Abstract
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.
Highlights
Destruction of olfactory system reportedly impairs learning and memory [1,2,3] and Alzheimer’s disease (AD) patients show severe impairment of olfactory bulb functions even in the early stage [4,5]
We evaluated whether donepezil-induced elevated phosphorylation of Akt and extracellular signal-regulated kinase (ERK) is mediated by nicotinic acetylcholine receptor (nAChR) stimulation in the medial septum
We previously documented that Akt and ERK activities are decreased in the medial septum 14 days after OBX, with a concomitant reduce the number of ChATpositive neurons [7]
Summary
Destruction of olfactory system reportedly impairs learning and memory [1,2,3] and Alzheimer’s disease (AD) patients show severe impairment of olfactory bulb functions even in the early stage [4,5]. The cholinergic neurons in the basal forebrain and olfactory bulb are originated from the medial septum, thereby providing cholinergic innervation to the hippocampus, olfactory blub, amygdala and overall neocortex [6]. Olfactory bulbectomy (OBX) causes degeneration of cholinergic neurons in the medial septum and in the hippocampus, thereby eliciting hippocampus -dependent memory deficits in mice [7]. In support to this idea, OBX treatment elicits reduction of acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) levels in the hippocampus [8,9] and nicotine-induced acetylcholine (ACh) release in the hippocampus was largely impaired in OBX mice [10]. OBX mouse could be a useful model to test AD-like cognitive dysfunction following degeneration of cholinergic neurons in the septum
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