The anti-amnesic and neuroprotective effects of donepezil against amyloid beta25-35 peptide-induced toxicity in mice involve an interaction with the sigma1 receptor.
OBJECTIVE
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) peptide-induced toxicity in mice.


METHODS
Mice were given an intracerebroventricular (i.c.v.) injection of Abeta(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 Abeta(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 Abeta(25-35) injection, or 24 h after Abeta(25-35) injection and then once daily before behavioural sessions, to check their pre- and post-i.c.v. neuroprotective activity, respectively.


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
The potent anti-amnesic and neuroprotective effects of donepezil against Abeta(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.
Meunier
J
J
INSERM U. 710, Montpellier, France.
Ieni
J
J
Maurice
T
T
D000647:Amnesia / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D005029:Ethylenediamines / Q000494:pharmacology; D005456:Fluorescent Dyes; D005702:Galantamine / Q000494:pharmacology; D007189:Indans / Q000008:administration & dosage / Q000494:pharmacology*; D007276:Injections, Intraventricular; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D018696:Neuroprotective Agents; D018697:Nootropic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D010636:Phenols; D048448:Phenylcarbamates / Q000494:pharmacology; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D017480:Receptors, sigma / Q000187:drug effects*; D000068836:Rivastigmine; D013454:Sulfoxides; D014992:Xylenes
D016229:Amyloid beta-Peptides; D005029:Ethylenediamines; D005456:Fluorescent Dyes; D007189:Indans; D018696:Neuroprotective Agents; D018697:Nootropic Agents; D010446:Peptide Fragments; D010636:Phenols; D048448:Phenylcarbamates; D010880:Piperidines; D017480:Receptors, sigma; D013454:Sulfoxides; D014992:Xylenes; C074636:amyloid beta-protein (25-35); D005702:Galantamine; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin; D000077265:Donepezil; D000068836:Rivastigmine; C016833:xylenol orange