Acetylcholinesterase inhibitors ameliorate the chronic stress-induced memory impairment in ovariectomized mice

It is well known that estrogen decline after menopause may influence cognitive performance and increase risk for Alzheimer's disease (AD) in women. However, the relationship between postmenopausal memory impairment and AD remains unclear. In this study, to determine the involvement of cholinergic system in postmenopausal memory impairment, we examined the effects of donepezil and galantamine, which are acetylcholinesterase inhibitors and clinically used for AD therapy, on the stress-induced cognitive dysfunction in ovariectomized(OVX) mice. Two weeks after OVX or sham-operation, the mice were further assigned to a daily restraint stress (21 days, 6 h/day) or non-stress group. Memory impairment was evaluated by a contextual fear conditioning test, consist of training and 24 h later test sessions. When donepezil and galantamine were administered before the test session, the stress-induced memory impairment in OVX mice was significantly improved. The memory enhancing effect of donepezil was antagonized by an alpha 7 nicotinic receptor antagonist methyllyeaconitine. We further carried out histological analysis in hippocampal regions of mice. Immunostaining using anti-cholineacetyltransferase revealed that cholinergic neuronal loss was occurred in the hippocampal CA3 region. These data suggest that cholinergic dysfunction in the hippocampus involves in postmenopausal memory impairment and that this mouse model is useful to study the molecular mechanisms in the early stage of AD.