The Effects of Donepezil, an Acetylcholinesterase Inhibitor, on Impaired Learning and Memory in Rodents

( Chang Yell Shin ),( Hae-sun Kim ),( Kwang-ho Cha ),( Dong Han Won ),( Ji-yun Lee ),( Sun Woo Jang ),( Uy Dong Sohn ) 한국응용약물학회 2018 Biomolecules & Therapeutics(구 응용약물학회지) Vol.26 No.3

A previous study in humans demonstrated the sustained inhibitory effects of donepezil on acetylcholinesterase (AChE) activity; however, the effective concentration of donepezil in humans and animals is unclear. This study aimed to characterize the effective concentration of donepezil on AChE inhibition and impaired learning and memory in rodents. A pharmacokinetic study of donepezil showed a mean peak plasma concentration of donepezil after oral treatment (3 and 10 mg/kg) of approximately 1.2 ± 0.4 h and 1.4 ± 0.5 h, respectively; absolute bioavailability was calculated as 3.6%. Further, AChE activity was inhibited by increasing plasma concentrations of donepezil, and a maximum inhibition of 31.5 ± 5.7% was observed after donepezil treatment in hairless rats. Plasma AChE activity was negatively correlated with plasma donepezil concentration. The pharmacological effects of donepezil are dependent upon its concentration and AChE activity; therefore, we assessed the effects of donepezil on learning and memory using a Y-maze in mice. Donepezil treatment (3 mg/kg) significantly prevented the progression of scopolamine-induced memory impairment in mice. As the concentration of donepezil in the brain increased, the recovery of spontaneous alternations also improved; maximal improvement was observed at 46.5 ± 3.5 ng/g in the brain. In conclusion, our findings suggest that the AChE inhibitory activity and pharmacological effects of donepezil can be predicted by the concentration of donepezil. Further, 46.5 ± 3.5 ng/g donepezil is an efficacious target concentration in the brain for treating learning and memory impairment in rodents.

The Effects of Donepezil, an Acetylcholinesterase Inhibitor, on Impaired Learning and Memory in Rodents

신창열,김해선,차광호,원동한,이지윤,장선우,손의동 한국응용약물학회 2018 Biomolecules & Therapeutics(구 응용약물학회지) Vol.26 No.3

A previous study in humans demonstrated the sustained inhibitory effects of donepezil on acetylcholinesterase (AChE) activity; however, the effective concentration of donepezil in humans and animals is unclear. This study aimed to characterize the effective concentration of donepezil on AChE inhibition and impaired learning and memory in rodents. A pharmacokinetic study of donepezil showed a mean peak plasma concentration of donepezil after oral treatment (3 and 10 mg/kg) of approximately 1.2 ± 0.4 h and 1.4 ± 0.5 h, respectively; absolute bioavailability was calculated as 3.6%. Further, AChE activity was inhibited by increasing plasma concentrations of donepezil, and a maximum inhibition of 31.5 ± 5.7% was observed after donepezil treatment in hairless rats. Plasma AChE activity was negatively correlated with plasma donepezil concentration. The pharmacological effects of donepezil are dependent upon its concentration and AChE activity; therefore, we assessed the effects of donepezil on learning and memory using a Y-maze in mice. Donepezil treatment (3 mg/kg) significantly prevented the progression of scopolamine-induced memory impairment in mice. As the concentration of donepezil in the brain increased, the recovery of spontaneous alternations also improved; maximal improvement was observed at 46.5 ± 3.5 ng/g in the brain. In conclusion, our findings suggest that the AChE inhibitory activity and pharmacological effects of donepezil can be predicted by the concentration of donepezil. Further, 46.5 ± 3.5 ng/g donepezil is an efficacious target concentration in the brain for treating learning and memory impairment in rodents.

The Effects of Donepezil, an Acetylcholinesterase Inhibitor, on Impaired Learning and Memory in Rodents

Shin, Chang Yell,Kim, Hae-Sun,Cha, Kwang-Ho,Won, Dong Han,Lee, Ji-Yun,Jang, Sun Woo,Sohn, Uy Dong The Korean Society of Applied Pharmacology 2018 Biomolecules & Therapeutics(구 응용약물학회지) Vol.26 No.3

