Cholinesterase Inhibitors Research Articles

Disease-Modifying Activity of Huperzine A on Alzheimer’s Disease: Evidence from Preclinical Studies on Rodent Models

(1) Background: Huperzine A, a natural cholinesterase (AChE) inhibitor isolated from the Chinese herb Huperzia Serrata, has been used as a dietary supplement in the United States and a drug in China for therapeutic intervention on Alzheimer's disease (AD). This review aims to determine whether Huperzine A exerts disease-modifying activity through systematic analysis of preclinical studies on rodent AD models. (2) Methods: Sixteen preclinical studies were included based on specific criteria, and the methodological qualities were analyzed by SYRCLE's risk of bias tool. Some outcomes were meta-analyzed: latencies and time spent in quadrant of Morris water maze, soluble amyloid-β (Aβ) level measured by ELISA in the cortex and hippocampus, Aβ plaque numbers measured by immunohistochemistry in hippocampus, choline acetyltransferase (ChAT) activity, and AChE activity. Finally, the mechanisms of Huperzine A on AD models were summarized. (3) Conclusions: The outcomes showed that Huperzine A displayed AChE inhibition, ChAT activity enhancement, memory improvement, and Aβ decreasing activity, indicating the disease-modifying effect of Huperzine A. However, due to the uneven methodological quality, the results need to be rationally viewed, and extensively repeated.

N-Substituted piperidine-3-carbohydrazide-hydrazones against Alzheimer's disease: Synthesis and evaluation of cholinesterase, beta-amyloid inhibitory activity, and antioxidant capacity.

A series of piperidine-3-carbohydrazide-hydrazones bearing phenylethyl, phenylpropyl, and phenylbutyl substituents on piperidine nitrogen were designed and synthesized as cholinesterase (ChE) inhibitors. The title compounds were screened for acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) inhibitory activitiesand antioxidant capacities, and the active ones for Aβ42 self-aggregation inhibition, in vitro. The chemiluminescence method was used to determine the effect of the selected compounds on the reactive oxygen species (ROS) levels in brain tissue. Physicochemical properties were calculated by theMOE program. Kinetic analysis and molecular modeling studies were also carried out for the most active compounds. Generally, the final compounds exhibited moderate to good AChE or BuChE inhibitory activity. Among them, 3g and 3j showed the most potent activity against AChE (IC50 = 4.32 µM) and BuChE (IC50 = 1.27 µM), respectively. The kinetic results showed that both compounds exhibited mixed-type inhibition. Among the selected compounds, nitro derivatives (3g, 4g, and5g) provided better Aβ42 inhibition. According to the chemiluminescence assay, 4i exhibited the most active superoxide free-radical scavenger activity and 3g, 3j, and 4i showed similar scavenger activity on other ROS. All results suggested that 3g, 3j, and 4i have good AChE/BuChE, Aβ42 inhibitory potentials and antioxidant capacities and can therefore be suggested as promising multifunctional agents to combat Alzheimer's disease.

Deafness-Infertility Syndrome and Auditory Hallucinations

Deafness-Infertility Syndrome and Auditory Hallucinations

Multitargeted C9-substituted ester and ether derivatives of berberrubine for Alzheimer's disease: Design, synthesis, biological evaluation, metabolic stability, and pharmacokinetics.

Berberrubine is a naturally occurring isoquinoline alkaloid and a bioactive metabolite of berberine. Berberine exhibits a wide range of pharmacological activities, including cholinesterase inhibition. The cholinesterase inhibitors provide symptomatic treatment for Alzheimer's disease; however, multitarget-directed ligands have the potential as disease-modifying therapeutics. Herein, we prepared a series of C9-substituted berberrubine derivatives intending to discover dual cholinesterase and beta-site amyloid-precursor protein cleaving enzyme 1 (BACE-1) inhibitors. Most synthesized derivatives possessed balanced dual inhibition (AChE and BChE) activity in the submicromolar range and a moderate inhibition against BACE-1. Two most active ester derivatives, 12a and 11d, display inhibition of AChE, BChE, and BACE-1. The 3-methoxybenzoyl ester derivative, 12a, inhibits electric eel acetylcholinesterase (EeAChE), equine serum butyrylcholinesterase (eqBChE), and human hBACE-1 with IC50 values of 0.5, 4.3, and 11.9 μM, respectively and excellent BBB permeability (Pe = 8 × 10-6 cm/s). The ester derivative 12a is metabolically unstable; however, its ether analog 13 is stable in HLM and exhibits inhibition of AChE, BChE, and BACE-1 with IC50 values of 0.44, 3.8, and 17.9 μM, respectively. The ether analog also inhibits self-aggregation of Aβ and crosses BBB (Pe = 7.3 × 10-6 cm/s). Administration of 13 at 5 mg/kg (iv) in Wistar rats showed excellent plasma exposure with AUC0-∞ of 28,834 ng min/ml. In conclusion, the multitargeted berberrubine ether derivative 13 is CNS permeable and has good ADME properties.

