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The anti‐amnesic and neuroprotective effects of donepezil against amyloid β 25‐35 peptide‐induced toxicity in mice involve an interaction with the σ 1 receptor
Author(s) -
Meunier J,
Ieni J,
Maurice T
Publication year - 2006
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0706927
Subject(s) - donepezil , neuroprotection , pharmacology , acetylcholinesterase , agonist , chemistry , rivastigmine , lipid peroxidation , tacrine , oxidative stress , receptor , medicine , biochemistry , dementia , enzyme , disease
Background and purpose: The acetylcholinesterase inhibitor, donepezil, is also a high affinity σ 1 receptor agonist. We examined the involvement of σ 1 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 σ 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 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 σ 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 Aβ 25‐35 ‐induced toxicity involve both its cholinergic and σ 1 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