Butyrylcholinesterase inhibitors ameliorate cognitive dysfunction induced by amyloid-β peptide in mice

Abstract

The cholinesterase inhibitor, rivastigmine, ameliorates cognitive dysfunction and is approved for the treatment of Alzheimer's disease (AD). Rivastigmine is a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE); however, the impact of BuChE inhibition on cognitive dysfunction remains to be determined. We compared the effects of a selective BuChE inhibitor, N1-phenethylnorcymserine (PEC), rivastigmine and donepezil (an AChE-selective inhibitor) on cognitive dysfunction induced by amyloid-β peptide (Aβ1–40) in mice. Five-week-old imprinting control region (ICR) mice were injected intracerebroventricularly (i.c.v.) with either Aβ1–40 or the control peptide Aβ40–1 on Day 0, and their recognition memory was analyzed by a novel object recognition test. Treatment with donepezil (1.0 mg/kg), rivastigmine (0.03, 0.1, 0.3 mg/kg) or PEC (1.0, 3.0 mg/kg) 20 min prior to, or immediately after the acquisition session (Day 4) ameliorated the Aβ1–40 induced memory impairment, indicating a beneficial effect on memory acquisition and consolidation. In contrast, none of the investigated drugs proved effective when administrated before the retention session (Day 5). Repeated daily administration of donepezil, rivastigmine or PEC, on Days 0–3 inclusively, ameliorated the cognitive dysfunction in Aβ1–40 challenged mice. Consistent with the reversal of memory impairments, donepezil, rivastigmine or PEC treatment significantly reduced Aβ1–40 induced tyrosine nitration of hippocampal proteins, a marker of oxidative damage. These results indicate that BuChE inhibition, as well as AChE inhibition, is a viable therapeutic strategy for cognitive dysfunction in AD.

Conditioned medium from the stem cells of human dental pulp improves cognitive function in a mouse model of Alzheimer’s disease

“…The peptides were then administered by intracerebroventricular (i.c.v.) injection as described previously [37][38][39][40][41].…”

“…injection of Aβ 1-40 (day 0) [39,41,42]. This method is used to measure of cognitive dysfunction in mouse models of natural aging and AD [43].…”

Structure-based development of nitroxoline derivatives as potential multifunctional anti-Alzheimer agents

“…8 Inhibition of BChE also ameliorates Aβ peptide (Aβ 1-40 )-induced memory impairment in mice, which further relates BChE to AD pathogenesis. 14 Pharmacogenomic studies have also revealed the impact of different BChE genotypes on the rate of cognitive decline. Patients with BChE enzyme variants that show reduced activity who were enrolled in a trial of a cholinesterase inhibitor retained attention performance and showed reduced rates of cognitive decline.…”

Potential Use of Nicotinic Receptor Agonists for the Treatment of Chemotherapy-Induced Cognitive Deficits

“…The beneficial effects of drugs increasing activity at nAChRs are also observed in impaired animals. Nicotine and the AChE inhibitor donepezil reverse scopolamine-induced impairment of novel object recognition [134] and both donepezil and the AChE inhibitor rivastigmine reverse impaired novel object recognition in amyloid-beta peptide mice [135]. Further, the a7 nAChR agonist PNU-282987 reverses phencyclidine-induced deficits in novel object recognition [111] and galantamine improves novel object recognition in beta amyloid injected mice and mice impaired by methamphetamine [136,137].…”