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

Abstract

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.

An acetylcholinesterase inhibitor, donepezil, increases anxiety and cortisol levels in adult zebrafish

“…Furthermore, since donepezil exposure decreased AChE levels in zebrafish brain (Figure 2), these findings parallel rodent and human data on donepezil-evoked changes in brain AChE activity (Ben-Azu et al, 2019; Kasa et al, 2000; Shin et al, 2018), and corroborate the proposed link between cholinergic signaling and stress responses (Janowsky and Risch, 1984). However, the dose-dependent aspect of such effects on zebrafish behavior, cortisol, and AChE activity merit further consideration, since behavior and cortisol showed a clear dose-dependent curve here, whereas the AChE activity did not (Figures 1 and 2).…”

“…Indeed, zebrafish exposure to physostigmine and scopolamine (a muscarinic receptor antagonist) concomitantly suppresses these anxiolytic effects (Cho et al, 2012). Because donepezil has long been associated with modulating the nicotinic acetylcholine receptors (Shin et al, 2018), this mechanism may underlie its distinct anxiety effects (Figures 1 and 2) from those of physostigmine.…”

HPLC-PDA-MS/MS profiling of secondary metabolites from Opuntia ficus-indica cladode, peel and fruit pulp extracts and their antioxidant, neuroprotective effect in rats with aluminum chloride induced neurotoxicity

“…Group 3 received donepezil (an inhibitor of acetylcholinesterase) at a daily oral dose by gavage of 10 mg/kg body weight (b.w.) ( Shin et al, 2018 ) with daily dose of AlCl 3 (70 mg/kg, ip). Groups 4 to 7 received a daily oral dose of extracts (cladodes, fruit peel, fruit pulp and polysaccharide) (100 mg/kg b.w.)…”

A metabolomic study of the urine of rats with Alzheimer's disease and the efficacy of Ding‐Zhi‐Xiao‐Wan on the afflicted rats

“…In the past few decades, it has been observed that drugs such as donepezil [4] and Huperzine A [5] could alleviate distinct symptoms associated with AD. However, there are still no drugs that can retard the progression of AD.…”