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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 -
Metabolic Brain Disease Dec 2021The present study compared the effect of donepezil only and combination of donepezil and gallic acid on oxidative status and cholinesterase activity in the brain of...
The present study compared the effect of donepezil only and combination of donepezil and gallic acid on oxidative status and cholinesterase activity in the brain of Wistar rats administered AlCl for 60 days. Twenty-eight rats (180 - 200 g) were arbitrarily distributed into four groups of seven animals apiece. Group 1 served as normal control and received distilled water throughout the study. Group 2 animals received only AlCl throughout the study while animals in groups 3 and 4 were administered donepezil only (10 mg/kg) and combination of donepezil (10 mg/kg) and gallic acid (50 mg/kg), respectively, in addition to AlCl. Treatments were administered orally by gavage. At the end of the study, animals were sacrificed and activities of acetylcholinesterase, butyrylcholinesterase, superoxide dismutase (SOD) and catalase as well as levels of malondialdehyde (MDA), total thiol and nitric oxide (NO) were evaluated in the brain. Histopathological study was conducted on the hippocampus of experimental animals. Results showed that AlCl significantly (p < 0.05) increased brain activities of cholinesterases and levels of MDA and NO with a concomitant decrease in total thiol level as well as activities of SOD and catalase. Donepezil only and combination of donepezil and gallic acid reversed these alterations. Also, combination of donepezil and gallic acid significantly (p < 0.05) improved antioxidant status better than donepezil only. It could be concluded that a synergy might exist between gallic acid and donepezil especially in ameliorating oxidative stress associated with AlCl-induced neurotoxicity.
Topics: Acetylcholinesterase; Aluminum Chloride; Animals; Antioxidants; Butyrylcholinesterase; Donepezil; Gallic Acid; Lipid Peroxidation; Oxidative Stress; Rats; Rats, Wistar
PubMed: 33978901
DOI: 10.1007/s11011-021-00749-w -
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 -
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 -
Current Pharmaceutical Design 2019In the brain, acetylcholine (ACh) is regarded as one of the major neurotransmitters. During the advancement of Alzheimer's disease (AD) cholinergic deficits occur and... (Review)
Review
In the brain, acetylcholine (ACh) is regarded as one of the major neurotransmitters. During the advancement of Alzheimer's disease (AD) cholinergic deficits occur and this can lead to extensive cognitive dysfunction and decline. Acetylcholinesterase (AChE) remains a highly feasible target for the symptomatic improvement of AD. Acetylcholinesterase (AChE) remains a highly viable target for the symptomatic improvement in AD because cholinergic deficit is a consistent and early finding in AD. The treatment approach of inhibiting peripheral AChE for myasthenia gravis had effectively proven that AChE inhibition was a reachable therapeutic target. Subsequently tacrine, donepezil, rivastigmine, and galantamine were developed and approved for the symptomatic treatment of AD. Since then, multiple cholinesterase inhibitors (ChEIs) have been continued to be developed. These include newer ChEIs, naturally derived ChEIs, hybrids, and synthetic analogues. In this paper, we summarize the different types of ChEIs which are under development and their respective mechanisms of actions.
Topics: Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Drug Repositioning; Galantamine; Humans; Rivastigmine; Tacrine
PubMed: 31593530
DOI: 10.2174/1381612825666191008103141 -
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 -
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 -
Brazilian Journal of Microbiology :... Sep 2023Neuroprotection is one of the important protection methods against neuronal cells and tissue damage caused by neurodegenerative diseases such as Alzheimer's,... (Review)
Review
Neuroprotection is one of the important protection methods against neuronal cells and tissue damage caused by neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and multiple sclerosis. Various bioactive compounds produced by medicinal plants can potentially treat central nervous system (CNS) disorders. Apart from these resources, endophytes also produce diverse secondary metabolites capable of protecting the CNS. The bioactive compounds produced by endophytes play essential roles in enhancing the growth factors, antioxidant defence functions, diminishing neuroinflammatory, and apoptotic pathways. The efficacy of compounds produced by endophytic fungi was also evaluated by enzymes, cell lines, and in vivo models. Acetylcholine esterase (AChE) inhibition is frequently used to assess in vitro neuroprotective activity along with cytotoxicity-induced neuronal cell lines. Some of drugs, such as tacrine, donepezil, rivastigmine, galantamine, and other compounds, are generally used as reference standards. Furthermore, clinical trials are required to confirm the role of these natural compounds in neuroprotection efficacy and evaluate their safety profile. This review illustrates the production of various bioactive compounds produced by endophytic fungi and their role in preventing neurodegeneration.
