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PloS One 2023Alzheimer's disease (AD) is a neurodegenerative disorder considered as a global public health threat influencing many people. Despite the concerning rise in the affected...
Alzheimer's disease (AD) is a neurodegenerative disorder considered as a global public health threat influencing many people. Despite the concerning rise in the affected population, there is still a shortage of potent and safe therapeutic agents. The aim of this research is to discover novel natural source molecules with high therapeutic effects, stability and less toxicity for the treatment of AD, specifically targeting acetylcholinesterase (AChE). This research can be divided into two steps: in silico search for molecules by systematic simulations and in vitro experimental validations. We identified five leading compounds, namely Queuine, Etoperidone, Thiamine, Ademetionine and Tetrahydrofolic acid by screening natural molecule database, conducting molecular docking and druggability evaluations. Stability of the complexes were investigated by Molecular Dynamics simulations and free energy calculations were conducted by Molecular Mechanics Generalized Born Surface Area method. All five complexes were stable within the binding catalytic site (CAS) of AChE, with the exception of Queuine which remains stable on the peripheral site (PAS). On the other hand Etoperidone both interacts with CAS and PAS sites showing dual binding properties. Binding free energy values of Queuine and Etoperidone were -71.9 and -91.0 kcal/mol respectively, being comparable to control molecules Galantamine (-71.3 kcal/mol) and Donepezil (-80.9 kcal/mol). Computational results were validated through in vitro experiments using the SH-SY5Y(neuroblastoma) cell line with Real Time Cell Analysis (RTCA) and cell viability assays. The results showed that the selected doses were effective with half inhibitory concentrations estimated to be: Queuine (IC50 = 70,90 μM), Etoperidone (IC50 = 712,80 μM), Thiamine (IC50 = 18780,34 μM), Galantamine (IC50 = 556,01 μM) and Donepezil (IC50 = 222,23 μM), respectively. The promising results for these molecules suggest the development of the next step in vivo animal testing and provide hope for natural therapeutic aids in the treatment of AD.
Topics: Animals; Humans; Alzheimer Disease; Donepezil; Acetylcholinesterase; Galantamine; Cholinesterase Inhibitors; Molecular Docking Simulation; Neuroblastoma; Thiamine
PubMed: 37104478
DOI: 10.1371/journal.pone.0284994 -
Yakugaku Zasshi : Journal of the... 2016Since 1998, when the laboratory of Medicinal Pharmacology was established in the Graduate School of Pharmaceutical Sciences, Osaka University, I have been interested in... (Review)
Review
Since 1998, when the laboratory of Medicinal Pharmacology was established in the Graduate School of Pharmaceutical Sciences, Osaka University, I have been interested in psychopharmacological research topics. During this period, we identified a number of novel regulatory mechanisms that control the prefrontal dopamine system through functional interaction between serotonin1A and dopamine D2 receptors or between serotonin1A and σ1 receptors. Our findings suggest that strategies that enhance the prefrontal dopamine system may have therapeutic potential in the treatment of psychiatric disorders. We also found that environmental factors during development strongly impact the psychological state in adulthood. Furthermore, we clarified the pharmacological profiles of the acetylcholinesterase inhibitors donepezil, galantamine, and rivastigmine, providing novel insights into their mechanisms of action. Finally, we developed the female encounter test, a novel method for evaluating motivation in mice. This simple method should help advance future psychopharmacological research. In this review, we summarize the major findings obtained from our recent studies in mice.
