) and Their Potential Implications for Food and Nutraceutical Applications

Investigations into the phenolic constituents of the butanolic fraction of Crataegus monogyna were optimized using LC-ESI-MS/MS analysis, identifying and quantifying at least 23 fingerprint phytochemical compounds. The major phenolic compounds were epicatechin (99.916 ± 2.208 mg/g), isoquercetrin (53.31 ± 1.172 mg/g), chlorogenic acid (47.457 ± 1.010 mg/g), quinic acid (37.819 ± 1.406 mg/g), rutin (29.98 ± 0.740 mg/g), hesperidin (5.296 ± 0.177 mg/g, detected for the first time in the C. monogyna species), astragalin (1.774 ± 0.020 mg/g), and nicotiflorin (1.482 ± 0.016 mg/g). The antioxidant properties of the lyophilized butanolic fraction were evaluated using DPPH, GOR, ABTS, CUPRAC, and reducing power assays, all of which demonstrated that there was strong activity. Additionally, the neuroprotective effect was evaluated in vitro, showing a potent inhibitory effect on acetylcholinesterase (AChE) with an IC50 of 43.65 ± 2.10 µg/mL. The antidiabetic effect was investigated through α-amylase inhibition (IC50 = 91.19 ± 0.10 µg/mL), showing high inhibitory activity. In addition, the butanolic extract exhibited significant urease inhibition with an IC50 of 26.36 ± 0.05 µg/mL. These results suggest that Algerian C. monogyna has potential as a therapeutic agent for managing diabetes complications and as a natural source of AChE inhibitors, making it a promising subject for the treatment of urease-related conditions. Its high concentrations of natural antioxidants, such as epicatechin, isoquercetrin, chlorogenic acid, quinic acid, rutin, hesperidin, and astragalin, make it suitable for integration into medicine, pharmaceuticals, cosmetics, and the food sector.

Synthesis, biological evaluation and in silico study of 4-(benzo[d]thiazole-2-yl) phenols based on 4-hydroxy coumarin as acetylcholinesterase inhibitors

Alzheimer’s disease, characterized by cognitive decline and memory loss, is associated with decreased acetylcholine levels due to acetylcholinesterase (AChE) activity. Compounds containing a coumarin heterocyclic core coupled with thiazole exhibit excellent acetylcholinesterase inhibitory activity. In this work, we designed and synthesized a series of 4-(benzo[d]thiazole-2-yl) phenols based on 4-hydroxycoumarin. The compounds were synthesized and their inhibitory activities were evaluated through in vitro biological assays. Of the compounds investigated, 3i exhibited the strongest inhibitory activity, with an IC50 value of 2.7 µM. Molecular docking and molecular dynamics simulations were employed to elucidate the binding interactions and stability of the synthesized compounds with AChE. The results demonstrated promising inhibitory activity, suggesting potential therapeutic applications for Alzheimer’s disease. This research contributes to the development of coumarin-based heterocyclic compounds as effective AChE inhibitors.