Cholinergic drug downregulates annexin A3 in platelets of Alzheimer’s Disease patients

AbstractBackgroundInvestigation of the expression of annexin A3 (ANXA3) platelets of Alzheimer´s Disease patients pre and post three‐month treatment with cholinesterase inhibitors and compared to healthy controls.MethodThe sample consisted of healthy controls (n=24) and AD drug‐naïve patients (n=34), diagnosed according to DSM‐IV and specificized according to NINCDS‐ADRDA diagnostic criteria. After three months of treatment with cholinesterase inhibitors, platelets were extracted from blood samples of the same AD patients (n=34). The Cambridge cognitive test (CAMCOG) was used as a measure of global cognitive performance, however, scores on both tests were not used to establish the patients' diagnosis. The method of Western Blotting sample analysis was performed through primary antibodies against ANXA3 and secondary antibody, anti‐rabbit IgG‐HRP peroxidase. Student's t‐test or Mann‐Whitney, Pearson's Chi‐square tests were used for numerical variables, Kolmogorov‐Smirnov test were used to analyze a normal distribution and Wilcoxon test to longitudinal variables. Spearman’s rank correlation coefficient was performed for association between ANXA3 levels and clinical parameters.ResultThere was no difference in ANXA3 expression between AD patients before treatment and healthy controls (p=0.926). However, after three months with anticholinergic treatment the AD patients present a decrease in ANXA3 expressions (p=0.012).ConclusionANXA3 levels on platelets samples of patients diagnosed with AD decrease before an evident improvement of the clinical manifestation of the disease.

Synthesis andin vitro assessment of anticholinesterase andantioxidant properties of triazineamide derivatives.

Aim: Cholinesterase inhibitors and radical scavengers have been recognized as powerful symptomatic anti-Alzheimer's disease agents. Hence, the present study aimed to develop new triazineamides as potent anticholinesterase and antioxidant agents. Methods: Triazineamide (7a-i) derivatives were synthesized using cyanuric chloride via nucleophilic substitution followed by condensation. Ellman assay, 2,2-azinobis(3-ethylbenzthiazoline-6-sulfonic acid) radical scavenging assay and molecular docking studies with Autodock 4.2.3 program were conducted. Results: Triazineamide 7c was assessed as a potent, selective and mixed-type dual inhibitor of acetylcholinesterase, with and IC50 of 5.306±0.002μM, by binding simultaneously with the catalytic active and peripheral anionic sites of acetylcholinesterase, and it had strong 2,2-azinobis(3-ethylbenzthiazoline-6-sulfonic acid) radical scavenging abilities. Conclusion: These results suggest that triazineamides may be of interest to establish a structural basis for new anti-Alzheimer's disease agents.

Scoping Review of Randomized Trials With Discontinuation of Medicines in Older Adults.