Topics: Alzheimer Disease; Animals; Cholinesterase Inhibitors; Disease Models, Animal; Donepezil; Dopamine; Drug Discovery; Environment; Female; Galantamine; Indans; Male; Mental Disorders; Mice; Molecular Targeted Therapy; Motivation; Piperidines; Psychopharmacology; Rats; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT1D; Receptors, Dopamine D2; Research; Rivastigmine
PubMed: 27150930
DOI: 10.1248/yakushi.15-00282 -
International Journal of Molecular... Aug 2022Since 1906, when Dr. Alois Alzheimer first described in a patient "a peculiar severe disease process of the cerebral cortex", people suffering from this pathology have... (Review)
Review
Since 1906, when Dr. Alois Alzheimer first described in a patient "a peculiar severe disease process of the cerebral cortex", people suffering from this pathology have been waiting for a breakthrough therapy. Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative brain disorder and the most common form of dementia in the elderly with a long presymptomatic phase. Worldwide, approximately 50 million people are living with dementia, with AD comprising 60-70% of cases. Pathologically, AD is characterized by the deposition of amyloid β-peptide (Aβ) in the neuropil (neuritic plaques) and blood vessels (amyloid angiopathy), and by the accumulation of hyperphosphorylated tau in neurons (neurofibrillary tangles) in the brain, with associated loss of synapses and neurons, together with glial activation, and neuroinflammation, resulting in cognitive deficits and eventually dementia. The current competitive landscape in AD consists of symptomatic treatments, of which there are currently six approved medications: three AChEIs (donepezil, rivastigmine, and galantamine), one NMDA-R antagonist (memantine), one combination therapy (memantine/donepezil), and GV-971 (sodium oligomannate, a mixture of oligosaccharides derived from algae) only approved in China. Improvements to the approved therapies, such as easier routes of administration and reduced dosing frequencies, along with the developments of new strategies and combined treatments are expected to occur within the next decade and will positively impact the way the disease is managed. Recently, Aducanumab, the first disease-modifying therapy (DMT) has been approved for AD, and several DMTs are in advanced stages of clinical development or regulatory review. Small molecules, mAbs, or multimodal strategies showing promise in animal studies have not confirmed that promise in the clinic (where small to moderate changes in clinical efficacy have been observed), and therefore, there is a significant unmet need for a better understanding of the AD pathogenesis and the exploration of alternative etiologies and therapeutic effective disease-modifying therapies strategies for AD. Therefore, a critical review of the disease-modifying therapy pipeline for Alzheimer's disease is needed.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Donepezil; Humans; Memantine; Patient-Centered Care; Polypharmacology
PubMed: 36012569
DOI: 10.3390/ijms23169305 -
Journal of Cellular Physiology Aug 2023This study was designed to determine whether the use of acetylcholinesterase inhibitors (AChEIs), a group of drugs that stimulate acetylcholine receptors and are used to...
This study was designed to determine whether the use of acetylcholinesterase inhibitors (AChEIs), a group of drugs that stimulate acetylcholine receptors and are used to treat Alzheimer's disease (AD), is associated with osteoporosis protection and inhibition of osteoclast differentiation and function. Firstly, we examined the effects of AChEIs on RANKL-induced osteoclast differentiation and function with osteoclastogenesis and bone resorption assays. Next, we investigated the impacts of AChEIs on RANKL-induced nuclear factor κB and NFATc1 activation and expression of osteoclast marker proteins CA-2, CTSK and NFATc1, and dissected the MAPK signaling in osteoclasts in vitro by using luciferase assay and Western blot. Finally, we assessed the in vivo efficacy of AChEIs using an ovariectomy-induced osteoporosis mouse model, which was analyzed using microcomputed tomography, in vivo osteoclast and osteoblast parameters were assessed using histomorphometry. We found that Donepezil and Rivastigmine inhibited RANKL-induced osteoclastogenesis and impaired osteoclastic bone resorption. Moreover, AChEIs reduced the RANKL-induced transcription of Nfatc1, and expression of osteoclast marker genes to varying degrees (mainly Donepezil and Rivastigmine but not Galantamine). Furthermore, AChEIs variably inhibited RANKL-induced MAPK signaling accompanied by downregulation of AChE transcription. Finally, AChEIs protected against OVX-induced bone loss mainly by inhibiting osteoclast activity. Taken together, AChEIs (mainly Donepezil and Rivastigmine) exerted a positive effect on bone protection by inhibiting osteoclast function through MAPK and NFATc1 signaling pathways through downregulating AChE. Our findings have important clinical implications that elderly patients with dementia who are at risk of developing osteoporosis may potentially benefit from therapy with the AChEI drugs. Our study may influence drug choice in those patients with both AD and osteoporosis.
