The anti‐amnesic and neuroprotective effects of donepezil against amyloid β25‐35 peptide‐induced toxicity in mice involve an interaction with the σ1 receptor

Abstract

Background and purpose: The acetylcholinesterase inhibitor, donepezil, is also a high affinity σ₁ receptor agonist. We examined the involvement of σ₁ receptors in its anti‐amnesic and neuroprotective properties against amyloid β_25‐35 peptide‐induced toxicity in mice. Experimental approach: Mice were given an intracerebroventricular (i.c.v.) injection of Aβ_25‐35 peptide (9 nmol) 7‐9 days before being tested for spontaneous alternation and passive avoidance. Hippocampal lipid peroxidation was measured 7 days after Aβ_25‐35 injection to evaluate oxidative stress. Donepezil, the σ₁ agonist PRE‐084 or the cholinesterase (ChE) inhibitors tacrine, rivastigmine and galantamine were administered either 20 min before behavioural sessions to check their anti‐amnesic effects, or 20 min before Aβ_25‐35 injection, or 24 h after Aβ_25‐35 injection and then once daily before behavioural sessions, to check their pre‐ and post‐i.c.v. neuroprotective activity, respectively. Key results: All the drugs tested were anti‐amnesic, but only the effects of PRE‐084 and donepezil were prevented by the σ₁ antagonist BD1047. Only PRE‐084 and donepezil showed neuroprotection when administered pre i.c.v.; they blocked lipid peroxidation and learning deficits, effects inhibited by BD1047. Post i.c.v., PRE‐084 and donepezil showed complete neuroprotection whereas the other ChE inhibitors showed partial effects. BD1047 blocked these effects of PRE‐084, attenuated those of donepezil, but did not affect the partial effects of the other ChE inhibitors. Conclusions and implications. The potent anti‐amnesic and neuroprotective effects of donepezil against Aβ_25‐35‐induced toxicity involve both its cholinergic and σ₁ agonistic properties. This dual action may explain its sustained activity compared to other ChE inhibitors. British Journal of Pharmacology (2006) 149, 998–1012. doi:10.1038/sj.bjp.0706927