To map the randomized trial evidence describing the feasibility of discontinuing active medications with potential adverse effects in older patients. Scoping review with systematic search of PubMed, Embase, and Cochrane Library. Randomized trials investigating discontinuation of a single medicine or medicine class in patients with mean age ≥65years. We extracted trial characteristics including study design and assessed bias. As proxies for the "feasibility of discontinuation," we extracted the "dropout rate" and "disease recurrence rate." We identified 40 trials investigating discontinuation of symptomatic (n= 26), preventive (n= 6), or both preventive and symptomatic medicines (n= 8) against psychiatric (n= 10), neurologic (n= 9), musculoskeletal (n= 8), cardiovascular (n= 5), respiratory (n= 4), and urologic diseases (n= 4). Five discontinuation designs were used, 75% (30/40) of trials were placebo-controlled, and 48% (19/40) of trials had bias disfavoring discontinuation. The dropout rate was similar between the discontinuation group and the continuation group in 79% of the trials (30/38), whereas disease recurrence was similar in 72% (23/32) of the trials. In 42% (13/31) of trials reporting both dropout rate and disease recurrence rate, the differences between groups were statistically insignificant and less than 10%; these trials investigated discontinuation of cholinesterase inhibitors for Alzheimer's disease in various settings (n= 3), alendronate for osteoporosis (n= 3), glucosamine for osteoarthritis, lithium as adjunct for unipolar depression, statins for cardiovascular disease in patients with limited life expectancy, droxidopa for neurogenic orthostatic hypotension, tamsulosin for lower urinary tract symptoms, sertraline for major depressive episode, and fentanyl patch for low back or osteoarthritis pain. We identified 40 randomized trials using a variety of designs investigating discontinuation of both symptomatic and preventive medicines in older patients. Discontinuation of medicines seems feasible for most of the investigated medicines. This scoping review can guide clinical practice and future trials on deprescribing.

Impact of amyloid PET in the clinical care of US Veterans in a Tertiary Memory Disorders Clinic

AbstractBackgroundPrior studies assessing the clinical impact of amyloid PET have been limited to assessments before and after the scan. We aim to characterize the impact of amyloid PET in a veterans population with cognitive decline by comparing differences in clinical management within two years of follow‐up.MethodsThe current retrospective observational study includes all patients seen for an initial evaluation for cognitive complaints in the Memory Disorders Clinic at the VA Boston Healthcare System from October 2016 to January 2020. Clinical impact outcomes within two years of follow‐up were compared between patients with and without an aPET scan. Poisson regressions, negative binomial regressions, and binomial logistic regression were used for the analysis. Age, cognitive syndrome, follow‐up time, clinical diagnosis after initial evaluation and MoCA scores were used as covariates. Additionally, propensity score matching was performed to balance confounders between the two groups. To further understand the clinical impact outcomes in the aPET group, multiple regressions were performed within the group.ResultsFive‐hundred‐sixty‐five veterans were included in the analysis. Thirty‐five percent of patients underwent aPET imaging in addition to routine diagnostic workup. The study was positive in 72 patients (36.56%). Having an aPET, in addition to the usual diagnostic workup, was associated with a longer follow‐up time, and a higher diagnostic variability at follow‐up. We did not find an association between aPET use and the number of additional diagnostic studies ordered, early cholinesterase inhibitors prescription, or referrals to social work, research and clinical trials. When analyzing the same clinical utility outcomes within the group with an aPET, we found that a positive result was associated with fewer additional diagnostic tests, less diagnostic variability at follow up visits, more cholinesterase inhibitors prescription, and more research referrals.ConclusionsIn medically complex populations, aPET positivity might be lower than prior studies have described, used more to “rule out” than confirm the diagnosis of Alzheimer’s disease. This lower positivity rate results in less robust differences in classically explored clinical impact variables when comparing patients with and without an aPET.

Treatments of Alzheimer’s Disease: A Review

Alzheimer’s Disease (AD) affects about 24 million people worldwide and costs Americans billions of dollars every year.1 With the prevalence of AD, treatments are needed to combat the disease and reduce its effect. In the past, cholinesterase inhibitors were used to treat the symptoms of the disease. In recent years, however, a new type of drug, monoclonal antibody, has been used for the treatment of AD. The purpose of this paper is to review the old and new Alzheimer’s treatment through the lens of affordability and accessibility, and provide insight into the future of the treatment options. In the end, innovative treatments such as vaccines and targeting different mechanisms of action are the next step in Alzheimer’s treatment. Access to these treatments should be more readily available and affordable to low-income families. To support this, the FDA should modify its accelerated approval program to reward rigorous scientific research.