Topics: Mice; Animals; Female; Humans; Osteogenesis; Cholinesterase Inhibitors; Acetylcholinesterase; Rivastigmine; Donepezil; X-Ray Microtomography; Bone Resorption; Osteoclasts; Transcription Factors; NF-kappa B; Osteoporosis; RANK Ligand; NFATC Transcription Factors; Cell Differentiation; Ovariectomy
PubMed: 37334837
DOI: 10.1002/jcp.31057 -
The Cochrane Database of Systematic... Nov 2022Cognitive deficits are common in people who have received cranial irradiation and have a serious impact on daily functioning and quality of life. The benefit of... (Review)
Review
BACKGROUND
Cognitive deficits are common in people who have received cranial irradiation and have a serious impact on daily functioning and quality of life. The benefit of pharmacological and non-pharmacological treatment of cognitive deficits in this population is unclear. This is an updated version of the original Cochrane Review published in Issue 12, 2014.
OBJECTIVES
To assess the effectiveness of interventions for preventing or ameliorating cognitive deficits in adults treated with cranial irradiation.
SEARCH METHODS
For this review update we searched the Cochrane Register of Controlled Trials (CENTRAL), MEDLINE via Ovid, Embase via Ovid, and PsycInfo via Ovid to 12 September 2022.
SELECTION CRITERIA
We included randomised controlled (RCTs) trials that evaluated pharmacological or non-pharmacological interventions in cranial irradiated adults, with objective cognitive functioning as a primary or secondary outcome measure.
DATA COLLECTION AND ANALYSIS
Two review authors (MK, JD) independently extracted data from selected studies and carried out a risk of bias assessment. Cognitive function, fatigue and mood outcomes were reported. No data were pooled.
MAIN RESULTS
Eight studies met the inclusion criteria and were included in this updated review. Six were from the original version of the review, and two more were added when the search was updated. Nineteen further studies were assessed as part of this update but did not fulfil the inclusion criteria. Of the eight included studies, four studies investigated "prevention" of cognitive problems (during radiotherapy and follow-up) and four studies investigated "amelioration" (interventions to treat cognitive impairment as a late complication of radiotherapy). There were five pharmacological studies (two studies on prevention and three in amelioration) and three non-pharmacological studies (two on prevention and one in amelioration). Due to differences between studies in the interventions being evaluated, a meta-analysis was not possible. Studies in early radiotherapy treatment phase (five studies) Pharmacological studies in the "early radiotherapy treatment phase" were designed to prevent or ameliorate cognitive deficits and included drugs used in dementia (memantine) and fatigue (d-threo-methylphenidate hydrochloride). Non-pharmacological studies in the "early radiotherapy treatment phase" included a ketogenic diet and a two-week cognitive rehabilitation and problem-solving programme. In the memantine study, the primary cognitive outcome of memory at six months did not reach significance, but there was significant improvement in overall cognitive function compared to placebo, with similar adverse events across groups. The d-threo-methylphenidate hydrochloride study found no statistically significant difference between arms, with few adverse events. The study of a calorie-restricted ketogenic diet found no effect, although a lower than expected calorie intake in the control group complicates interpretation of the results. The study investigating the utility of a rehabilitation program did not carry out a statistical comparison of cognitive performance between groups. Studies in delayed radiation or late effect phase (four studies) The "amelioration" pharmacological studies to treat cognitive complications of radiotherapy included drugs used in dementia (donepezil) or psychostimulants (methylphenidate and modafinil). Non-pharmacological measures included cognitive rehabilitation and problem solving (Goal Management Training). These studies included patients with cognitive problems at entry who had "stable" brain cancer. The donepezil study did not find an improvement in the primary cognitive outcome of overall cognitive performance, but did find improvement in an individual test of memory, compared to placebo; adverse events were not reported. A study comparing methylphenidate with modafinil found improvements in cognitive function in both the methylphenidate and modafinil arms; few adverse events were reported. Another study comparing two different doses of modafinil combined treatment arms and found improvements across all cognitive tests, however, a number of adverse events were reported. Both studies were limited by a small sample size. The Goal Management Training study suggested a benefit of the intervention, a behavioural intervention that combined mindfulness and strategy training, on executive function and processing speed. There were a number of limitations across studies and few were without high risks of bias.
