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European Journal of Pharmacology Nov 2021We previously demonstrated that donepezil, an anti-Alzheimer's disease drug, improved skeletal muscle atrophy by enhancing the angiogenesis of endothelial cells and...
Donepezil, an anti-Alzheimer's disease drug, promotes differentiation and regeneration in injured skeletal muscle through the elevation of the expression of myogenic regulatory factors.
We previously demonstrated that donepezil, an anti-Alzheimer's disease drug, improved skeletal muscle atrophy by enhancing the angiogenesis of endothelial cells and activating the proliferation of satellite cells in a mouse model of peripheral arterial disease. However, the effect of donepezil on muscle differentiation during regeneration remains unclear. Therefore, we measured the expressions of myogenic regulatory factors and late muscle differentiation markers in donepezil-treated C2C12 myoblast cells before and after the induction of cell differentiation. The results indicate that the expressions of myogenin, troponin T (TnT) and myosin heavy chain (MyHC) were significantly increased and myotube formation was accelerated in donepezil-treated cells under the differentiation condition. However, the promotive effect of donepezil on muscle differentiation could not be reproduced by the addition of acetylcholine (ACh) and was not disrupted after treatment with ACh receptor blockers. Moreover, other kinds of acetylcholinesterase inhibitors failed to promote muscle differentiation in C2C12 cells. These results indicate that the specific characteristics of donepezil in the promotion of muscle differentiation are independent of its acetylcholinesterase-inhibitory action. We further found that donepezil induced an incremental shift of the cross-sectional area of myofibers and elevated the expressions of myogenin, TnT and MyHC in a mouse model of cardiotoxin injury. These results suggest that donepezil promotes the differentiation of muscle regeneration upon injury via the elevation of the expressions of myogenic regulatory factors and late muscle differentiation markers. Our findings suggest that donepezil can be a useful therapeutic agent for injured skeletal muscle treatment.
Topics: Donepezil
PubMed: 34582845
DOI: 10.1016/j.ejphar.2021.174528 -
BMJ Case Reports Mar 2019An elderly man presented with the history of diphenhydramine hydrochloride overdose as a suicidal attempt. At presentation, he was in an acute confusional state with...
An elderly man presented with the history of diphenhydramine hydrochloride overdose as a suicidal attempt. At presentation, he was in an acute confusional state with several anticholinergic features and had to be managed in intensive care unit. As an antidote for diphenhydramine hydrochloride, donepezil was used instead of physostigmine due to the unavailability of physostigmine in Bangladesh. The patient improved within the next 24 hours; his level of consciousness improved and the anticholinergic features regressed.
Topics: Administration, Oral; Aged, 80 and over; Cholinesterase Inhibitors; Diphenhydramine; Donepezil; Drug Overdose; Humans; Male; Suicide, Attempted; Treatment Outcome
PubMed: 30898954
DOI: 10.1136/bcr-2018-226836 -
Inflammopharmacology Feb 2021Donepezil has proven to be an effective drug to reduce neuronal death and subsequently injury in neurodegenerative diseases. The current study evaluated the...
Donepezil has proven to be an effective drug to reduce neuronal death and subsequently injury in neurodegenerative diseases. The current study evaluated the neuroprotective effects of donepezil in a rat model of ischaemic stroke and explored possible mechanisms which by this drug may reduce cell death. Temporary middle cerebral artery occlusion (tMCAO) was exerted for 45 min to induce ischaemic stroke. The animals were assigned into five groups: sham, control, and three groups treated with different doses of donepezil. Donepezil was intraperitoneally (IP) injected 4 h after reperfusion for 10 consecutive days. Infarct size was determined using TTC staining. The expression of proteins was evaluated using immunohistochemistry assays. Compared with the control group, infarct size was significantly reduced in tMCAO rats treated with different doses of donepezil. Moreover, our results showed significant decreased expression levels of apoptotic markers and pro-inflammatory mediators after treatment with different doses of donepezil for 10 days (P < 0.05). Likewise, significant increase of brain-derived neurotrophic factor (BDNF) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) proteins were found in tMCAO rats treated with donepezil compared with the control group (P < 0.05). Collectively, our findings show the validity of donepezil as a new therapeutic agent for attenuation of injury following ischaemic stroke through attenuation of inflammation and improvement of mitochondrial function, neurogenesis, and angiogenesis.
