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Postoperative Administration of the Acetylcholinesterase Inhibitor, Donepezil, Interferes with Bone Healing and Implant Osseointegration in a Rat Model.

ABSTRACT: Donepezil is an acetylcholinesterase inhibitor commonly used to treat mild to moderate Alzheimer's disease. Its use has been associated with increased bone mass in humans and animals. However, the effect of postoperative administration of donepezil on bone healing remains unknown. Therefore, this study aimed to assess the impact of postoperative injection of donepezil on bone healing, titanium-implant osseointegration, and soft tissue healing. Twenty-two Sprague-Dawley rats were randomly assigned to receive a daily dose of either donepezil (0.6 mg/kg) or saline as a control. In each rat, a uni-cortical defect was created in the right tibia metaphysis and a custom-made titanium implant was placed in the left tibiae. After two weeks, rats were euthanized, and their bones were analysed by Micro-CT and histology. The healing of bone defect and implant osseointegration in the rats treated with donepezil were significantly reduced compared to the saline-treated rats. Histomorphometric analysis showed lower immune cell infiltration in bone defects treated with donepezil compared to the saline-treated defects. On the other hand, the healing time of soft tissue wounds was significantly shorter in donepezil-treated rats compared to the controls. In conclusion, short-term administration of donepezil hinders bone healing whereas enhancing soft tissue healing.

SUBMITTER: Al-Hamed FS

PROVIDER: S-EPMC7563209 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Postoperative Administration of the Acetylcholinesterase Inhibitor, Donepezil, Interferes with Bone Healing and Implant Osseointegration in a Rat Model.

Al-Hamed Faez Saleh FS Maria Ola M OM Phan Jeff J Al Subaie Ahmed A Gao Qiman Q Mansour Alaa A Abu Nada Lina L Boukhatem Imane I Elkashty Osama A OA Tran Simon D SD Lordkipanidzé Marie M Badran Zahi Z Tamimi Faleh F

Biomolecules 20200914 9

Donepezil is an acetylcholinesterase inhibitor commonly used to treat mild to moderate Alzheimer's disease. Its use has been associated with increased bone mass in humans and animals. However, the effect of postoperative administration of donepezil on bone healing remains unknown. Therefore, this study aimed to assess the impact of postoperative injection of donepezil on bone healing, titanium-implant osseointegration, and soft tissue healing. Twenty-two Sprague-Dawley rats were randomly assigne ...[more]

PMID: 32937955

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Project description: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.

Project description:It is difficult to investigate the whole-body distribution of an orally administered drug by means of positron emission tomography (PET), owing to the short physical half-life of radionuclides, especially when 11C-labeled compounds are tested. Therefore, we aimed to examine the whole-body distribution of donepezil (DNP) as an acetylcholinesterase inhibitor by means of 11C-DNP PET imaging, combined with the oral administration of pharmacological doses of DNP.We studied 14 healthy volunteers, divided into group A (n=4) and group B (n=10). At first, we studied four females (mean age: 57.3±4.5 y), three of whom underwent 11C-DNP PET scan at 2.5 h after the oral administration of 1 mg and 30 µg of DNP, respectively, while one patient was scanned following the oral administration of 30 µg of DNP (group A). Then, we studied five females and five males (48.3±6.1 y), who underwent 11C-DNP PET scan, without the oral administration of DNP (group B). Plasma DNP concentration upon scanning was measured by tandem mass spectrometry. Arterialized venous blood samples were collected periodically to measure plasma radioactivity and metabolites. In group A, 11C-DNP PET scan of the brain and whole body continued for 60 and 20 min, respectively. Subjects in group B underwent sequential whole-body scan for 60 min. The regional uptake of 11C-DNP was analyzed by measuring the standard uptake value (SUV) through setting regions of interest on major organs with reference CT.In group A, plasma DNP concentration was significantly correlated with the orally administered dose of DNP. The mean plasma concentration was 2.00 nM (n=3) after 1 mg oral administration and 0.06 nM (n=4) after 30 µg oral administration. No significant difference in plasma radioactivity or fraction of metabolites was found between groups A and B. High 11C-DNP accumulation was found in the liver, stomach, pancreas, brain, salivary glands, bone marrow, and myocardium in groups A and B, in this order. No significant difference in SUV value was found among 11C-DNP PET studies after the oral administration of 1 mg of DNP, 30 µg of DNP, or no DNP.The present study demonstrated that the whole-body distribution of DNP after the oral administration of pharmacological doses could be evaluated by 11C-DNP PET studies, combined with the oral administration of DNP.

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Postoperative Administration of the Acetylcholinesterase Inhibitor, Donepezil, Interferes with Bone Healing and Implant Osseointegration in a Rat Model.

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Postoperative Administration of the Acetylcholinesterase Inhibitor, Donepezil, Interferes with Bone Healing and Implant Osseointegration in a Rat Model.

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