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Journal of Biomolecular Structure &... Jun 2022Donepezil is an acetylcholinesterase inhibitor (AChEI) in use to treat symptomatic patients of mild to moderate Alzheimer's disease (AD). Ferritin is an iron protein...
Donepezil is an acetylcholinesterase inhibitor (AChEI) in use to treat symptomatic patients of mild to moderate Alzheimer's disease (AD). Ferritin is an iron protein associated with storage and sequestration of excess ferrous iron in a way maintaining proper function of cellular processes and plays a key role in AD since steady-state dysregulation of metal ion metabolism is associated with AD pathology. In lieu of therapeutics importance of ferritin and donepezil in AD, this study aims at investigating the binding between these two employing molecular docking and molecular dynamics (MD) simulation. In this study, we performed structure-based docking of donepezil with human Ferritin. Primarily, the top pose based on the binding affinity was selected and then interaction analysis was carried out to find the stable pose. Structural annotations by docking analysis were further accompanied by all-atom MD simulation for 100 ns followed by principal component and free energy landscape analyses to investigate the conformational changes, stability, and interaction mechanism of ferritin with donepezil. MD simulation suggested that the binding of donepezil stabilizes the ferritin structure and leads to fewer conformational changes. This study gives an insight at the atomistic level into the interaction between donepezil and ferritin thereby aiding in understanding the activity and mechanism of protein and drug binding. The study is clinically significant as iron participates in the occurrence of AD.
Topics: Acetylcholinesterase; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Ferritins; Humans; Iron; Molecular Docking Simulation; Molecular Dynamics Simulation
PubMed: 33228460
DOI: 10.1080/07391102.2020.1851302 -
Journal of Neuroinflammation Dec 2017Microglia are resident innate immune cells which release many factors including proinflammatory cytokines or nitric oxide (NO) when they are activated in response to...
BACKGROUND
Microglia are resident innate immune cells which release many factors including proinflammatory cytokines or nitric oxide (NO) when they are activated in response to immunological stimuli. Pathophysiology of Alzheimer's disease (AD) is related to the inflammatory responses mediated by microglia. Intracellular Ca signaling is important for microglial functions such as release of NO and cytokines. In addition, alteration of intracellular Ca signaling underlies the pathophysiology of AD, while it remains unclear how donepezil, an acetylcholinesterase inhibitor, affects intracellular Ca mobilization in microglial cells.
METHODS
We examined whether pretreatment with donepezil affects the intracellular Ca mobilization using fura-2 imaging and tested the effects of donepezil on phagocytic activity by phagocytosis assay in rodent microglial cells.
RESULTS
In this study, we observed that pretreatment with donepezil suppressed the TNFα-induced sustained intracellular Ca elevation in both rat HAPI and mouse primary microglial cells. On the other hand, pretreatment with donepezil did not suppress the mRNA expression of both TNFR1 and TNFR2 in rodent microglia we used. Pretreatment with acetylcholine but not donepezil suppressed the TNFα-induced intracellular Ca elevation through the nicotinic α7 receptors. In addition, sigma 1 receptors were not involved in the donepezil-induced suppression of the TNFα-mediated intracellular Ca elevation. Pretreatment with donepezil suppressed the TNFα-induced intracellular Ca elevation through the PI3K pathway in rodent microglial cells. Using DAF-2 imaging, we also found that pretreatment with donepezil suppressed the production of NO induced by TNFα treatment and the PI3K pathway could be important for the donepezil-induced suppression of NO production in rodent microglial cells. Finally, phagocytosis assay showed that pretreatment with donepezil promoted phagocytic activity of rodent microglial cells through the PI3K but not MAPK/ERK pathway.
CONCLUSIONS
These suggest that donepezil could directly modulate the microglial function through the PI3K pathway in the rodent brain, which might be important to understand the effect of donepezil in the brain.
Topics: Animals; Calcium; Cell Line; Cholinesterase Inhibitors; Donepezil; Male; Mice; Microglia; Nitric Oxide; Phosphatidylinositol 3-Kinases; Rats; Signal Transduction; Tumor Necrosis Factor-alpha
PubMed: 29273047
DOI: 10.1186/s12974-017-1033-0 -
Clinical and Experimental Pharmacology... Oct 2020Vascular dementia (VaD), caused by stroke or small vessel disease, is the second-most common type of dementia after Alzheimer's disease (AD). Donepezil is an...
