Effects Of Donepezil Research Articles

Effect of Donepezil on Cognitive Disorders Due to the Selective Serotonin Reuptake Inhibitors in the Patients with Major Depressive Disorder

Introduction: Many factors cause cognitive impairment, including medication, such as selective serotonine reuptake inhibitor drugs use. On the other hand, many drugs are used in cognitive impairment therapy, including donepezil, which act by inhibiting the cholinesterase enzyme and increase brain acetylcholine. Methods: This study was a double-blind controlled randomized controlled clinical trial on the 73 numbers of 20-50 years-old patients treated with selective serotonine reuptake inhibitor drugs using Montreal Cognitive Assessment Test. They were randomly divided into two groups: placebo recipient and donepezil recipient. The Montreal Cognitive Test- reliability 92% and IC 83% - was performed two months after drug administration in both groups.The results were analyzed by Mann-Whitney, Chi-Square, T-test and has been reviewed by SPSS Inc., Chicago, IL; Version 16. Results: There was a significant difference in the Montreal Cognitive Test score before and after the intervention in the Donepezil group as the score increased. (Paired-T Test & P-Value < 0.0001). There was also a significant difference in Montreal Cognitive Test scores before and after the intervention in the placebo group (Paired-T Test & P-Value < 0.0001) as the score dropped.Conclusion: Cholinesterase inhibitors, such as donepezil, have had beneficial effects in improving cognitive impairment caused by selective serotonin reuptake inhibitor drugs compared to placebo.

Intracerebroventricular infusion of donepezil prevents cardiac remodeling and improves the prognosis of chronic heart failure rats

Oral administration of donepezil, a centrally acting acetylcholinesterase inhibitor, improves the survival of rats with chronic heart failure (CHF). The mechanisms of cardioprotective effects of donepezil, however, remain totally unknown. To elucidate potential mechanisms, we examined whether central microinfusion of donepezil would exert cardioprotection. Intracerebroventricular microinfusion pumps with cerebroventricular cannula were implanted in rats with myocardial infarction. The rats were randomly divided into central saline treatment (CST) and central donepezil treatment (CDT) groups. We evaluated cardiac remodeling and function after a 6-week treatment and examined the 160-day survival rate. Compared to the CST, the CDT markedly improved the 160-day survival rate (68% vs. 32%, P = 0.002) through the prevention of cardiac remodeling and the lowering of plasma catecholamine, brain natriuretic peptide, and angiotensin II. These results suggest that the central mechanism plays an important role in the cardioprotective effects of donepezil.

Effect of Donepezil and Vitamin B12 Supplement on Serum Thyroid Profile in Alzheimer’s Disease

Aims: The aim of this study was to investigate thyroid status in Alzheimer’s Disease (AD) patients and its response to donepezil and vitamin B12 supplement therapy for 6 months.
 Design: Case-Control Observational study.
 Place and Duration: Department of Biochemistry, GGMC & Sir J. J. Group of Hospitals, Mumbai, India between March 2017 and July 2019.
 Methodology: Case-Control study comprised of 71 AD patients and 70 healthy controls above 60 years of age. Blood serum samples were analyzed for thyroid hormones levels by the chemiluminescence method. AD patients were treated with donepezil (5 mg/day) and vitamin B12 supplement (1.5 mg/day) and thyroid profile was observed at intervals of 3 and 6 months. Statistical evaluation was done by using IMB SPSS statistics version 25.
 Results: Serum levels of thyroid hormones were low in euthyroid AD patients when compared with controls at the baseline level [T3 (120.64 ± 20.64 vs 127.8 ± 17.29), T4 (7.71 ± 2.34 vs 7.54 ± 1.85), FT3 (1.2 ± 0.13 vs 2.26 ± 0.63) and FT4 (0.79 ± 0.08 vs 1.29 ± 0.27)] except TSH which was increased in AD [TSH (2.71 ± 1.19 vs 2.34 ± 0.65)]. During follow-ups at 3 and 6 months, there was a slight decrease in TSH levels in response to the therapy.
 Conclusion: The AD patients were euthyroid with low T3, FT3 and FT4 serum levels and high TSH serum levels. Thyroid hormones might play a role as markers for disease progression. Donepezil and vitamin B12 therapy could not benefit restore the normal thyroid functioning in a period of 6 months. Further longitudinal research with larger cohort might help in elucidating thyroid dysfunction in AD and develop novel therapeutic strategies.