Topics: Angiogenesis Inducing Agents; Animals; Apoptosis; Donepezil; Dose-Response Relationship, Drug; Infarction, Middle Cerebral Artery; Inflammation; Ischemic Stroke; Male; Mitochondria; Neurogenesis; Neuroprotective Agents; Rats; Rats, Wistar
PubMed: 33201349
DOI: 10.1007/s10787-020-00769-5 -
Journal of Alzheimer's Disease : JAD 2021Vascular factors and mitochondria dysfunction contribute to the pathogenesis of Alzheimer's disease (AD). DL-3-n-butylphthalide (NBP) has an effect in protecting...
BACKGROUND
Vascular factors and mitochondria dysfunction contribute to the pathogenesis of Alzheimer's disease (AD). DL-3-n-butylphthalide (NBP) has an effect in protecting mitochondria and improving microcirculation.
OBJECTIVE
The aim was to investigate the effect of donepezil combined NBP therapy in patients with mild-moderate AD.
METHODS
It was a prospective cohort study. 92 mild-moderate AD patients were classified into the donepezil alone group (n = 43) or the donepezil combined NBP group (n = 49) for 48 weeks. All patients were evaluated with Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-cog), Clinician's Interview-Based Impression of Change plus caregiver input (CIBIC-plus), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), and Neuropsychiatric Inventory (NPI) every 12 weeks. All patients were monitored for adverse events (AEs). The efficacy was analyzed using multivariate logistic regression analysis.
RESULTS
The multivariate logistic regression analysis showed that the changes of ADAS-cog score (OR = 2.778, 95% CI: [1.087, 7. 100], p = 0.033) and ADCS-ADL score (OR = 2.733, 95% CI: [1.002, 7.459], p = 0.049) had significant difference between donepezil alone group and donepezil combined NBP group, while the changes of NPI (OR = 1.145, 95% CI: [0.463, 2.829], p = 0.769), MMSE (OR = 1.563, 95% CI: [0.615, 3.971], p = 0.348) and CIBIC-plus (OR = 2.593, 95% CI: [0.696, 9.685], p = 0.156) had no significant difference. The occurrence of AEs was similar in the two groups.
CONCLUSION
Over the 48-week treatment period, donepezil combined NBP group had slower cognitive decline and better activities of daily living in patients with mild to moderate AD. These indicated that the multi-target therapeutic effect of NBP may be a new choice for AD treatment.
Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Benzofurans; Cognitive Dysfunction; Cohort Studies; Donepezil; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Neuroprotective Agents; Neuropsychological Tests; Prospective Studies; Treatment Outcome
PubMed: 33579850
DOI: 10.3233/JAD-201381 -
Journal of Inorganic Biochemistry May 2020The intricate and multifactorial nature of Alzheimer's disease (AD) requires the development of compounds able to hit different pathophysiological targets, such as...
The intricate and multifactorial nature of Alzheimer's disease (AD) requires the development of compounds able to hit different pathophysiological targets, such as cholinergic dysfunction, deposits of amyloid beta (Aβ) peptide and metal dyshomeostasis. In order to continue the search for new anti-AD drugs, a design strategy was once more followed based on repositioning donepezil (DNP) drug, by ortho-attaching a benzylpiperidine mimetic of DNP moiety to a hydroxyphenyl-benzimidazole (BIM) chelating unit (compound 1). Herein, compound 1 and a positional isomer 2 are compared in terms of their potential multiple properties: both present good acetylcholinesterase (AChE) inhibition (low μmolar range) and are moderate/good inhibitors of Aβ self- and Cu-mediated aggregation, the inhibition process being mainly due to ligand intercalation between the β-sheets of the fibrils; compound 1 has a higher chelating capacity towards Cu and Zn (pCu = 14.3, pZn = 6.4, pH 7.4, C/C = 10, C = 10 M) than 2 (pCu = 10.7, pZn = 6.3), attributed to its ability to establish a tridentate (N,O,O) coordination to the metal ion. Both compounds are eligible as drug candidates for oral administration but compound 1 shows improved neuroprotective role by completely preventing Aβ-induced cell toxicity.
Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Chelating Agents; Cholinesterase Inhibitors; Copper; Donepezil; Humans; Isomerism; Models, Molecular; Molecular Structure; Neuroblastoma; Neuroprotective Agents; Structure-Activity Relationship; Tumor Cells, Cultured
PubMed: 32171933
DOI: 10.1016/j.jinorgbio.2020.111039 -
Scientific Reports Aug 2019Donepezil, a therapeutic drug for Alzheimer's disease, ameliorates cognitive dysfunction through selective inhibition of acetylcholinesterase. However, recent studies...
Donepezil, a therapeutic drug for Alzheimer's disease, ameliorates cognitive dysfunction through selective inhibition of acetylcholinesterase. However, recent studies have also reported off-target effects of donepezil that likely contribute to its therapeutic effects. In this study, we investigated the (i) role of donepezil in amyloid precursor protein (APP) processing and (ii) involvement of sorting nexin protein 33 (SNX33), a member of the sorting nexin protein family, in this processing. Results showed that donepezil induces an increase in SNX33 expression in primary cortical neurons. The secretion of sAPPα in culture media increased, whereas the expression of full-length APP in the cell lysate remained unchanged. Exposure of cortical cultures to donepezil led to a decrease in amyloid β (Aβ) protein levels in a concentration- and time-dependent manner. This decrease was not affected by concomitant treatment with acetylcholine receptor antagonists. SNX33 knockdown by target-specific morpholino oligos inhibited the effects of donepezil. Donepezil treatment increased cell membrane surface expression of APP in SNX33 expression-dependent manner. These results suggested that donepezil decreases the level of Aβ by increasing SNX33 expression and APP cleavage by α-secretase in cortical neurons.
Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Cell Membrane; Cells, Cultured; Cerebral Cortex; Cholinergic Antagonists; Donepezil; Endocytosis; Morpholinos; Neurons; Protein Processing, Post-Translational; Rats, Wistar; Receptors, Cholinergic; Sorting Nexins; Up-Regulation
PubMed: 31417133
DOI: 10.1038/s41598-019-47462-4 -
Substance Abuse 2021Pharmacological and psychosocial interventions have only modest efficacy for Alcohol Use Disorder (AUD), and continued alcohol use has brain effects on neurocognition,... (Clinical Trial)
Clinical Trial
Donepezil and cognitive remediation therapy to augment treatment of alcohol use disorder related mild cognitive impairment (AUD-MCI): An open label pilot study with historical controls.
Pharmacological and psychosocial interventions have only modest efficacy for Alcohol Use Disorder (AUD), and continued alcohol use has brain effects on neurocognition, which place heavy drinkers at increased risk of early onset dementia. The most common neurocognitive deficits are in the domains of executive function and memory, and these deficits may impact AUD treatment outcomes. AUD related Mild Cognitive Impairment (AUD-MCI) is a diagnosis in DSM-V and ICD-10. Donepezil, a cholinesterase inhibitor, is currently FDA approved for treatment of dementia, and recent preclinical research suggests anticholinesterase agents may treat alcoholism. Another approach to cognitive recovery is Cognitive Remediation Therapy (CRT). Recent research supports CRT efficacy in schizophrenia and related disorders, and some research suggests that CRT could improve neurocognition in substance abuse disorders (SUDs). This is the first report of an open-label clinical trial that combined donepezil with CRT to improve neurocognitive and clinical outcomes in the early phase of AUD recovery. Eleven older male US Veterans with AUD-MCI as determined by Level II neurocognitive criteria and who had recently relapsed participated in an open-label trial of 13 weeks of donepezil combined with CRT. They were compared with matched historical control samples on neurocognitive and clinical outcomes. Participants had excellent adherence to donepezil and CRT. Neurocognitive improvements were highly significant on a composite score of learning and memory and executive function measures ( < .0001) and was significantly better than historical matched controls ( < .001). On a Clinical Global Impression scale, 90.9% of participants had a good clinical recovery compared with 59.5% of historical matched controls ( <.052). AUD-MCI has not received much research attention but is of considerable public health importance. Findings in this open-label trial of donepezil + CRT should encourage further investigation into the clinical benefit of this combined treatment for AUD-MCI.