AUTHORS' CONCLUSIONS
In this update, limited additional evidence was found for the treatment or amelioration of cognitive deficits in adults treated with cranial irradiation. As concluded in the original review, there is supportive evidence that memantine may help prevent cognitive deficits for adults with brain metastases receiving cranial irradiation. There is supportive evidence that donepezil, methylphenidate and modafinil may have a role in treating cognitive deficits in adults with brain tumours who have been treated with cranial irradiation; patient withdrawal affected the statistical power of these studies. Further research that tries to minimise the withdrawal of consent, and subsequently reduce the requirement for imputation procedures, may offer a higher certainty of evidence. There is evidence from only a single small study to support non-pharmacological interventions in the amelioration of cognitive deficits. Further research is required.
Topics: Adult; Humans; Modafinil; Donepezil; Memantine; Quality of Life; Cognitive Dysfunction; Cranial Irradiation; Cognition; Methylphenidate; Brain Neoplasms; Fatigue; Dementia
PubMed: 36427235
DOI: 10.1002/14651858.CD011335.pub3 -
Molecular Brain Jul 2022The cholinesterase inhibitor donepezil is used to improve Aβ pathology and cognitive function in patients with Alzheimer's disease (AD). However, the impact of...
The cholinesterase inhibitor donepezil is used to improve Aβ pathology and cognitive function in patients with Alzheimer's disease (AD). However, the impact of donepezil on tau pathology is unclear. Thus, we examined the effects of donepezil on Aβ and tau pathology in 5xFAD mice (a model of AD) in this study. We found that intraperitoneal injection of donepezil (1 mg/kg, i.p.) exhibited significant reductions in Aβ plaque number in the cortex and hippocampal DG region. In addition, donepezil treatment (1 mg/kg, i.p.) reduced Aβ-mediated microglial and, to a lesser extent, astrocytic activation in 5xFAD mice. However, neither intraperitoneal/oral injection of donepezil nor oral injection of rivastigmine altered tau phosphorylation at Thr212/Ser214 (AT100), Thr396, and Thr231 in 5xFAD mice. Surprisingly, we observed that intraperitoneal/oral injection of donepezil treatment significantly increased tau phosphorylation at Thr212 in 5xFAD mice. Taken together, these data suggest that intraperitoneal injection of donepezil suppresses Aβ pathology but not tau pathology in 5xFAD mice.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Disease Models, Animal; Donepezil; Mice; Mice, Transgenic; Plaque, Amyloid
PubMed: 35850693
DOI: 10.1186/s13041-022-00948-1 -
European Review For Medical and... Dec 2021To identify candidate differentially expressed genes (DEGs) and pathways in diabetic mice brain with metformin/donepezil, network pharmacology analysis was used and...
OBJECTIVE
To identify candidate differentially expressed genes (DEGs) and pathways in diabetic mice brain with metformin/donepezil, network pharmacology analysis was used and verified by experiments.
MATERIALS AND METHODS
We analyzed GSE62013 microarray datasets derived from the Gene Expression Omnibus (GEO) database for diabetic brain. Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed using the Database. Subsequently, the protein-protein interaction network (PPI) and Cytoscape were used for visualizing the most significant module and hub genes. Metformin/donepezil were used to treat streptozotocin (STZ)-induced diabetic mice models. Blood glucose levels and Morris water maze test were measured. The apoptotic rate of diabetic brain tissue was analyzed using Annexin V/propidium iodide double staining. The levels of PI3K and AKT in the mice brain tissues were detected by Western blot.