A previous study in humans demonstrated the sustained inhibitory effects of donepezil on acetylcholinesterase (AChE) activity; however, the effective concentration of donepezil in humans and animals is unclear. This study aimed to characterize the effective concentration of donepezil on AChE inhibition and impaired learning and memory in rodents. A pharmacokinetic study of donepezil showed a mean peak plasma concentration of donepezil after oral treatment (3 and 10 mg/kg) of approximately $1.2{\pm}0.4h$ and $1.4{\pm}0.5h$, respectively; absolute bioavailability was calculated as 3.6%. Further, AChE activity was inhibited by increasing plasma concentrations of donepezil, and a maximum inhibition of $31.5{\pm}5.7%$ was observed after donepezil treatment in hairless rats. Plasma AChE activity was negatively correlated with plasma donepezil concentration. The pharmacological effects of donepezil are dependent upon its concentration and AChE activity; therefore, we assessed the effects of donepezil on learning and memory using a Y-maze in mice. Donepezil treatment (3 mg/kg) significantly prevented the progression of scopolamine-induced memory impairment in mice. As the concentration of donepezil in the brain increased, the recovery of spontaneous alternations also improved; maximal improvement was observed at $46.5{\pm}3.5ng/g$ in the brain. In conclusion, our findings suggest that the AChE inhibitory activity and pharmacological effects of donepezil can be predicted by the concentration of donepezil. Further, $46.5{\pm}3.5ng/g$ donepezil is an efficacious target concentration in the brain for treating learning and memory impairment in rodents.

Cholinesterase Inhibitor Donepezil Increases Mitochondrial Biogenesis through AMP-Activated Protein Kinase in the Hippocampus

Kim, Eosu,Park, Minsun,Jeong, Jihyeon,Kim, Hyunjeong,Lee, Su Kyoung,Lee, Eun,Oh, Byoung Hoon,Namkoong, Kee S. Karger 2016 Neuropsychobiology Vol.73 No.2

<P>Objective: Donepezil, a widely prescribed drug for Alzheimer's disease (AD), is now considered to have multimodal actions beyond cholinesterase inhibition. We aimed to see whether donepezil enhances mitochondrial biogenesis and relevant signaling pathways since mitochondrial dysfunction is a key feature of the hypometabolic AD brain. Methods: As a metabolic gauge, AMP-activated protein kinase (AMPK) was investigated as a tentative mediator of neurometabolic action of donepezil. Changes in phospho-AMPK levels, mitochondrial biogenesis, and ATP levels were measured upon donepezil treatment using neuroblastoma cells, primary cultured neurons and ex vivo hippocampal tissue of adult mice. Results: Donepezil dose-dependently increased mitochondrial biogenesis and ATP levels as well as expression of PGC-1 alpha and NRF-1 in neuroblastoma cells. Donepezil dose-dependently activated AMPK; however, inhibition of AMPK abolished the observed effects of donepezil, indicating that AMPK is a key mediator of donepezil's action. Notably, mitochondrial biogenesis upon donepezil treatment was mainly observed within dendritic regions of primary cultured hippocampal neurons. Levels of synaptic markers were also increased by donepezil. Finally, AMPK-dependent mitochondrial biogenesis by donepezil was confirmed in organotypic hippocampal tissue. Conclusions: Our findings indicate that AMPK/PGC-1 alpha signaling is involved in beneficial actions of donepezil on neurometabolism. Pharmacological activation of AMPK might be a promising approach to counteract AD pathogenesis associated with brain hypometabolism. (C) 2016 S. Karger AG, Basel</P>

알츠하이머병 치매 환자에서 도네페질(Donepezil)에 대한 최초 투약군과 전환군 간의 임상적 효용 비교 평가 : 12개월 추적관찰 연구

강효신(Hyo Shin Kang),안인숙(Inn Sook Ahn),윤지혜(Ji Hae Yun),문유진(Yu Jin Moon),황태영(Tae Young Hwang),이영민(Young Min Lee),김혜란(Hyeran Kim),정재원(Jae Won Chung),김도관(Doh Kwan Kim) 대한노인정신의학회 2010 노인정신의학 Vol.14 No.2