Carrier-free Chinese herbal small molecules self-assembly with 3D-porous crystal framework as a synergistic anti-AD agent

Alzheimer's disease (AD) is a devastating neurodegenerative disease caused by multiple factors. Single-target drugs have limited efficacy for AD treatment. Therefore, multi-target intervention strategy has great potential. Traditional Chinese medicine (TCM) is mostly used in the form of compound prescription, which has the polypharmacology behavior. Rhizoma Coptidis and Radix et Rhizoma Rhei are frequently used as the couplet medicines of TCM for AD therapy. In this study, the novel carrier-free nanoassembly with 3D-porous frame crystal structure has formulated from supramolecular self-assembly of berberine (BER) and rhein (RHE), the main active components of Rhizoma Coptidis and Radix et Rhizoma Rhei, respectively. Combining with the spectral data and single crystal structure, the self-assembly process was clarified as dominated by electrostatic interaction and π-π stacking. In vitro release property, cholinesterase (ChE) inhibition, β-amyloid (Aβ) aggregation regulation, radical elimination, metal ions chelation and cytotoxicity assay indicated that the obtained BER-RHE assembly had the Fickian diffusion-controlled sustained release ability, synergistic biological activities and virtually no neurotoxicity. In addition, in vivo reactive oxygen species (ROS) level evaluation showed that the assembly could reduce the accumulation of intracellular ROS in Caenorhabditis elegans (C. elegans). Meanwhile, BER-RHE assembly could also be used as a novel potential carrier for drug delivery due to its superior 3D-porous frame. This green and facile strategy for carrier-free nanoassembly microscopic construction via supramolecular self-assembly might provide inspiration for the development of multi-target therapy for AD and the design of the novel drug delivery system.

From tryptamine to the discovery of efficient multi-target directed ligands against cholinesterase-associated neurodegenerative disorders.

A novel class of benzyl-free and benzyl-substituted carbamylated tryptamine derivatives (CDTs) was designed and synthesized to serve as effective building blocks for the development of novel multi-target directed ligands (MTDLs) for the treatment of neurological disorders linked to cholinesterase (ChE) activity. The majority of them endowed butyrylcholinesterase (BuChE) with more substantial inhibition potency than acetylcholinesterase (AChE), according to the full study of ChE inhibition. Particularly, hybrids with dibenzyl groups (2b-2f, 2j, 2o, and 2q) showed weak or no neuronal toxicity and hepatotoxicity and single-digit nanomolar inhibitory effects against BuChE. Through molecular docking and kinetic analyses, the potential mechanism of action on BuChE was first investigated. In vitro H2O2-induced HT-22 cells assay demonstrated the favorable neuroprotective potency of 2g, 2h, 2j, 2m, 2o, and 2p. Besides, 2g, 2h, 2j, 2m, 2o, and 2p endowed good antioxidant activities and COX-2 inhibitory effects. This study suggested that this series of hybrids can be applied to treat various ChE-associated neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD), as well as promising building blocks for further structure modification to develop efficient MTDLs.

Discovery of chalcone derivatives as potential α-glucosidase and cholinesterase inhibitors: Effect of hyperglycemia in paving a path to dementia

In the present study, a series of fascinating chalcone derivatives 1C-14C has been designed and synthesized by Claisen-Schmidt condensation. The target compounds were screened for in vitro α-glucosidase and cholinesterase inhibitory activities. For the first time, the enzyme inhibitory activities of the target derivatives were assessed for antihyperglycemic and neuroprotective activities on streptozotocin (STZ) induced diabetic animal models using in vivo mechanism-based assays. Based on α-glucosidase and cholinesterase inhibitory activities, the compounds 2C, 3C, 13C and 14C were chosen in vivo for further evaluation of antidiabetic and neuroprotective activities in STZ-induced diabetic Wistar rats. All these evaluated compounds demonstrated significant antidiabetic and antiamnesic activities and found nontoxic in nature. The target compounds were then tested in vivo for cognitive function in a STZ-induced amnesic animal paradigm, where four compounds 2C, 3C, 13C, and 14C considerably reduced the amnesic effects as measured by the Y-Maze Paradigm and novel object discrimination (NOD) tasks. Furthermore, the structure-activity relationship of these substituted chalcone derivatives was established. According to kinetic studies, 2C and 7C have Ki values of 0.017±0.00078 µM and 0.00060±0.00004 µM, respectively, and were competitive inhibitors of cholinesterase and α-glucosidase. Molecular docking study revealed that the co-crystallized ligand and potent compounds exhibited same binding orientation within the target enzyme's active site (α-glucosidase (PDB ID: 3AJ7), AChE (PDB ID: 1ACL) and BChE (PDB ID: 4TPK)). The QSAR studies were conducted based on anti-glucosidase and anti-cholinesterases (AChE, BChE) assays. The value of coefficient of multiple determinant (R2) 0.9999 depicts a strong relationship between 1C-14C structures and selected properties. Most of these substances are selective inhibitors of cholinesterase that may be used for age-related problems and to treat the progressive neurodegenerative disorder.

