Donepezil, an acetylcholinesterase inhibitor, enhances adult hippocampal neurogenesis
Introduction
Donepezil is a potent and selective acetylcholinesterase (AChE) inhibitor [1]. Donepezil upregulates brain ACh contents by microdialysis study in rats [2] and this action leads to the improvement of cognitive impairment [3]. And now it has been treated for Alzheimer's disease (AD) in which the degeneration of cholinergic nuclei is observed [4], [5].
The central cholinergic system is likely to affect hippocampal neurogenesis. Neural progenitor cells exist in the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) of adult animals, including humans, and new neurons are continuously produced [6], [7]. These processes are known to be modulated by some kinds of neurotransmitter [8], [9]. Lesion of septal cholinergic nuclei projecting to the hippocampus suppresses neurogenesis in rats [10], [11]. Then, it is considered that activation of the central cholinergic system enhances hippocampal neurogenesis.
The purpose of this study is to clarify how chronic pharmacological manipulation to activate or inhibit cholinergic transmission modulates adult hippocampal neurogenesis. We investigated the effect of donepezil and scopolamine, which was a potent muscarinic acetylcholine receptor (mAChR) blocker. Finally, we examined the expression of phosphorylated cAMP response element binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) in the hippocampus after these treatments to address the mechanism of modulation of neurogenesis by the cholinergic system.
This work has already been published as a journal article [12].
Section snippets
Animals
Male Sprague–Dawley rats (5-week old) were used (Japan SLC, Hamamatsu, Japan). They were housed in groups of five or six per cage maintained at 24 ± 2 °C under a 12:12-h light/dark cycle (lights on at 07:00 h) and allowed food and water ad libitum. All animal experiments were approved by the Animal Care and Use Committee of Eisai.
Drug treatment
Animals were administered with 50 mg/kg of 5′-bromo-2′-deoxyuridine (BrdU) (Sigma, St. Louis, MO, USA) intraperitoneally three times at 4 h intervals. After that, the
Results
Daily treatment with donepezil was started after BrdU injection, and the animals were sacrificed after 4 weeks. The treatment with donepezil significantly increased the number of BrdU-positive cells in the SGZ and granule cell layer (GCL) (Table 1; F(2, 31) = 5.23, P = 0.011, one-way ANOVA). Post hoc analyses revealed that donepezil significantly increased BrdU-positive cells at both 0.5 mg/kg (t = 2.96, P = 0.011, Dunnett's test) and 2 mg/kg (t = 2.56, P = 0.029). To examine the involvement of mAChR in
Discussion
Our results indicate that the AChE inhibitor donepezil enhances the hippocampal neurogenesis, in particular, the survival of newborn cells. In contrast, mAChR blockade by scopolamine suppresses it. These suggest that central cholinergic system is critically involved in neurogenesis in the adult hippocampal DG.
In the present study, dividing neural progenitor cells were labeled with BrdU just before starting the drug treatment. After 4-week donepezil or scopolamine treatment, the number of
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2020, Archives of Medical ResearchCitation Excerpt :CREB needs to be phosphorylated on Ser133 to form p-CREB so that it can act as a transcriptional activator (102). CREB-dependent transcription can be triggered by the stimulation of membrane receptors, which leads to the activation of intracellular pathways to the cell nucleus (105). CREB phosphorylation stimulates gene transcription associated with cognitive performance, learning, and short- and long-term memory formation (106).