Effect of Donepezil on Cognitive Impairment, Quality of Life, and Depression in Multiple Sclerosis Patients: A Randomized Clinical Trial.

Background:Cognitive impairment is one of the debilitating consequences of multiple sclerosis (MS) with negative effects on daily life, individual and social activities, quality of life (QOL), and depression. No approved medication is introduced so far for affected individuals. We aimed to evaluate the efficacy of donepezil on cognitive performance, QOL, and depression in MS.Methods:This is a double-blinded randomized clinical trial conducted on 100 patients with MS during 2018. Patients were assessed prior to intervention abbreviated mental test (AMT), prospective and retrospective mental questionnaire (PRMQ), everyday memory questionnaire (EMQ), digit span test, Beck depression inventory (BDI), and MSQOL questionnaire. Then patients were randomly divided into two groups of treatment (daily regimen of 10 mg donepezil) and placebo for 3 months. Subjects were reassessed using the same instruments at the end of intervention.Results:Fifty patients remained in each group at the end of study. The mean age in donepezil and placebo groups was 31.9 ± 5.89 and 30.65 ± 5.43 years, respectively. EMQ, PRMQ, digit span test, MSQOL, and depression scores improved following donepezil therapy (P < 0.001) while no statistically significant difference was found in the placebo group (P > 0.05). Comparison of two groups also showed more favorable scores in donepezil group with respect to all assessment tools (P < 0.001).Conclusions:Donepezil could effectively improve cognitive impairment in MS patients. Also, its positive effect on QOL and depression could result in a smaller number of interventions in this group of patients.

Effect of donepezil and memantine on improvement of cognitive function in patients with temporal lobe epilepsy

Background:Cognitive impairment is a common complication of patients with temporal lobe epilepsy (TLE). Therefore, the aim of this study was to compare the effects of donepezil and memantine on improving the cognitive function of patients with TLE.Materials and Methods:In a clinical trial study, 70 patients with TLE were divided into two groups of 35 each: 10 mg doses of donepezil (first group) and memantine (second group) were applied for 16 weeks. The level of cognitive function of patients in both groups before and after treatment was determined using Montreal Cognitive Assessment (MoCA) test.Results:The mean score of MoCA before and after intervention was 23.55 ± 3.67 and 26.09 ± 2.5, respectively, in the group treated with memantine, and the mean score of intervention was significantly improved (P < 0.001). In the group treated with donepezil, the score before and after the operation was 23.87 ± 3.18 and 24.35 ± 2.17, respectively, and no significant difference was observed in this group (P = 0.38).Conclusion:Hence, memantine was better than donepezil in the improvement of cognitive impairment in patients with TLE.

Donepezil-induced oligodendrocyte differentiation is mediated through estrogen receptors.

