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BEHAVIORAL PHARMACOLOGY

Antiamnesic and Neuroprotective Effects of Donepezil against Learning Impairments Induced in Mice by Exposure to Carbon Monoxide Gas

Unité 710 de l'Institut National de la Santé et de la Recherche Médicale, Ecole Pratique des Hautes Etudes, Université de Montpellier II, Montpellier, France (J.M., T.M.); and Eisai Inc., Teaneck, New Jersey (J.I.)

Donepezil is a potent acetylcholinesterase inhibitor that also interacts with the ₁ receptor, an intracellular neuromodulatory protein. In the present study, we analyzed the antiamnesic and neuroprotective activities of donepezil in a mouse hypoxia model induced by repetitive CO exposure, comparing donepezil's pharmacological profile with other cholinesterase inhibitors tacrine, rivastigmine, and galanthamine, and the reference ₁ agonist igmesine. CO exposure induced, after 7 days, hippocampal neurodegeneration, analyzed by Cresyl violet staining, and behavioral alterations, measured using spontaneous alternation and passive avoidance responses. When injected 20 min before the behavioral tests, i.e., 7 to 8 days after CO, all drugs showed antiamnesic properties. Preadministration of the ₁ receptor antagonist N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine (BD1047) blocked only the igmesine and donepezil effects. The neuroprotective activity of the drugs was tested by injection 20 min before the first CO exposure (preinsult protection) or by injection 1 h after the last CO exposure (postinsult protection). All drugs alleviated the hypoxia-induced neurodegeneration and behavioral impairments when injected before CO exposure. Preadministration of BD1047 blocked both the igmesine and donepezil effects. However, when injected after CO exposure, only igmesine and donepezil induced effective neuroprotection, and the morphological and behavioral effects were BD1047-sensitive. These results showed that donepezil is a potent antiamnesic and neuroprotective compound against the neurodegeneration induced by excitotoxic insult, and its pharmacological actions as both an acetylcholinesterase inhibitor and ₁ receptor agonist contribute to its marked efficacy. In particular, the drug is a more potent postinsult protecting agent compared with more selective cholinesterase inhibitors.

Address correspondence to: Dr. Tangui Maurice, INSERM U.710, EPHE, University of Montpellier II, c.c. 105, place Eugène Bataillon, 34095 Montpellier cedex 5, France. E-mail: tangui.maurice{at}univ-montp2.fr

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