Synthesis, in vitroandin silicoBiological Studies of Sulfonamide Chalcones as Esterase Inhibitors

AbstractInhibition profiles of synthesized 4‐methyl benzene sulfonamide derivatives on carbonic anhydrase I (CA I) and II (CA II), acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were investigated in this study. All sulfonamide based compounds showed the inhibition profiles with KIvalues in the range 0.39–2.46 nM for CA I, 4.81–14.43 nM for CA II, 52.10–58.83 nM AChE and 50.78–57.38 nM for BChE, respectively. CA Isoenzymes are essential therapeutic targets and their inhibitors have been used for pharmacological purposes particularly in the remedy of diseases such as glaucoma, edema, cancer, etc. Cholinesterase inhibitors are important compounds that can be used in many diverse therapeutic applications, especially Alzheimer's disease (AD). The 4‐methyl benzene sulfonamides examined here and acetazolamide, the clinically used CA Inhibitor, showed similar results for CA I and II. Similarly, synthesized compounds demonstrated close inhibition ranges with neostigmine, a cholinesterase inhibitor, on AChE and BChE enzymes. These results indicate that these molecules can be used as potential inhibitors for these esterase enzymes. In addition, molecular docking studies were carried out to elucidate the mechanism of the observed activities of the potent compounds.

The effect of combination pretreatment of donepezil and environmental enrichment on memory deficits in amyloid-beta-induced Alzheimer-like rat model

Alzheimer's disease (AD) is progressive neurodegeneration known as the most common cause of dementia, and it is the sixth leading cause of death in older people. Given the promising data on the additive effect of combination therapy with donepezil (Aricept), an acetylcholinesterase inhibitor (AChEI), and regarding the similar neuronal mechanisms through which donepezil (DON) and environmental enrichment (EE) exert their enhancing effects on cognition; we asked whether simultaneous treatment with two paradigms in amyloid-beta-induced AD rats may lead to greater protection against the cognitive impairments than either treatment individually. The experimental groups consisted of Alz, sham-operated, Alz + DON, Alz + EE, and Alz + DON + EE. AD was induced by intrahippocampal injection of amyloid-beta (1–42, 6 μg), and DON was orally administrated (4 mg/kg) for 21 days. Environmental enrichment consisted of housing animals in large cages (50 × 50 × 50 cm) containing a running wheel and differently shaped objects for 21 days. Spatial learning and memory were assessed in the Morris water maze (MWM) and Real-time PCR was performed to assess the expression of brain-derived neurotrophic factor (BDNF) and M1 muscarinic acetylcholine receptor (AchM1R) within the hippocampus. Spatial memory was impaired in Alz animals, and while neither pretreatment with DON nor EE alone could significantly restore spatial memory scores in Alz rats, combination therapy was effective. BDNF expression was suppressed in Alz rats and pretreatment with DON plus EE could increase it to the saline levels. The data suggest that a cholinesterase inhibitor and cognitive stimulation can be used effectively in combination to protect cognitive loss in an AD rat model. This additive protective effect may be in part due to the augmented influence of this combination on BDNF levels and cholinergic neuronal system within the hippocampus.

Anti-Dementia Drug Persistence Following Donepezil Initiation Among Alzheimer's Disease Patients in Japan: LIFE Study.

