Donepezil rescues the medial septum cholinergic neurons via nicotinic ACh receptor stimulation in olfactory bulbectomized mice

作     者：Yui Yamamoto Kohji Fukunaga 

作者机构：Department of Pharmacology Graduate School of Pharmaceutical Science Tohoku University Sendai Japan 

出 版 物：《Advances in Alzheimer's Disease》 (阿尔茨海默氏病研究进展（英文）)

年 卷 期：2013年第2卷第4期

页      面：161-170页

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

主　　题：Donepezil Neuroprotection Medial Septum Nicotinic Acetylcholine Receptors 

摘      要：Olfactory bulbectomy (OBX) causes cognitive dysfunction by degeneration of cholinergic neurons in the medial septum. Here, we define an involvement of nicotinic acetylcholine receptor (nAChR) in neuroprotective effect of donepezil in the septum neurons of OBX mice. Neuroprotective effects on the medial septal cholinergic neurons were assessed after chronic donepezil administration in OBX mice. We also measured Akt and ERK phosphorylation to define the neuroprotective mechanism of donepezil. We found that treatment with donepezil (1 - 3 mg/kg) for 15 consecutive days completely rescued cholinergic neurons in the OBX mice with concomitant improved memory. Reduction of both protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) phosphorylation were restored by chronic donepezil administration (1 - 3 mg/kg) in OBX mouse medial septum. Both phosphorylated Akt and ERK immunoreactivities were localized in cell bodies of choline acetyltransferase (ChAT)-positive cholinergic cells in the medial septum. Enhancement of Akt and ERK phosphorylation seen following donepezil administration was totally blocked by pre-administration of mecamylamine (10 μM), a nicotinic acetylcholine receptor antagonist. Donepezil increases phosphorylation of Akt and ERK via nAChR stimulation in the medial septum cholinergic neurons. The Akt and ERK stimulation by donepezil is associated with its ability of neuroprotection in the medial septum and memory improvement.