Loss of oligodendrocytes, the myelin-forming cells of the central nervous system, and subsequent failure of myelin development result in serious neurological disorders such as multiple sclerosis. Using primary mouse embryonic neural stem cells (NSCs), we previously demonstrated that donepezil, an acetylcholinesterase inhibitor developed for the treatment of Alzheimer's disease, stimulates the differentiation of NSCs into oligodendrocytes and neurons, albeit at the expense of astrogenesis. However, the precise mechanisms underlying donepezil-induced differentiation remain unclear. In this study, we aimed at elucidating the molecular pathways contributing to donepezil-induced differentiation of mouse-induced pluripotent stem cell-derived neural stem cells (miPSC-NSCs). We used cell-based reporter gene arrays to investigate effects of donepezil on differentiation of miPSC-NSCs. Subsequently, we assessed the molecular pathway underlying donepezil action on differentiation of miPSC-NSCs into mature oligodendrocytes. Donepezil increased the transcriptional activity of estrogen response element under differentiating conditions. Moreover, estrogen receptors α (ERα) and β (ERβ) were highly expressed in MBP-positive mature oligodendrocytes. The ER antagonist ICI 182,780 abrogated the number of MBP-positive oligodendrocytes induced by donepezil, but showed no effect on the differentiation of miPSC-NSCs into Tuj1-positive neurons and GFAP-positive astrocytes. Furthermore, the donepezil-induced generation of mature oligodendrocytes from miPSC-NSC was significantly attenuated by antagonists and siRNA targeting ERα and ERβ. In conclusion, we demonstrated, for the first time, that donepezil-induced oligodendrogenesis is mediated through both ER subtypes, ERα and ERβ. Cover Image for this issue: https://doi.org/10.1111/jnc.14771.

Effects of augmenting cholinergic neurotransmission on balance in Parkinson's disease

IntroductionDegeneration of cholinergic systems may contribute to impairments of balance and gait in Parkinson's disease (PD) and phase 2 clinical trials have suggested that centrally acting cholinesterase inhibitors reduce falls. Here, we examined the effects of augmenting cholinergic neurotransmission on static and dynamic balance, indices of fall risk. MethodsA single-site, randomized, double-blind, crossover trial examined the effect of donepezil in patients with PD. Forty-nine participants with idiopathic PD were randomized and 45 completed the trial. Each treatment period was 6 weeks with a 6-week washout between treatments. Donepezil in 2.5 mg capsules, or identical appearing placebo capsules, was increased from two per day (5 mg) to four capsules (10 mg) after 3 weeks. The primary outcome measures were the range of the medio-lateral sway when standing (static balance) and the variability of the stride duration when walking (dynamic balance). A linear mixed model was used to investigate whether the change in outcomes between weeks 0 and 6 differed between phases. ResultsThere were no significant differences in treatment effects between placebo and donepezil for medio-lateral sway range during quiet standing (p = 0.28), nor in gait variability (p = 0.31). None of the secondary outcome measures or exploratory analyses were significant although one secondary measure of static balance was increased by donepezil. ConclusionsContrary to our hypothesis, cholinergic augmentation with donepezil at 10 mg/day for 6 weeks did not affect measures of static or dynamic balance in people with PD. These results are compared with other phase 2 trials of cholinesterase inhibitors and considerations for future trials are discussed.

P3501Oral administration of donepezil markedly prevents the progression of chronic heart failure in renal artery stenosis-induced hypertensive rats

Abstract Introduction Parasympathetic activation by donepezil has been shown to improve prognosis in chronic heart failure (CHF) rats following myocardial infarction. We examined whether donepezil is effective in the treatment of another CHF model complicated with renal artery stenosis (RAS)-induced hypertension. Methods RAS was created by ligating the left renal artery up to 50% in SD rats, at the same time, we implanted a blood pressure (BP) transmitter for confirming RAS-induced hypertension (7-week post-RAS: systolic BP = 154±7 mmHg; diastolic BP = 115±8 mmHg). At the 11th week after induction of RAS, surviving animals were randomly assigned to untreated (UT, n=10) or donepezil treated [DT, n=10, dissolved in drinking water (3mg/kg/day)] group. After a 6-week treatment, the effects of donepezil were evaluated by hemodynamics, blood levels of neurohumoral markers, and morphology. Results Compared with UT, DT significantly prevented the progression of the left kidney atrophy (2.38±0.13 vs. 1.51±0.34 g/kg, P&lt;0.05). DT also significantly improved cardiac remodeling, through suppressing the progression of cardiac hypertrophy (2.30±0.06 vs. 2.57±0.08 g/kg, P&lt;0.01), cardiac dysfunction [cardiac index: 102±3 vs. 86±3ml/min/kg, P&lt;0.05; left ventricular (LV) end-diastolic pressure: 12±2 vs. 20±2 mmHg, P&lt;0.05; LV dp/dtmin: 5856±259 vs. 4924±227 mmHg/sec, P&lt;0.05]. DT not only decreased serum levels of creatinine (0.54±0.02 vs. 0.63±0.03 mg/dl, P&lt;0.05) and uric acid (1.4±0.2 vs. 1.9±0.2 mg/dl, P&lt;0.05); but also decreased plasma levels of norepinephrine (273±38 vs. 846±242, P&lt;0.01), angiotensin II (17±2 vs. 23±2 pg/ml, P&lt;0.05), AVP (2729±347 vs. 4783±695 pg/ml, P&lt;0.05) and BNP (360±13 vs. 460±39 pg/ml, P&lt;0.05), and suppressed the systemic inflammation (CRP: 190±12 vs. 382±58 mg/ml, P&lt;0.01). Conclusions Donepezil treatment markedly prevented the progression of cardiac remodeling and renal dysfunction, and improved the neurohumoral markers in the CHF rat model complicated with RAS-induced hypertension, suggesting that donepezil may be used as a new pharmacotherapy for CHF patients complicated with RAS-induced hypertension.