Objectives : The purpose of this study was to compare the efficacy between switching patients with Alzheimer's disease (AD) from galantamine or rivastigmine to donepezil because they were not responding adequately, and naive patients with AD who initiated therapy with donepezil. Methods : A total of 108 patients were recruited for this 52-week study. The effect of donepezil on cognitive function was measured using Alzheimer's Disease Assessment Scale-cognitive subscale-preliminary Korean version (ADAS-cog-K). Patients' activities of daily living using Seoul-Activities of Daily Living (S-ADL) and the Seoul-Instrumental Activities of Daily Living (S-IADL);behavioral symptoms using the Korean version Neuropsychiatric Inventory (K-NPI) were measured at baseline, 13-weeks, 26-weeks, 39-weeks and 52-weeks. We defined the responsive patients to donepezil at those who showed a cognitive improvement or no change during the first six-month clinical trial. Results : 86 naive patients and 22 switching patients were enrolled in the study. 74 patients completed the study and 34 discontinued their treatment before week 52. There was no significant difference between two patient groups in demographic data, baseline characteristics and dementia severity except duration of illness. The total ADAS-cog-K scores were not significantly different from baseline after 52 weeks of treatment in both groups. Both groups demonstrated deterioration of S-ADL and S-IADL at 52 weeks. The NPI scores did not significantly change in both groups. Based on the operational criteria, 61.6% of the naive group and 54.5% of the switching group were responders to donepezil. Conclusion : The switching group had similar levels of efficacy with the naive group who initiated therapy with donepezil. These results suggest that patients not responding adequately to rivastigmine or galantamine may improve or stabilize after switching to donepezil and prior medication does not effect donepezil's efficacy.

Donepezil, a Potent Acetylcholinesterase Inhibitor, Induces Caspase-Dependent Apoptosis in Human Promyelocytic Leukemia HL-60 Cells

Ki, Yo Sook,Park, Eun Young,Lee, Heon-Woo,Oh, Myung Sook,Cho, Young-Wuk,Kwon, Yunhee K<small>IM</small>,Moon, Ji Hee,Lee, Kyung-Tae Pharmaceutical Society of Japan 2010 Biological & pharmaceutical bulletin Vol.33 No.6

<P>Although donepezil, a potent acetylcholinesterase (AChE) inhibitor, has been used to treat Alzheimer's disease (AD) due to its neuroprotective effects, its mode of action to inhibit the growth of cancer cells is poorly understood. In the present study, we investigated the pro-apoptotic activities of donepezil in HL-60 human promyelocytic leukemia cells and the underlying molecular mechanism involved. It was found that donepezil induced the apoptosis of HL-60 and U937 cells in a dose- and time-dependent manner, as evidenced by the formation of DNA fragmentation and the accumulation of positive cells for Annexin V. In addition, the activations of caspase-8, -9, and -3 were significantly increased 36 h after donepezil treatment. Furthermore, the broad caspase inhibitor (z-VAD-fmk) blocked donepezil-induced apoptosis. In addition, donepezil was found to cause the loss of mitochondrial membrane potential (ΔΨ<SUB>m</SUB>), to increase the release of cytochrome <I>c</I> to the cytosol, and to alter the expressions of Bcl-2 family proteins. Taken together, these results demonstrate for the first time that donepezil displayed an induction of apoptosis in HL-60 cells <I>via</I> a mitochondria-mediated caspase-dependent pathway.</P>

순수 알츠하이머병 치매 환자군과 혼합성 치매 환자군에서 12개월간의 도네페질(Donepezil) 투여에 따른 치료 성적의 비교 평가

강효신(Hyo Shin Kang),안인숙(Inn Sook Ahn),윤지혜(Ji Hae Yun),문유진(Yu Jin Moon),황태영(Tae Young Hwang),이영민(Young Min Lee),김혜란(Hyeran Kim),정재원(Jae Won Chung),김도관(Doh Kwan Kim) 대한노인정신의학회 2010 노인정신의학 Vol.14 No.1

Objectives:The purpose of this study was to compare the efficacy of donepezil treatment between patients with pure Alzheimer’s disease (AD) and Mixed dementia (MD) during a 12-month trial. Methods:A total of 139 patients were recruited for this 52-week study. The effect of donepezil on cognitive function was measured using Alzheimer’s Disease Assessment Scale-cognitive subscale-preliminary Korean version (ADAS-cog-K). Patients’ activities of daily living using the Seoul-Instrumental Activities of Daily Living (S-IADL) and Seoul-Activities of Daily Living (S-ADL);behavioral symptoms using the Korean version Neuropsychiatric Inventory (K-NPI) were measured at baseline, 13-weeks, 26-weeks, 39-weeks and 52-weeks. We defined the responsive patients to donepezil at those who showed a cognitive improvement or no change during the first six-month clinical trial. Results:84 pure AD patients and 34 MD patients were available for intent-to-treat (ITT) last observation carried forward (LOCF) analysis. There was no significant difference between two groups in mean change from baseline in the total ADAS-cog-k, S-ADL, SIADL and K-NPI scores at 52-week. Based on the operational criteria, 60.7% of pure AD patients and 58.8% of MD patients were responders to donepezil. Conclusion:MD patients had similar levels of efficacy with pure AD patients and donepezil was well tolerated in both groups. These results suggest that donepezil is an effective and well-tolerated treatment for MD patients as well as for pure AD patients.