Donepezil is frequently used to treat Alzheimer's disease (AD) symptoms but is associated with early discontinuation. Determining the persistence rates of anti-dementia drug use after donepezil initiation may inform the development and improvement of treatment strategies, but there is little evidence from Japan. To determine anti-dementia drug persistence following donepezil initiation among AD patients in Japan using insurance claims data. Insurance claims data for AD patients with newly prescribed donepezil were obtained from 17 municipalities between April 2014 and October 2021. Anti-dementia drug persistence was defined as a gap of ≤60 days between the last donepezil prescription and a subsequent prescription of donepezil, another cholinesterase inhibitor, or memantine. Cox proportional hazards models were used to analyze the association between care needs levels and discontinuation. We analyzed 20,474 AD patients (mean age±standard deviation: 82.2±6.3 years, women: 65.7%). The persistence rates were 89.1% at 30 days, 79.4% at 90 days, 72.6% at 180 days, 64.5% at 360 days, and 58.3% at 540 days after initiation. Among the care needs levels, the hazard ratio (95% confidence interval) for discontinuation was 1.01 (0.94-1.07) for patients with support needs, 1.12 (1.06-1.18) for patients with low long-term care needs, and 1.31 (1.21-1.40) for patients with moderate-to-high long-term care needs relative to independent patients. Japanese AD patients demonstrated low anti-dementia drug persistence rates that were similar to those of other countries. Higher long-term care needs were associated with discontinuation. Further measures are needed to improve drug persistence in AD patients.

Benzoxazole based thiazole hybrid analogs: Synthesis, in vitro cholinesterase inhibition, and molecular docking studies

Acetylcholinesterase and butyrylcholinesterase enzymes are therapeutic target for Alzheimer disease and their inhibitors play a vital role for the treatment of this disease. A new series of benzoxazole based 1,3-thiazole hybrid scaffolds (1–20) were synthesized and assessed for acetylcholinesterase and butyrylcholinesterase inhibition profile and then characterized by using different spectroscopic tools such as 1H NMR, 13C NMR and HREI-MS spectroscopy. Four scaffolds such as 1, 4, 12 and 19 showed AChE potency almost comparable to standard drug having IC50 values 0.692 ± 0.087, 0.947 ± 0.089, 0.38 ± 0.016 and 0.742 ± 0.042 µM, while nine scaffolds such as 1, 4, 6, 8, 9, 12, 13, 14 and 19 showed superior BuChE potency than standard drug having IC50 values 2.54 ± 0.10, 1.79 ± 0.20, 3.25 ± 0.18, 2.48 ± 0.05, 1.33 ± 0.05, 2.19 ± 0.08, 2.81 ± 0.20, 2.23 ± 0.10 and 2.10 ± 0.05 µM respectively. Nonetheless, remaining analogs were found to have moderate activity. Among the synthesized series, analogs 12 (IC50 = 0.38 ± 0.016 µM) and 9 (IC50 = 1.33 ± 0.05 µM) were identified as the most potent inhibitors of acetylcholinesterase and butyrylcholinesterase enzymes. In addition, the molecular docking studies were carried out to find out the possible binding mode of interactions of most active analogs with enzymes active site and results supported the experimental data.

Effects of Pharmacological Treatments in Alzheimer's Disease: Permutation Entropy-Based EEG Complexity Study.

Alzheimer's disease (AD) is a neurodegenerative brain disease affecting cognitive and physical functioning. The currently available pharmacological treatments for AD mainly contain cholinesterase inhibitors (AChE-I) and N-methyl-D-aspartic acid (NMDA) receptor antagonists (i.e., memantine). Because brain signals have complex nonlinear dynamics, there has been an increase in interest in researching complexity changes in the time series of brain signals in individuals with AD. In this study, we explore the electroencephalographic (EEG) complexity for making better observation of pharmacological therapy-based treatment effects on AD patients using the permutation entropy (PE) method. We examined EEG sub-band (delta, theta, alpha, beta, and gamma) complexity in de-novo, monotherapy (AChE-I), dual therapy (AChE-I and memantine) receiving AD participants compared with healthy elderly controls. We showed that each frequency band depicts its own complexity profile, which is regionally altered between groups. These alterations were also found to be associated with global cognitive scores. Overall, our findings indicate that entropy measures could be useful to show medication effects in AD.

Cinnamomum verum J. Presl. Bark essential oil: in vitro investigation of anti-cholinesterase, anti-BACE1, and neuroprotective activity

