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

Background and purpose: The acetylcholinesterase inhibitor, donepezil, is also a high affinity sigma 1 receptor agonist. We examined the involvement of sigma 1 receptors in its anti-amnesic and neuroprotective properties against amyloid beta(25-35) peptideinduced toxicity in mice. Experimental approach: Mice were given an intracerebroventricular (i.c.v.) injection of A beta(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 A beta(25-35) injection to evaluate oxidative stress. Donepezil, the sigma 1 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 A beta(25-35) injection, or 24 h after A beta(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 sigma 1 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 A beta(25-35)-induced toxicity involve both its cholinergic and sigma 1 agonistic properties. This dual action may explain its sustained activity compared to other ChE inhibitors.