Topics: Humans; Plants, Medicinal; Donepezil; Rivastigmine; Endophytes; Fungi; Central Nervous System Diseases
PubMed: 37165297
DOI: 10.1007/s42770-023-00997-1 -
Journal of Controlled Release :... Dec 2021Novel formulations of donepezil (DNP)-loaded microspheres based on a bio-degradable polymer of poly(lactic-co-glycolic acid) (PLGA) with a one-month duration of effect...
Novel formulations of donepezil (DNP)-loaded microspheres based on a bio-degradable polymer of poly(lactic-co-glycolic acid) (PLGA) with a one-month duration of effect were developed, aimed at reducing dosing frequency and adverse effects and improving patient adherence. The spherical and monodispersed DNP-loaded microspheres were precisely fabricated by the Inventage Lab Precision Particle Fabrication method (IVL-PPFM®) based on micro-electromechanical systems (MEMS) and microfluidic technology. The types of polymers and end-groups, the drug/polymer ratio (DPR), and the routes of administration for DNP were studied to ensure an effective concentration and desired duration. Laser-light particle size analysis and scanning electron microscopy were used to characterization. Also, non-clinical animal models of beagle dogs are used to optimize DNP formulations and evaluate their pharmacokinetic properties. The PK results showed that the DPR was a critical factor in determining the exposure level and duration of DNR release. Furthermore, the lactide ratio, which varied depending upon the type of polymer, determined the hydrophobic interaction and was also an important factor affecting the desired DNP release. Since DNP shows a large inter-species variation between dogs and humans, PK modeling and simulation of the reference drug (i.e., Aricept®) and DNP-loaded microspheres were used for formulation development to overcome and interpret these variations. In addition, the developed PK model was extrapolated to humans using the estimated PK parameter and published clinical pharmacology data for DNP. The predicted PK profile of the DNP-loaded microsphere in humans showed that the formulation with PLGA 7525A and the DPR of 1/9 could maintain drug concentration for a month and could control initial burst release. The data obtained from the study could be used as scientific evidence for decision-making in future formulation development.
Topics: Animals; Dogs; Donepezil; Lactic Acid; Microscopy, Electron, Scanning; Microspheres; Particle Size; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer
PubMed: 34715262
DOI: 10.1016/j.jconrel.2021.10.022 -
European Journal of Cancer Care May 2019Many patients with brain cancer experience cognitive problems. In this narrative review, we comprehensively evaluated empirical studies on various intervention... (Review)
Review
INTRODUCTION
Many patients with brain cancer experience cognitive problems. In this narrative review, we comprehensively evaluated empirical studies on various intervention approaches for cognitive problems in these patients.
METHODS
Intervention studies that reported effects on cognitive functioning (either objectively tested or subjectively reported) in adult patients with primary and/or secondary brain tumours were identified through online searches in PubMed (MEDLINE) and Web of Science up to 13 March 2019.
RESULTS
Of the 364 identified records, 10 pharmacological (including five randomised placebo-controlled trials), 10 cognitive rehabilitation (including five [pilot] RCTs) and two multiple-group exercise studies matched the inclusion criteria. Seventeen of 22 studies had final sample sizes smaller than 40. Several cognitive rehabilitation studies and some pharmacological approaches (donepezil and memantine) showed (at least partial) benefits for cognitive problems in adults with brain cancer. The effects of other pharmacological and exercise interventions were inconclusive and/or preliminary.
CONCLUSION
Overall, drawing firm conclusions is complicated due to various methodological shortcomings, including the absence of a (placebo) control group and small sample sizes. Promising effects have been reported for cognitive rehabilitation and some pharmacological approaches. Suggestions for more thorough research with respect to the various approaches are provided.
Topics: Brain Neoplasms; Central Nervous System Stimulants; Cholinesterase Inhibitors; Cognition; Cognitive Dysfunction; Cognitive Remediation; Donepezil; Dopamine Agents; Exercise; Ginkgo biloba; Humans; Memantine; Plant Extracts
PubMed: 31090162
DOI: 10.1111/ecc.13088