Donepezil modulates amyloid precursor protein endocytosis and reduction by up-regulation of SNX33 expression in primary cortical neurons

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.

Donepezil ameliorates oxaliplatin-induced peripheral neuropathy via a neuroprotective effect

Oxaliplatin induces severe peripheral neuropathy. The effect of donepezil, a drug used for treatment of Alzheimer's disease, on oxaliplatin-induced peripheral neuropathy was investigated using both in vivo and in vitro models. Donepezil effectively attenuated oxaliplatin- and cisplatin-induced inhibition of neurite outgrowth in cultured PC12 cells. In a rat model, repeated oral administration of donepezil (5 times/week for 4 weeks) ameliorated oxaliplatin-induced mechanical allodynia (von Frey test) and sciatic nerve axonal degeneration. Moreover, donepezil did not inhibit the anti-tumor activity of oxaliplatin in any cultured cancer cell line. Therefore, donepezil may be useful for managing oxaliplatin-induced peripheral neuropathy.

P3‐041: A POTENTIAL TRI‐THERAPY FOR ALZHEIMER'S DISEASE

Cognitive symptoms in Alzheimer's disease (AD) are currently managed by moderately acting drugs which efficacy decreases fast over time. We previously showed that a combination of acamprosate and baclofen (PXT864) synergistically prevented cognitive impairments in AD mice. In this study, we investigated whether PXT864 could i) protect cognitive functions by synergizing with sub-therapeutic doses of donepezil (DNPz) to limit the occurrence of adverse events, or ii) rescue the efficacy of DNPz that is lost over time under therapeutic doses. We used the Aβ25-35 intracerebroventricular (ICV) injection mouse to model AD. First, PXT864 was tested in combination with sub-therapeutic doses of DNPz, both administered to mice before Aβ25-35 injection. Second, we modelized the loss of activity of DNPz treatment over time when initiated after Aβ25-35 ICV injection. Third, once DNPz effect was lost, we added PXT864 to DNPz and assessed the value of such tri-therapy. Efficacy was assessed by Y-maze and step-through passive avoidance cognitive tests. We found that combination of sub-therapeutic dose of PXT864 and DNPz yielded synergistic protection against Aβ-induced cognitive deficits. We then confirmed the declining efficacy of DNPz at a late stage of the disease in mice. Interestingly, adding PXT864 at that stage fully restored lost cognition in these animals that became all irresponsive to DNPz. These data highlight the importance of combinational strategies and suggest that PXT864 could be used either as a first line treatment or a second line treatment with a safe sub-therapeutic or even a full therapeutic dose of DNPz in Alzheimer's patients.