Donepezil down-regulates propionylation, 2-hydroxyisobutyrylation, butyrylation, succinylation, and crotonylation in the brain of bilateral common carotid artery occlusion-induced vascular dementia rats.
Vascular dementia (VaD), caused by stroke or small vessel disease, is the second-most common type of dementia after Alzheimer's disease (AD). Donepezil is an acetylcholinesterase inhibitor that is currently used in patients with mild to moderate AD, and has recently been shown to improve cognitive performance in patients with VaD. In this study, we evaluated the effects of donepezil on VaD, and investigated the underlying molecular mechanisms of action. VaD was established by ligation of the bilateral common carotid artery occlusion (BCCAO). Executive function was tested by the Morris water maze (MWM) test and the attentional set shifting task (ASST). Our results showed that donepezil improved executive dysfunction and cognitive flexibility in BCCAO rats. In addition, we showed that donepezil treatment decreased the level of Aβ1-42 in BCCAO rats by enzyme-linked immunosorbent assay. Post-translational modifications (PTMs) are known to be critical mechanisms in the regulation of various cellular processes. Furthermore, PTMs have been linked to the central nervous system, which highlights the importance of PTMs in neurodegenerative diseases. In this study, we used western blot analysis to identify several novel PTMs in the hippocampus of BCCAO rats that were treated with or without donepezil. The data revealed that lysine propionylation, 2-hydroxyisobutyrylation, butyrylation, succinylation, and crotonylation were elevated in the hippocampus of BCCAO rats when compared to sham rats. This increase was abolished by donepezil treatment. Taken together, we speculate that donepezil treatment improves cognitive function in our animal model of VaD, possibly by reducing aberrant acyl-PTMs.
Topics: Animals; Brain; Carotid Artery, Common; Cognition; Dementia, Vascular; Disease Models, Animal; Donepezil; Hippocampus; Male; Maze Learning; Rats
PubMed: 32424975
DOI: 10.1111/1440-1681.13352 -
Geriatrics & Gerontology International Apr 2023To assess non-inferiority of a donepezil patch 27.5 mg compared with donepezil hydrochloride tablets 5 mg in patients with mild-to-moderate Alzheimer's disease; and to... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and safety of a transdermal donepezil patch in patients with mild-to-moderate Alzheimer's disease: A 24-week, randomized, multicenter, double-blind, parallel group, non-inferiority study.
AIM
To assess non-inferiority of a donepezil patch 27.5 mg compared with donepezil hydrochloride tablets 5 mg in patients with mild-to-moderate Alzheimer's disease; and to compare the efficacy and safety profiles of a donepezil patch 27.5 mg with donepezil hydrochloride tablets 5 mg.
METHODS
This was a 24-week, multicenter, randomized, double-blind, double-dummy, parallel group, non-inferiority (phase III) study carried out in Japan. The primary end-point was the change in the Alzheimer's Disease Assessment Scale-cognitive component-Japanese version from baseline to week 24, with the aim of evaluating the non-inferiority of the donepezil patch 27.5 mg compared with donepezil hydrochloride tablets 5 mg.
RESULTS
Of 340 randomized patients, 303 completed the double-blind period. Changes from baseline in the Alzheimer's Disease Assessment Scale-cognitive component-Japanese version at week 24 (least squares mean ± standard error) were -0.7 ± 0.4 (donepezil patch 27.5 mg) and 0.2 ± 0.4 (donepezil hydrochloride tablet 5 mg). The difference in the least squares means (95% confidence interval) was -0.9 (-2.01 to 0.14). The upper bound of the 95% confidence interval for the difference between groups was less than the predefined non-inferiority margin of 2.15. The donepezil patches 27.5 mg also had a safety profile that showed good tolerability comparable with donepezil hydrochloride tablets 5 mg.
CONCLUSIONS
Non-inferiority on suppression of cognitive decline was shown for the donepezil patch 27.5 mg when compared with donepezil hydrochloride tablets 5 mg in Japanese patients with mild-to-moderate Alzheimer's disease. Geriatr Gerontol Int 2023; 23: 275-281.
Topics: Humans; Donepezil; Alzheimer Disease; Cholinesterase Inhibitors; Piperidines; Indans; Double-Blind Method; Treatment Outcome
PubMed: 36894171
DOI: 10.1111/ggi.14566 -
Annals of Clinical and Translational... Aug 2019De novo loss-of-function mutations in SCN1A are the main cause of Dravet syndrome, a catastrophic encephalopathy characterized by recurrent early-life febrile seizures,...