RESULTS
DEGs included 214 up-regulated genes and 100 down-regulated genes in diabetic brain tissues of mice. The enriched GO functions were multicellular organism development, negative regulation of transcription from RNA polymerase II promoter, and extracellular region. The enriched pathways were PI3K-Akt signaling pathway, Linoleic acid metabolism and Arachidonic acid metabolism. Blood glucose levels and apoptosis were reduced in STZ-induced diabetic mice following metformin/donepezil treatment. Metformin/donepezil could reverse this neurocognitive deficiency. Protein levels of PI3K and AKT were significantly increased in STZ-induced diabetic mice.
CONCLUSIONS
Overall, we proposed that 10 genes (Cdc20, Fbxo32, Igtp, Atg7, Fbxo15, Trim37, Psmb8, Ifi47, Asb12, and Asb5) that might be novel hub genes strongly associated with diabetic mice brain. Metformin/donepezil ameliorates STZ-induced brain injury by activating the PI3K/AKT pathway and alleviating apoptosis.
Topics: Animals; Apoptosis; Brain; Cholinesterase Inhibitors; Computational Biology; Diabetes Mellitus, Experimental; Donepezil; Hypoglycemic Agents; Male; Metformin; Mice, Inbred C57BL; Neuroprotective Agents; Nootropic Agents; Phosphatidylinositol 3-Kinases; Protein Interaction Maps; Proto-Oncogene Proteins c-akt; Mice
PubMed: 34982428
DOI: 10.26355/eurrev_202112_27613 -
Drug Design, Development and Therapy 2016Currently available therapies for the treatment of Alzheimer's disease (AD) consist of cholinesterase inhibitors (ChEIs), such as donepezil, and the -methyl-D-aspartate... (Review)
Review
Currently available therapies for the treatment of Alzheimer's disease (AD) consist of cholinesterase inhibitors (ChEIs), such as donepezil, and the -methyl-D-aspartate receptor antagonist memantine. In December 2014, the US Food and Drug Administration approved Namzaric™, a once-daily, fixed-dose combination (FDC) of memantine extended-release (ER) and donepezil for patients with moderate-to-severe AD. The FDC capsule is bioequivalent to the coadministered individual drugs, and its bioavailability is similar when taken fasting, with food, or sprinkled onto applesauce. The combination of memantine and ChEIs in moderate-to-severe AD provides additional benefits to ChEI monotherapy across multiple domains and may delay the time to nursing home admission. A dedicated study of memantine ER compared to placebo in patients on a stable dose of a ChEI found statistically significant benefits on cognition and global status but not functioning. Treatment with memantine ER and donepezil is generally well tolerated, although higher doses of ChEIs are associated with more serious adverse events such as vomiting, syncope, and weight loss. Potential advantages of the FDC include a simpler treatment regimen, reduction in pill burden, and the ability to sprinkle the capsule onto soft foods. Patients who may benefit from the FDC include those with significant dysphagia, a history of poor compliance, or limited caregiver interaction. However, available evidence that these advantages would increase treatment adherence and persistence is conflicting, meaning that the added cost of switching patients from generic options to an FDC may not always be justified.
Topics: Adolescent; Adult; Alzheimer Disease; Biological Availability; Cholinesterase Inhibitors; Cognition; Delayed-Action Preparations; Donepezil; Drug Therapy, Combination; Female; Humans; Indans; Male; Memantine; Middle Aged; Nootropic Agents; Piperidines; Severity of Illness Index; Young Adult
PubMed: 27757016
DOI: 10.2147/DDDT.S86463 -
Pharmacology Research & Perspectives Dec 2021Cardiovascular complications in Alzheimer's disease (AD) patients can occur years to decades prior to the onset of clinical symptoms of the disease. Donepezil represents...