SUVN-502 + DONEPEZIL + MEMANTINE (TRIPLE COMBINATION): FIRST-IN-CLASS AND A PROMISING NEW APPROACH FOR THE SYMPTOMATIC TREATMENT OF ALZHEIMER'S DISEASE DEMENTIA

SUVN-502 is a pure 5-HT6 receptor antagonist being developed for the symptomatic treatment of Alzheimer's disease (AD). It has excellent ADME properties and robust efficacy in preclinical cognition models. SUVN-502 exhibited procognitive effects and modulated acetylcholine levels in brain regions relevant for cognition when administered alone. SUVN-502 has excellent margin of safety in long-term preclinical safety evaluation. In healthy human subjects, SUVN-502 was well tolerated following single or multiple oral administrations. SUVN-502 is being evaluated in a phase 2a multicenter, randomized, double-blind, parallel group, 26-week, placebo-controlled study. This study is regulated by US FDA. A total of 563 subjects with moderate Alzheimer's disease receiving stable doses of donepezil HCl and memantine HCl have been recruited. Randomized subjects received either placebo or SUVN-502 (50 or 100 mg) on top of stable doses of donepezil and memantine for 26 weeks. The effect of SUVN-502 + donepezil + memantine combination was evaluated in animal models for procognitive property (Morris water maze task), acetylcholine modulation (microdialysis) and theta modulation (electrophysiology). The pharmacokinetic interaction of the SUVN-502, donepezil and memantine was also studied in a satellite group of rats. Co-treatment of SUVN-502 with donepezil and memantine significantly potentiated the procognitive effects when compared with memantine and donepezil treatment alone in the Morris water maze task. SUVN-502 also potentiated the effects of donepezil and memantine combination in hippocampal acetylcholine levels and brain oscillatory activity. There were no significant changes in the exposures of SUVN-502 or donepezil or memantine. SUVN-502 + Donepezil + Memantine represent a first in class promising new approach for the symptomatic treatment of Alzheimer's disease. These preclinical results provide the strong rational for the design of currently ongoing SUVN-502 clinical study.

PQM130, a Novel Feruloyl-Donepezil Hybrid Compound, Effectively Ameliorates the Cognitive Impairments and Pathology in a Mouse Model of Alzheimer's Disease.

Alzheimer’s disease (AD) is the most frequent type of dementia in older people. The complex nature of AD calls for the development of multitarget agents addressing key pathogenic processes. Donepezil, an acetylcholinesterase inhibitor, is a first-line acetylcholinesterase inhibitor used for the treatment of AD. Although several studies have demonstrated the symptomatic efficacy of donepezil treatment in AD patients, the possible effects of donepezil on the AD process are not yet known. In this study, a novel feruloyl–donepezil hybrid compound (PQM130) was synthesized and evaluated as a multitarget drug candidate against the neurotoxicity induced by Aβ1-42 oligomer (AβO) injection in mice. Interestingly, PQM130 had already shown anti-inflammatory activity in different in vivo models and neuroprotective activity in human neuronal cells. The intracerebroventricular (i.c.v.) injection of AβO in mice caused the increase of memory impairment, oxidative stress, neurodegeneration, and neuroinflammation. Instead, PQM130 (0.5–1 mg/kg) treatment after the i.c.v. AβO injection reduced oxidative damage and neuroinflammation and induced cell survival and protein synthesis through the modulation of glycogen synthase kinase 3β (GSK3β) and extracellular signal–regulated kinases (ERK1/2). Moreover, PQM130 increased brain plasticity and protected mice against the decline in spatial cognition. Even more interesting is that PQM130 modulated different pathways compared to donepezil, and it is much more effective in counteracting AβO damage. Therefore, our findings highlighted that PQM130 is a potent multi-functional agent against AD and could act as a promising neuroprotective compound for anti-AD drug development.

Meta-Analysis of Randomized Controlled Trials on the Efficacy and Safety of Donepezil, Galantamine, Rivastigmine, and Memantine for the Treatment of Alzheimer's Disease.

