Donepezil hydrochloride (
donepezil: (+/-)-2-[(1-benzylpiperidin-4-yl)methyl]-5,6-dimethoxy-
indan-1-one monohydrochloride) is a potent
acetylcholinesterase inhibitor used for treatment of
Alzheimer's disease. Although
acetylcholinesterase inhibitors are used as a symptomatic treatment for
Alzheimer's disease, it is not clear whether or not they are effective against progressive degeneration of neuronal cells. In this study, we investigated the
neuroprotective effects of
donepezil and other
acetylcholinesterase inhibitors used for treatment of
Alzheimer's disease, i.e.,
galantamine,
rivastigmine, and
tacrine. As a neurodegenerative model, we used rat cortical neurons exposed to
oxygen-
glucose deprivation.
Lactate dehydrogenase (LDH) released into the culture medium was measured as a marker of neuronal cell damage. First, the effects of
donepezil (10 microM) on three different treatment schedules (from 12 h before to 24 h after
oxygen-
glucose deprivation (pre-12 h), from 1 h before to 24 h after
oxygen-
glucose deprivation (pre-1 h) and from 1 h after to 24 h after
oxygen-
glucose deprivation (post-1 h)) were compared. The pre-12-h treatment most effectively inhibited LDH release. The protective effect of
donepezil was confirmed morphologically. Next, the effects of
donepezil and the other three
acetylcholinesterase inhibitors were compared under the pre-12-h treatment condition.
Donepezil (0.1, 1, and 10 microM) significantly decreased LDH release in a concentration-dependent manner. However,
galantamine (1, 10, and 100 microM),
tacrine (0.1, 1, and 10 microM), and
rivastigmine (0.1, 1, and 10 microM) did not significantly decrease LDH release. The
neuroprotective effect of
donepezil was not antagonized by
scopolamine or
mecamylamine. These results demonstrate that
donepezil has a protective effect against
oxygen-
glucose deprivation-induced injury to rat primary cultured cerebral cortical neurons. Besides, it is suggested that this effect of
donepezil is independent of
muscarinic cholinergic system and nicotinic
cholinergic system. Thus,
donepezil is expected to have a protective effect against progressive degeneration of brain neuronal cells in ischemic
cerebrovascular disease and
Alzheimer's disease.