Cardiovascular complications in Alzheimer's disease (AD) patients can occur years to decades prior to the onset of clinical symptoms of the disease. Donepezil represents the most effective drug in the treatment of AD. However, the potential effect of donepezil on vascular function and structure remains largely unexplored. Here, we assessed the impact of donepezil on the vascular phenotype of an established model of accelerated senescence that develops spontaneously AD, the SAMP8 mouse. Three groups of animals were included: SAMR1 (control strain), SAMP8, and SAMP8 treated with donepezil. Treatment with donepezil was administered from the 4th to the 6th month of life. At 6 months, after cognitive tests by Morris Water Maze, animals were euthanized, and their mesenteric arteries were processed for functional experiments. Untreated SAMP8 developed cognitive impairment compared to SAMR1, while donepezil treatment significantly attenuated cognitive dysfunction. SAMP8 exhibited a higher media-to-lumen ratio than SAMR1 and donepezil-treated animals. Endothelial function was impaired in SAMP8 animals compared to SAMR1. The addition of vitamin C improved the vasodilatory response to acetylcholine in SAMP8. Treatment with donepezil improved endothelial function in SAMP8 animals and reduced the additional vasodilation induced by vitamin C. In conclusion, in the SAMP8 AD model, cognitive impairment is associated with endothelial dysfunction and vascular remodeling which could contribute to cardiovascular events in AD since the prodromal phases of the disease. Treatment with donepezil alleviates vascular dysfunction associated with AD through an increase in NO availability likely by counteracting inflammation and oxidative stress.
Topics: Acetylcholine; Alzheimer Disease; Animals; Cardiovascular Diseases; Cholinesterase Inhibitors; Cognitive Dysfunction; Disease Models, Animal; Donepezil; Inflammation; Maze Learning; Mice; Nitric Oxide; Oxidative Stress; Vascular Remodeling; Vasodilation
PubMed: 34713597
DOI: 10.1002/prp2.871 -
Molecular Medicine Reports Apr 2022Ischemia/reperfusion (I/R) injury is a serious clinical condition characterized by high morbidity and mortality rates. Donepezil plays a neuroprotective role in...
Ischemia/reperfusion (I/R) injury is a serious clinical condition characterized by high morbidity and mortality rates. Donepezil plays a neuroprotective role in I/R‑associated diseases. The aim of the present study was to investigate the role and the potential mechanism of action of donepezil in I/R‑induced myocardial microvascular endothelial cell dysfunction. An I/R model was simulated using oxygen‑glucose deprivation/reoxygenation (OGD/R) injury in human cardiac microvascular endothelial cells (CMECs). Cell viability and lactate dehydrogenase release were examined following treatment with donepezil. Commercial kits were used to evaluate cell apoptosis, cell permeability and caspase‑3 activity. The expression levels of apoptosis‑associated proteins, as well as proteins found in tight junctions or involved in the poly(ADP‑ribose) polymerase 1 (PARP1)/NF‑κB pathway, were measured using western blotting. These parameters were also examined following PARP1 overexpression. The results demonstrated that donepezil increased cell viability and reduced toxicity in OGD/R‑treated CMECs. The apoptotic rate, caspase‑3 activity and protein expression levels of Bax and cleaved caspase‑3 were significantly reduced following donepezil treatment, which was accompanied by Bcl‑2 upregulation. Moreover, cell permeability was notably reduced, coupled with a marked increase in the expression of tight junction‑associated proteins. The expression levels of proteins related to PARP1/NF‑κB signaling were significantly downregulated in CMECs following donepezil treatment. However, the protective effects of donepezil on OGD/R‑induced CMEC injury were reversed following PARP1 overexpression. In conclusion, donepezil suppressed OGD/R‑induced CMEC dysfunction via PARP1/NF‑κB signaling. This finding provided insight into the mechanism underlying myocardial I/R injury.
Topics: Adolescent; Adult; Apoptosis; Cell Line; Cell Survival; Donepezil; Endothelial Cells; Female; Glucose; Humans; Male; Myocardial Infarction; Myocardial Reperfusion Injury; NF-kappa B; Neuroprotective Agents; Oxygen; Permeability; Poly (ADP-Ribose) Polymerase-1; Reperfusion Injury; Signal Transduction; Young Adult
PubMed: 35147204
DOI: 10.3892/mmr.2022.12637