To study the impact of donepezil, rivastigmine, galantamine, and memantine on cognitive, functional, behavioral, global changes and adverse effects in patients with mild, moderate and severe Alzheimer’s disease (AD), we screened the literature published before September 2017 in the Pubmed, Embase, Cochrane library and Web of Science Electronic databases according to the inclusion criteria. Thirty-six studies were finally determined from 1560 preliminary screened articles. The AD Assessment Scale-cognitive Subscale (ADAS-cog), AD Cooperative Study-Activities of Daily Living (ADCS-ADL), Neuropsychiatric Inventory (NPI), and Clinician’s Interview-Based Impression of Change Plus Caregiver Input scale (CIBIC+) were used as valid endpoints. Of the 36 trials included, meta-analyses of these placebo-control trials showed that there were significant differences between the donepezil, rivastigmine and placebo groups using ADAS-cog, ADCS-ADL, and CIBIC+. Meta-analyses of these placebo-controlled trials showed that there were significant differences between the galantamine and placebo groups using ADAS-cog, ADCS-ADL, NPI, and CIBIC+. These observations suggest that memantine is beneficial for stabilizing or slowing the decline in ADAS-cog and ADCS-ADL19 changes in AD patients. However, there was no significant effect according to the ADCS-ADL23, NPI, and CIBIC+ tests, which indicated that memantine treatment has no significant effect on these cognitive aspects of AD patients. Different effects of donepezil, rivastigmine, galantamine, or memantine on AD were found in this study. According to the results, we conclude that galantamine is effective in treating all aspects of AD and is the first choice for the treatment of AD. However, due to limited data, we should consider additional data to obtain more stable results.

Attenuating Effects of Myrothamnus flabellifolius Hydroethanolic Extract on Aluminium chloride Induced Amnesia in BALB/c Mice

Alzheimer’s disease (AD) is a neurodegenerative disease that commonly occurs in the elderly and affects memory, thinking and behaviour. Myrothamnus flabellifolius has been found to possess anti-oxidative properties that could possibly reduce oxidative stress in cells. This study was therefore carried out to investigate the in vivo effect of a crude extract of Myrothamnus flabellifolius on memory in an aluminium chloride induced Alzheimer’s disease mouse model. A total of 42 BALB/c mice were divided into 6 groups. Myrothamnus flabellifolius hydroethanolic extract was administered orally in doses of 100, 200 and 400 mg /kg to 3 of the groups simultaneously with AlCl3. Donepezil plus AlCl3 was used as a positive control and AlCl3 only as the negative control and control received normal saline only. The Y-maze and novel object recognition tests were carried out to ascertain the effects of these treatments on memory. Myrothamnus flabellifolius retained short term memory as demonstrated by the dose dependent increase in spontaneous alternation performance in the Y-maze task. At a dose of 400 mg/kg, it is comparable to the effect of donepezil. M. flabellifolius also showed a positive effect on memory in the short-term novel object recognition test as evidenced by the dose dependent increase in the discrimination index which was higher than that of donepezil. In the long-term memory task, it did not however show any effect on long term memory.

Effect of donepezil on the expression and responsiveness to LPS of CHRNA7 and CHRFAM7A in macrophages: A possible link to the cholinergic anti-inflammatory pathway

The α7 nicotinic acetylcholine receptor (CHRNA7) modulates the inflammatory response by activating the cholinergic anti-inflammatory pathway. CHRFAM7A, the human-restricted duplicated form of CHRNA7, has a negative effect on the functioning of α7 receptors, suggesting that CHRFAM7A expression regulation may be a key step in the modulation of inflammation in the human setting. The analysis of the CHRFAM7A gene's regulatory region reveals some of the mechanisms driving its expression and responsiveness to LPS in human immune cell models. Moreover, given the immunomodulatory potential of donepezil we show that it differently modulates CHRFAM7A and CHRNA7 responsiveness to LPS, thus contributing to its therapeutic potential.

The Effect of Donepezil in Radiotherapy-related Cognitive Impairment.

The Effect of Donepezil in Radiotherapy-related Cognitive Impairment.

Donepezil, a drug for Alzheimer's disease, promotes oligodendrocyte generation and remyelination.