Topics: Alcoholism; Cognitive Dysfunction; Cognitive Remediation; Donepezil; Humans; Male; Pilot Projects
PubMed: 33284058
DOI: 10.1080/08897077.2020.1844847 -
Journal of Controlled Release :... Jul 2018According to the Alzheimer Association Report (2017), Alzheimer's disease (AD) is the 6th primary cause of death in the USA, which affects nearly 5.5 million people. In... (Review)
Review
According to the Alzheimer Association Report (2017), Alzheimer's disease (AD) is the 6th primary cause of death in the USA, which affects nearly 5.5 million people. In the year 2017 itself, the cost of AD treatment in the USA has been reported to rise to $259 billion. This statistic shows the severity of the disease in the USA which is very much similar across the globe. On the other hand, the treatment remains limited to a few conventional oral medications (approved by FDA). These are mainly acting superficially from mild to the moderate AD. The therapeutic efficacy of the drug is not only affected by its reduced concentration in the brain owing to the existence of blood-brain-barrier (BBB) but also due to its low brain permeability. In this context, the intranasal (IN) route of drug administration has emerged as an alternative route over the systemic (oral and parenteral) drug delivery to the brain. The delivery of the drug via an IN route offers various advantages over systemic drug delivery system, as it directly delivers the drug into the brain via olfactory route. Presence of drug in the olfactory bulb, in turn, increases the drug bioavailability in the brain and reduces the drug degradation as well as wastage of the drug through` systemic clearance. However, there is also some limitation associated with IN like poor drug permeation through the nasal mucosa and mucociliary clearance. The delivery system various through novel strategies (nano drug carrier system, colloidal carriers, mucoadhesive devices, controlled delivery system, pro-drug, etc.) are adapted to overcome the above-stated limitations. Although, after all, such successful research claims, very few of the nose-to-brain drug delivery of anti-AD drugs have gained market approval due to lack of sufficient clinical evidence. Onzetra Xsail® is one such marketed preparations approved for IN delivery used for the treatment of a brain disorder; migraine. In the field of patents also, no work is found which could present sufficient experimental findings to support its clinical safety profile. It also underlines the fact that majority of work related to the nose-to-brain delivery of anti-AD drugs is limited only up to preclinical studies. In this review article, we have discussed the latest works on various novel formulations loaded with various anti-Alzheimer agents. These agents include galantamine, deferoxamine, tacrine, tarenflurbil, rivastigmine, risperidone, curcumin, quercetin, piperine, insulin, etc. and various peptides towards the development of a promising IN drug delivery system for the treatment of AD. Through this review article, we want to drag the attention of the researchers working in this field towards the challenges and hurdles of practical applicability IN delivery of anti-AD drugs. Moreover, the attention towards the clinical studies will ease the approval process for the administration of anti-Alzheimer drugs via IN route.