Prediction of Treatment Response to Donepezil using Automated Hippocampal Subfields Volumes Segmentation in Patients with Mild Alzheimer’s Disease

엄유현,김태원,정종현,서호준,한진희,홍승철,이창욱,임현국 대한신경정신의학회 2017 PSYCHIATRY INVESTIGATION Vol.14 No.5

Previous studies reported some relationships between donepezil treatment and hippocampus in Alzheimer’s disease (AD). However, due to methodological limitations, their close relationships remain unclear. The aim of this study is to predict treatment response to donepezil by utilizing the automated segmentation of hippocampal subfields volumes (ASHS) in AD. Sixty four AD patients were prescribed with donepezil and were followed up for 24 weeks. Cognitive function was measured to assess whether there was a response from the donepezil treatment. ASHS was implemented on non-responder (NR) and responder (TR) groups, and receiver operator characteristic (ROC) analysis was conducted to evaluate the sensitivity, specificity, and accuracy of hippocampal subfields in predicting response to donepezil. The left total hippocampus and the CA1 area of the NR were significantly smaller than those of the TR group. The ROC curve analysis showed the left CA1 volumes showed highest area under curve (AUC) of 0.85 with a sensitivity of 88.0%, a specificity of 74.0% in predicting treatment response to donepezil treatment. We expect that hippocampal subfields volume measurements that predict treatment responses to current AD drugs will enable more evidence-based, individualized prescription of medications that will lead to more favorable treatment outcomes.

Bioequivalence study of Donepezil hydrochloride in healthy Korean volunteers

최예원,장인진,임성빈,유경상,김보형 대한임상약리학회 2015 Translational and Clinical Pharmacology Vol.23 No.1

Donepezil is a centrally acting, reversible acetylcholinesterase inhibitor that is widely used for treating Alzheimer’s disease. This study aimed to compare the pharmacokinetics of Bastia®, a test tablet formulation of donepezil hydrochloride 10 mg, with those of Aricept®, the reference tablet formulation of donepezil hydrochloride 10 mg, in healthy Korean male volunteers. A randomized, singledose, two-way crossover study was conducted in 32 subjects. Subjects received a single dose of either test or reference compound and the alternate drug after a 4-week washout period. Serial blood samples for pharmacokinetic analysis were collected prior to dosing and periodically for 288 h after dosing for measurement of the plasma concentrations of donepezil. A non-compartmental method was used to estimate the pharmacokinetic parameters. The maximum concentration (Cmax) and the area under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUC288h) for the two formulations were compared to evaluate bioequivalence. The Cmax of the test and reference drugs were 27.58±7.46 and 26.35±6.51 μg/L (mean±SD), respectively, while AUC288h was 1080.14±229.77 and 1043.07±242.28 μg·h/L (mean±SD), respectively. The geometric mean ratios (90% confidence interval) of the Cmax and AUC288h of the two tablets were 1.043 (0.990- 1.099) and 1.039 (1.013-1.065). In conclusion, the newly formulated tablet of donepezil hydrochloride 10 mg is bioequivalent to the currently marketed 10 mg tablet

Development of donepezil-induced hypokalemia following treatment of cognitive impairment

( Dongryul Kim ),( Hye Eun Yoon ),( Hoon Suk Park ),( Seok Joon Shin ),( Bum Soon Choi ),( Byung Soo Kim ),( Tae Hyun Ban ) 영남대학교 의과대학 2021 Yeungnam University Journal of Medicine Vol.38 No.1

Donepezil is a cholinesterase inhibitor used extensively to treat Alzheimer disease. The increased cholinergic activity is associated with adverse effects, therefore gastrointestinal symptoms, including nausea, vomiting, and diarrhea, are common. Hypokalemia is a rare adverse event that occurs in less than 1% of donepezil-treated patients. Although hypokalemia of mild and moderate grade does not present serious signs and symptoms, severe hypokalemia often results in prolonged hospitalization and mortality. Herein, we report a case of hypokalemia developed after the initiation of donepezil therapy for cognitive impairment.