Myelin sheaths play important roles in neuronal functions. In the central nervous system (CNS), the myelin is formed by oligodendrocytes (OLs), which are differentiated from oligodendrocyte precursor cells (OPCs). In CNS demyelinating disorders such as multiple sclerosis (MS), the myelin sheaths are damaged and the remyelination process is hindered. Small molecule drugs that promote OPC to OL differentiation and remyelination may provide a new way to treat these demyelinating diseases. Here we report that donepezil, an acetylcholinesterase inhibitor (AChEI) developed for the treatment of Alzheimer's disease (AD), significantly promotes OPC to OL differentiation. Interestingly, other AChEIs, including huperzine A, rivastigmine, and tacrine, have no such effect, indicating that donepezil's effect in promoting OPC differentiation is not dependent on the inhibition of AChE. Donepezil also facilitates the formation of myelin sheaths in OPC-DRG neuron co-culture. More interestingly, donepezil also promotes the repair of the myelin sheaths in vivo and provides significant therapeutic effect in a cuprizone-mediated demyelination animal model. Donepezil is a drug that has been used to treat AD safely for many years; our findings suggest that it might be repurposed to treat CNS demyelinating diseases such as MS by promoting OPC to OL differentiation and remyelination.

The acetylcholinesterase (AChE) inhibitor and anti-Alzheimer drug donepezil interacts with human erythrocytes

Donepezil is used to treat symptomatically the Alzheimer's disease (AD). This drug is a specific inhibitor of the enzyme acetylcholinesterase (AChE), whose main physiological function is to hydrolyze the neurotransmitter acetylcholine. The main objective of this work was to study the effect of donepezil on human erythrocytes as AChE is present in its membrane. For this purpose, human erythrocytes and molecular model of its membrane built-up of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE) were used. The latter correspond to classes of phospholipids present in the outer and inner monolayers of the human erythrocyte membrane, respectively. Our experimental evidences obtained from X-ray diffraction and differential scanning calorimetry (DSC) analysis indicated that donepezil was capable of interacting with both phospholipids. Fluorescence spectroscopy results showed a moderate increase in the fluidity of the hydrophobic tails of DMPC and isolated unsealed human erythrocyte membranes (IUM). On the other hand, results by scanning electron microscopy (SEM) and optical defocusing microscopy (DM) showed that the drug changed the normal biconcave shape of the erythrocytes inducing the formation of stomatocytes (cup-shaped cells). This effect was explained by the incorporation of donepezil molecules into the erythrocyte membrane and interactions with AChE.

Curcumin Ameliorates the Impaired Insulin Signaling Involved in the Pathogenesis of Alzheimer's Disease in Rats.

To date, dysregulation of the insulin signaling pathway in the brain has not been demonstrated unequivocally in Alzheimer’s disease (AD). The purpose of the study was to examine the possible dysregulation of insulin signaling pathway in an AD rat model. Furthermore, the present study investigated the effect of Donepezil and Curcumin on insulin signaling, insulin, and glucose levels in AD rat brain. The rats were induced to develop AD by intraperitoneal administration of Scopolamine. We found that glucose levels in plasma and brain were decreased in AD rats, whereas the insulin levels was increased in plasma but decreased in brain in AD rats. In addition, insulin signaling proteins IR-β, IGF-1, IRS-1, IRS-2 p-Akt (Ser473), and Akt were markedly reduced in the AD rats. Furthermore, GLUT3 and GLUT4 levels in the brain were markedly reduced in AD rats. All these data were compared to Saline-treated control rats. Curcumin significantly increased glucose levels in plasma and in brain. However, insulin levels was decreased in plasma and was increased in AD rats’ brain. Moreover, GLUT3 and GLUT4 levels were significantly increased in Curcumin-treated AD rats. All these data were compared to Scopolamine– induced AD rats. Thus amelioration of impaired insulin signaling and improved glucose regulation in AD rats by Curcumin may be beneficial in the management of AD.