Topics: Administration, Intranasal; Alzheimer Disease; Animals; Biological Availability; Blood-Brain Barrier; Brain; Deferoxamine; Donepezil; Drug Carriers; Drug Liberation; Galantamine; Humans; Mucociliary Clearance; Nanoparticles; Nasal Mucosa; Nose; Olfactory Bulb; Risperidone; Tissue Distribution
PubMed: 29772289
DOI: 10.1016/j.jconrel.2018.05.011 -
Journal of Alzheimer's Disease : JAD 2022Evidence summaries for efficacy and safety of frequently employed treatments of Alzheimer's disease (AD) are sparse. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Evidence summaries for efficacy and safety of frequently employed treatments of Alzheimer's disease (AD) are sparse.
OBJECTIVE
We aimed to perform an updated umbrella review to identify an efficacious and safe treatment for AD patients.
METHODS
We conducted a search for meta-analyses and systematic reviews on the Embase, PubMed, The Cochrane Library, and Web of Science to address this knowledge gap. We examined the cognitive functions, behavioral symptoms, global clinical assessment, and Activities of Daily Living as efficacy endpoints, and the incidence of adverse events as safety profiles.
RESULTS
Sixteen eligible papers including 149 studies were included in the umbrella review. The results showed that AChE inhibitors (donepezil, galantamine, rivastigmine, Huperzine A), Ginkgo biloba, and cerebrolysin appear to be beneficial for cognitive, global performances, and activities of daily living in patients with AD. Furthermore, anti-Aβ agents are unlikely to have an important effect on slowing cognitive or functional impairment in mild to moderate AD.
CONCLUSION
Our study demonstrated that AChE inhibitors, Ginkgo biloba, and cerebrolysin are the optimum cognitive and activities of daily living medication for patients with AD.
Topics: Activities of Daily Living; Alzheimer Disease; Amino Acids; Cholinesterase Inhibitors; Cognition; Donepezil; Galantamine; Ginkgo biloba; Humans; Nootropic Agents; Patient Safety; Plant Extracts; Rivastigmine
PubMed: 34924395
DOI: 10.3233/JAD-215423 -
International Journal of Molecular... Aug 2023Alzheimer's disease (AD) is the most common neurodegenerative pathology among progressive dementias, and it is characterized by the accumulation in the brain of...
Alzheimer's disease (AD) is the most common neurodegenerative pathology among progressive dementias, and it is characterized by the accumulation in the brain of extracellular aggregates of beta-amyloid proteins and neurofibrillary intracellular tangles consisting of τ-hyperphosphorylated proteins. Under normal conditions, beta-amyloid peptides exert important trophic and antioxidant roles, while their massive presence leads to a cascade of events culminating in the onset of AD. The fibrils of beta-amyloid proteins are formed by the process of fibrillogenesis that, starting from individual monomers of beta-amyloid, can generate polymers of this protein, constituting the hypothesis of the "amyloid cascade". To date, due to the lack of pharmacological treatment for AD without toxic side effects, chemical research is directed towards the realization of hybrid compounds that can act as an adjuvant in the treatment of this neurodegenerative pathology. The hybrid compounds used in this work include moieties of a hydroxytyrosol, a nitrohydroxytyrosol, a tyrosol, and a homovanillyl alcohol bound to the N-benzylpiperidine moiety of donepezil, the main drug used in AD. Previous experiments have shown different properties of these hybrids, including low toxicity and antioxidant and chelating activities. The purpose of this work was to test the effects of hybrid compounds mixed with A to induce fibrillogenesis and mimic AD pathogenesis. This condition has been studied both in test tubes and by an in vitro model of neuronal differentiated human SH-SY5Y neuroblastoma cells. The results obtained from test tube experiments showed that some hybrids inhibit the activity of the enzymes AChE, BuChE, and BACE-1. Cell experiments suggested that hybrids could inhibit fibrillogenesis, negatively modulating caspase-3. They were also shown to exert antioxidant effects, and the acetylated hybrids were found to be more functional and efficient than nonacetylated forms.
Topics: Humans; Alzheimer Disease; Donepezil; Antioxidants; Neuroblastoma; tau Proteins
PubMed: 37686262
DOI: 10.3390/ijms241713461