De novo loss-of-function mutations in SCN1A are the main cause of Dravet syndrome, a catastrophic encephalopathy characterized by recurrent early-life febrile seizures, a number of other afebrile seizure types that are often refractory to treatment, and behavioral abnormalities including social deficits, motor dysfunction, and cognitive impairment. We previously demonstrated that the reversible acetylcholinesterase inhibitor, Huperzine A, increases seizure resistance in Scn1a mutants. In the present study, we evaluated the therapeutic potential of donepezil, a reversible acetylcholinesterase inhibitor approved by the Food and Drug Administration, in a mouse model of Dravet syndrome (Scn1a ). We found that donepezil conferred robust protection against induced seizures in Scn1a mutants.
Topics: Animals; Disease Models, Animal; Donepezil; Epilepsies, Myoclonic; Male; Mice; Mutation; NAV1.1 Voltage-Gated Sodium Channel; Receptors, GABA-A; Receptors, Muscarinic; Seizures
PubMed: 31402621
DOI: 10.1002/acn3.50848 -
Journal of Alzheimer's Disease : JAD 2023In Japan, only oral formulation of donepezil hydrochloride is approved for the treatment of Alzheimer's disease. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In Japan, only oral formulation of donepezil hydrochloride is approved for the treatment of Alzheimer's disease.
OBJECTIVE
To evaluate safety and efficacy of a donepezil patch 27.5 mg application for 52 weeks in patients with mild-to-moderate Alzheimer's disease; and to evaluate safety on switching from donepezil hydrochloride tablets.
METHODS
This 28-week, open-label study (jRCT2080224517) is an extension of a 24-week double-blind (donepezil patch 27.5 mg versus donepezil hydrochloride tablet 5 mg) noninferiority study. The patch group (continuation group) continued administration of the patch and the tablet group (switch group) switched to the patch in this study.
RESULTS
A total of 301 patients participated (156 patients continued using patches; 145 patients switched). Both groups showed similar course on the Alzheimer's Disease Assessment Scale-cognitive component-Japanese version (ADAS-Jcog) and ABC dementia scales. At weeks 36 and 52, changes in ADAS-Jcog from week 24 [mean (standard deviation)] were 1.4 (4.8) and 2.1 (4.9) in the continuation group, and 1.0 (4.2), and 1.6 (5.4) in the switch group. The incidence of adverse events at application site in the continuation group over 52 weeks was 56.6% (98/173). Erythema, pruritus, and contact dermatitis at application site were observed in more than 10 patients each. There was no additional adverse event of clinical concern, and no increase in their incidence from the double-blind study. During the four weeks following switching, no patient discontinued or suspended administration due to adverse events.
CONCLUSION
Application of the patch for 52 weeks was well tolerated and feasible, including switching from tablets.
Topics: Humans; Donepezil; Alzheimer Disease; Cholinesterase Inhibitors; Piperidines; Indans; Double-Blind Method; Treatment Outcome
PubMed: 37334610
DOI: 10.3233/JAD-230387 -
Biochemistry. Biokhimiia Jan 2023A novel donepezil-caffeic acid (DP-CA) hybrid molecule was designed, synthesis, and investigated by molecular modeling. Its biological activity and protective effect...
A novel donepezil-caffeic acid (DP-CA) hybrid molecule was designed, synthesis, and investigated by molecular modeling. Its biological activity and protective effect were investigated by the IR spectroscopy, H and C NMR spectroscopy, and mass spectrometry. DP-CA was highly active against acetylcholine esterase and inhibited it at the micromolar concentrations. Fluorescence and UV-Vis spectroscopy studies showed strong binding of DP-CA to DNA. Moreover, DP-CA exhibited protective effects against H2O2-induced toxicity in U-118 MG glioblastoma cells. Finally, molecular docking showed a high affinity of DP-CA in all concentrations, and the active 4EY7 site exhibited essential residues with polar and apolar contacts. Taken together, these findings indicate that DP-CA could be a prospective multifunctional agent for the treatment of neurodegenerative diseases.
Topics: Donepezil; Molecular Docking Simulation; Hydrogen Peroxide; Prospective Studies; Acetylcholinesterase; Cholinesterase Inhibitors
PubMed: 37068881
DOI: 10.1134/S0006297923010054 -
The Journal of Physiological Sciences :... Jun 2022Despite the presence of clinical guidelines recommending that β-blocker treatment be initiated early after reperfused myocardial infarction (RMI), acute myocardial...