BackgroundCinnamomum verum J. Presl. (Lauraceae), Myrtus communis L. (Myrtaceae), Ruta graveolens L. (Rutaaceae), Anethum graveolens L. (Apiaceae), Myristica fragrans Houtt. (Myristicaceae), and Crocus sativus L. (Iridaceae) have been recommended for improvement of memory via inhalation, in Iranian Traditional Medicine (ITM). In this respect, the essential oils (EOs) from those plants were obtained and evaluated for cholinesterase (ChE) inhibitory activity as ChE inhibitors are the available drugs in the treatment of Alzheimer’s disease (AD).MethodsEOs obtained from the plants under investigation, were evaluated for their potential to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in vitro based on the modified Ellman’s method. The most potent EO was candidate for the investigation of its beta-secretase 1 (BACE1) inhibitory activity and neuroprotectivity.ResultsAmong all EOs, C. verum demonstrated the most potent activity toward AChE and BChE with IC50 values of 453.7 and 184.7 µg/mL, respectively. It also showed 62.64% and 41.79% inhibition against BACE1 at the concentration of 500 and 100 mg/mL, respectively. However, it depicted no neuroprotective potential against β-amyloid (Aβ)-induced neurotoxicity in PC12 cells. Also, identification of chemical composition of C. verum EO was achieved via gas chromatography-mass spectrometry (GC-MS) analysis and the major constituent; (E)-cinnamaldehyde, was detected as 68.23%.ConclusionPotent BChE inhibitory activity of C. verum EO can be considered in the development of cinnamon based dietary supplements for the management of patients with advanced AD.

Promising candidates from drug clinical trials: Implications for clinical treatment of Alzheimer's disease in China.

Alzheimer's disease is the most common neurodegenerative disease. Prior to 2017, National Medical Products Administration approved only four drugs to treat Alzheimer's disease, including three cholinesterase inhibitors and one N-methyl-D-aspartate receptor antagonist. We queried ClinicalTrials.gov to better understand Alzheimer's drug development over the past 5 years and found 16 promising candidates that have entered late-stage trials and analyzed their impact on clinical treatment of Alzheimer's disease in China. The 16 compounds selected include disease-modifying therapies and symptomatic therapies. The research and development pipeline now focuses on disease-modifying therapies such as gantenerumab, aducanumab, ALZ-801, ALZT-OP1, donanemab, lecanemab, simufilam, NE3107, semaglutide, and GV-971, which could put an end to the situation where Alzheimer's patients in China have no effective treatment alternatives. The reuse of drugs or combinations currently under investigation for the psychiatric treatment of Alzheimer's disease, including AXS-05, AVP-786, nabilone, brexpiprazole, methylphenidate, and pimavanserin, could provide physicians with additional treatment options. Although most of these drugs have not been explored in China yet, due to the current development trend in this field in China, it is expected that China will be involved in research on these drugs in the future.

Asiatic Acid Fabricated Nanoconstructs to Mitigate Amyloid Beta1-42 Induced Injury in SH-SY5Y Cells In-Vitro and Ameliorates Cognitive Impairment by Dual Cholinesterase Inhibition and Attenuation of Oxidative Stress In-Vivo.

Asiatic acid (AA) is reported for its neuroprotective potential in Alzheimer's disease (AD). This present work aimed to develop AA loaded nanostructured lipid carriers (AAN) for targeting the delivery of AA into the brain and ameliorating the cognitive deficits in AD rats. AAN was optimized using the Box-Behnken design, considering 3 factors (soya lecithin, tween 80, and high pressure homogenizer (HPH) pressure) as independent variables while particle size (PS), zeta potential (ZP) and entrapment efficiency (EE) were dependent variables. Cytotoxicity assay and internalization studies of AAN were evaluated in SH-SY5Y cells and further neuroprotective efficiency on intracellular amyloid beta (Aβ) aggregation was evaluated in Aβ 1-42 treated cells with thioflavin T (ThT). The behavioral acquisition effects were evaluated in Aβ 1-42 (5µg/ 5 µL, intracerebroventricular (ICV), unilateral) induced AD model followed by the histology and quantification of neurotransmitters levels. The optimized AAN revealed desired PS (44.1 ± 12.4nm), ZP (- 47.1 ± 0.017 mv) and EE (73.41 ± 2.53%) for brain targeting delivery of AA. In-vitro, AAN exhibited better neuroprotective potential than AA suspension (AAS). AA content was 1.28 folds and 2.99 folds heightened in plasma and brain respectively after the i.p. administration of AAN as compared to AAS. The results of pharmacodynamic studies manifested the AAN treatment significantly (p < 0.05) ameliorated the cognitive deficits. Hence, developed AAN has neuroprotective potential and should be further considered as an unconventional platform in preclinical model for the management of AD.