Donepezil-induced neuroprotection of acetylcholinergic neurons in olfactory bulbectomized mice

In the brain of Alzheimer's patients, the cholinergic neurons innervated the hippocampus and cerebral cortex degenerates before accumulation of beta-amyloid protein. Donepezil, a potent acetylcholinesterase (AChE) inhibitor is reported to rescue neurons from excitotoxic injury in culture. However, there is no evidence to confirm its neuroprotective effect on ACh neurons in vivo. Using olfactory bulbectomy (OBX) mice, we defined the neuroprotective mechanisms of donepezil on the medial septum cholinergic neurons with concomitant improvement of the impaired cognitive function. Bilateral olfactory bulbs of DDY mouse were removed by surgery. After olfactory bulbectomized (OBX), donepezil (1 or 3mg/kg/day) was administered for 15 days and mouse brain was fixed with paraformaldehyde perfusion at day 18. Then, the neuroprotective effect of donepezil was evaluated by counting the number of Chdine acetyltrans-ferase (ChAT) immunoreactive neurons in the medial septum. The number of ChAT immunoreactive neurons in the medial septum reduced by 40% of that in sham-operated animals. The reduced ChAT positive neurons were restored by donepezil treatments. Consistent with these observations, the cognitive deficits observed in OBX mice were significantly improved by the donepezil treatment. Taken together, donepezil treatment rescues the cholinergic neurons in the medial septum from the neurodegeneration by OBX.We will also discuss the mechanism underlying the donepezil-induced neuroprotection in the medial septum cholinergic neurons.