Despite the presence of clinical guidelines recommending that β-blocker treatment be initiated early after reperfused myocardial infarction (RMI), acute myocardial infarction remains a leading cause of chronic heart failure (CHF). In this study, we compared the effects of donepezil, metoprolol, and their combination on the progression of cardiac remodeling in rats with RMI. The animals were randomly assigned to untreated (UT), donepezil-treated (DT), metoprolol-treated (MT), and a combination of donepezil and metoprolol (DMT) groups. On day 8 after surgery, compared to the UT, the DT and DMT significantly improved myocardial salvage, owing to the suppression of macrophage infiltration and apoptosis. After the 10-week treatment, the DT and DMT exhibited decreased heart rate, reduced myocardial infarct size, attenuated cardiac dysfunction, and decreased plasma levels of brain natriuretic peptide and catecholamine, thereby preventing subsequent CHF. These results suggest that donepezil monotherapy or combined therapy with β-blocker may be an alternative pharmacotherapy post-RMI.
Topics: Adrenergic beta-Antagonists; Animals; Donepezil; Heart Failure; Metoprolol; Myocardial Infarction; Rats; Rats, Sprague-Dawley
PubMed: 35725377
DOI: 10.1186/s12576-022-00836-2 -
Molecules (Basel, Switzerland) Mar 2021Alzheimer's disease (AD) is one of the most devastating neurodegenerative disorders, characterized by multiple pathological features. Therefore, multi-target drug...
Alzheimer's disease (AD) is one of the most devastating neurodegenerative disorders, characterized by multiple pathological features. Therefore, multi-target drug discovery has been one of the most active fields searching for new effective anti-AD therapies. Herein, a series of hybrid compounds are reported which were designed and developed by combining an aryl-sulfonamide function with a benzyl-piperidine moiety, the pharmacophore of donepezil (a current anti-AD acetylcholinesterase AChE inhibitor drug) or its benzyl-piperazine analogue. The in vitro results indicate that some of these hybrids achieve optimized activity towards two main AD targets, by displaying excellent AChE inhibitory potencies, as well as the capability to prevent amyloid- (A) aggregation. Some of these hybrids also prevented A-induced cell toxicity. Significantly, drug-like properties were predicted, including for blood-brain permeability. Compound emerged as a promising multi-target lead compound (AChE inhibition (IC 1.6 μM); A aggregation inhibition 60.7%). Overall, this family of hybrids is worthy of further exploration, due to the wide biological activity of sulfonamides.
Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Cell Line, Tumor; Cholinesterase Inhibitors; Donepezil; Humans; Ligands; Piperazines; Piperidines; Structure-Activity Relationship; Sulfonamides
PubMed: 33809771
DOI: 10.3390/molecules26061658 -
Journal of Psychopharmacology (Oxford,... Dec 2020A potent acetylcholinesterase inhibitor, donepezil is a cognitive enhancer clinically used to treat neurodegenerative diseases. However, its complete pharmacological...
BACKGROUND
A potent acetylcholinesterase inhibitor, donepezil is a cognitive enhancer clinically used to treat neurodegenerative diseases. However, its complete pharmacological profile beyond cognition remains unclear. The zebrafish () is rapidly becoming a powerful novel model organism in neuroscience and central nervous system drug screening.
AIM
Here, we characterize the effects of 24-h donepezil administration on anxiety-like behavioral and endocrine responses in adult zebrafish.
METHODS
We evaluated zebrafish anxiety-like behaviors in the novel tank, the light-dark and the shoaling tests, paralleled by assessing brain acetylcholinesterase activity and whole-body cortisol levels.
RESULTS
Overall, donepezil dose-dependently decreased zebrafish locomotor activity in the novel tank test and reduced time in light in the light-dark test, likely representing hypolocomotion and anxiety-like behaviors. Donepezil predictably decreased brain acetylcholinesterase activity, also increasing whole-body cortisol levels, thus further linking acetylcholinesterase inhibition to anxiety-like behavioral and endocrine responses.
CONCLUSION
Collectively, these findings suggest negative modulation of zebrafish affective behavior by donepezil, support the key role of cholinergic mechanisms in behavioral regulation in zebrafish, and reinforce the growing utility of zebrafish models for studying complex behavioral processess and their neuroendocrine and neurochemical regulation.
Topics: Animals; Anxiety; Behavior, Animal; Cholinesterase Inhibitors; Disease Models, Animal; Donepezil; Female; Hydrocortisone; Locomotion; Male; Zebrafish
PubMed: 32854587
DOI: 10.1177/0269881120944155