Donepezil hydrochloride: A treatment drug for Alzheimer?s disease

Sugimoto, Hachiro

doi:10.1002/1528-0691(2001)1:1<63::aid-tcr9>3.0.co;2-j

Cited by 66 publications

(19 citation statements)

References 15 publications

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“…Donepezil, which is an inhibitor of acetylcholinesterase (AChE) and thereby leads to increased concentrations of acetylcholine in the brain, is widely used for the treatment of patients with Alzheimer's disease [4] . Of note, recent clinical data suggested that donepezil administration dose-dependently reduced the increased risk of hip fracture independently of falling in patients with Alzheimer's disease [5] .…”

Section: Introductionmentioning

confidence: 99%

Donepezil prevents RANK-induced bone loss via inhibition of osteoclast differentiation by downregulating acetylcholinesterase

Sato

Enoki

Sakamoto

et al. 2015

Heliyon

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ObjectiveDonepezil, an inhibitor of acetylcholinesterase (AChE) targeting the brain, is a common medication for Alzheimer's disease. Interestingly, a recent clinical study found that administration of this agent is associated with lower risk of hip fracture independently of falling, suggesting its direct effect on bone tissues as well. AChE has been reported to be involved in osteoblast function, but the role of AChE on osteoclastogenesis still remains unclear. We analyzed the effect of AChE and donepezil on osteoclastogenesis in vivo and in vitro.MethodsCell-based assays were conducted using osteoclasts generated in cultures of murine bone marrow macrophages (BMMs) with receptor activator of nuclear factor-kappa B ligand (RANKL). The effect of donepezil was also determined in vivo using a mouse model of RANKL-induced bone loss.ResultsRecombinant AChE in BMMs cultured with RANKL further promoted RANKL-induced tartrate-resistant acid phosphatase (TRAP)-positive osteoclast differentiation. RANKL also upregulated AChE expression in BMMs. RNA interference-mediated knockdown of AChE significantly inhibited RANKL-induced osteoclast differentiation and suppressed gene expression specific for osteoclasts. AChE upregulated expression of RANK, the receptor of RANKL, in BMMs. Donepezil decreased cathepsin K expression in BMMs and the resorptive function of osteoclasts on dentine slices. Donepezil decreased RANK expression in BMMs, resulting in the inhibition of osteoclast differentiation with downregulation of c-Fos and upregulation of Id2. Moreover, administration of donepezil prevented RANKL-induced bone loss in vivo, which was associated with the inhibition of bone resorption by osteoclasts.ConclusionsAChE promotes osteoclast differentiation in vitro. Donepezil inhibits osteoclast function in vitro and prevents bone loss by suppressing bone resorption in vivo, suggesting the possibility that donepezil reduces fracture risk in patients with Alzheimer's disease.

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Section: Introductionmentioning

confidence: 99%

Donepezil prevents RANK-induced bone loss via inhibition of osteoclast differentiation by downregulating acetylcholinesterase

Sato

Enoki

Sakamoto

et al. 2015

Heliyon

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“…DPZ is known to inhibit AChE and to delay the progression of AD symptoms [3]. The effective plasma concentration of DPZ has been reported to be 10-20 ng/ml, but there are no reliable data available on the optimum dose [6].…”

Section: Discussionmentioning

confidence: 99%

“…Although the pathogenic mechanism has not been elucidated yet, the level of acetylcholine in the brain has been found to decrease in AD patients, which might be important in the pathogenesis and progression of this disease [1,2]. Donepezil hydrochloride (DPZ), an acetylcholinesterase (AChE) inhibitor, has been shown to prevent the progression of AD symptoms, probably through increasing the acetylcholine level in the brain [3]. In addition, it has recently been suggested that DPZ reduces β-amyloid plaque in vitro, which might contribute to its anti-AD effects [4].…”

Section: Introductionmentioning

confidence: 99%

Effects of Different Administration Protocols on the Plasma Concentration of Donepezil Hydrochloride in Dementia Patients with Stage 5 Chronic Kidney Disease

et al. 2013

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The prevalence of chronic kidney disease (CKD) as well as Alzheimer's disease (AD) increases with age. With the aging of the population in Japan, there is an increasing likelihood that patients with CKD will receive donepezil hydrochloride (DPZ), an antidementia drug, in the near future. Nevertheless, there have been few reports on how to use DPZ in patients with severe CKD. We report on 2 CKD stage 5 patients who received DPZ under different prescriptions. In case 1, 3 mg/day of DPZ was initially administered for 4 months, after which the dose was increased to 5 mg/day. In case 2, 5 mg was administered twice a week. The plasma concentration of DPZ was measured and the effectiveness was assessed using the Mini-Mental Health State Examination and the Hasegawa Dementia Rating Scale. We found that (1) only a slight increase in the plasma concentration of DPZ was observed with a dose of 3 mg daily, (2) there was a significant increase in the plasma concentration with a dose of 5 mg daily, and (3) when 5 mg of DPZ was administered twice a week, the plasma concentration did not differ significantly from healthy controls who had received 5 mg daily. Although cognitive function was improved best when the 5-mg dose was administered daily with no apparent side effects, the plasma concentration came close to reaching a toxic level at this dose. Careful follow-up may be essential when DPZ is used at 5 mg/day or greater in severe CKD patients.

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“…The current therapeutic approach exploits the enhancement of the central cholinergic function [13] to increase the acetylcholine levels in the brain. As a result, various cholinergic drugs, such as tacrine, [14] donepezil, [15] rivastigmine, [16] and more recently galantamine [17] have been developed to alleviate the symptoms of AD (Fig. 1 ).…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of New Dual Binding Site Cholinesterase Inhibitors: in vitro Inhibition Studies with in silico Docking

Yar¹,

Bajda²,

Mehmood³

et al. 2014

LDDD

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Cholinesterases (ChEs) play a vital role in the regulation of cholinergic transmission. The inhibition of ChEs is considered to be involved in increasing acetylcholine level in the brain and thus has been implicated in the treatment of Alzheimer’s disease. We have designed and synthesized a series of novel indole derivatives and screened them for inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Most of the tested compounds exhibited inhibitory activity against AChE and BChE. Among them 4f and 6e showed the highest AChE inhibitory activity with IC50 91.21±0.06 and 68.52±0.04 μM, respectively. However compound 5a exhibited the highest inhibitory activity against BChE (IC50 55.21±0.12 μM).

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Donepezil hydrochloride: A treatment drug for Alzheimer?s disease

Cited by 66 publications

References 15 publications

Donepezil prevents RANK-induced bone loss via inhibition of osteoclast differentiation by downregulating acetylcholinesterase

Donepezil prevents RANK-induced bone loss via inhibition of osteoclast differentiation by downregulating acetylcholinesterase

Effects of Different Administration Protocols on the Plasma Concentration of Donepezil Hydrochloride in Dementia Patients with Stage 5 Chronic Kidney Disease

Design and Synthesis of New Dual Binding Site Cholinesterase Inhibitors: in vitro Inhibition Studies with in silico Docking

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