Biomol Ther  
The Effects of Donepezil, an Acetylcholinesterase Inhibitor, on Impaired Learning and Memory in Rodents
Chang Yell Shin1,2, Hae-Sun Kim1, Kwang-Ho Cha1, Dong Han Won1, Ji-Yun Lee2, Sun Woo Jang1,* and Uy Dong Sohn2,*
1Research Institute of Dong-A ST Co., Ltd., Yongin 17073,
2College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea
E-mail: (Jang SW), (Sohn UD)
Tel: +82-31-280-1324 (Jang SW), +82-2-820-5614 (Sohn UD)
Fax: +82-31-282-8564 (Jang SW), +82-2-826-8752 (Sohn UD)
Received: September 25, 2017; Revised: October 25, 2017; Accepted: November 7, 2017; Published online: February 21, 2018.
© The Korean Society of Applied Pharmacology. All rights reserved.

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.
Keywords: Acetylcholinesterase activity, Donepezil, Pharmacokinetic, Pharmacodynamic, Y-maze

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