Donepezil is a potent
acetylcholinesterase inhibitor that also interacts with the sigma1 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 sigma1 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 sigma1 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 sigma1 receptor agonist contribute to its marked efficacy. In particular, the
drug is a more potent postinsult protecting agent compared with more selective
cholinesterase inhibitors.