Donepezil, an acetylcholinesterase inhibitor, enhances adult hippocampal neurogenesis

doi:10.1016/j.cbi.2008.04.004

Chemico-Biological Interactions

Volume 175, Issues 1–3, 25 September 2008, Pages 227-230

https://doi.org/10.1016/j.cbi.2008.04.004 Get rights and content

Abstract

Donepezil hydrochloride is a potent and selective acetylcholinesterase inhibitor and has been treated for Alzheimer's disease, in which the cholinergic dysfunction is observed. Recently, the degeneration of medial septal cholinergic nuclei in adult rat suppressed the neurogenesis in hippocampal dentate gyrus (DG) was reported. Then, we determined whether donepezil which activated the brain cholinergic system could modulate hippocampal neurogenesis in normal rats. After the injection of 5′-bromo-2′-deoxyuridine (BrdU) to label dividing cells, we orally treated with donepezil (0.5 or 2 mg/kg) once a day for 4 weeks. In the other group, we performed 4-week subcutaneous infusion of scopolamine (0.75 or 3 mg/day), a muscarinic acetylcholine receptor blocker. The doses of donepezil and scopolamine we used in this study were reported to activate and inhibit cholinergic activity in rats, respectively. One day after the completion of drug treatment, the animals were sacrificed, and immunohistochemical analysis was performed. Donepezil increased, but scopolamine decreased, the number of BrdU-positive cells in the DG as compared with the vehicle-treated control. Neither drug had any effects on the percentage of BrdU-positive cells that were also positive for a neuronal marker NeuN, nor the number of proliferating cell nuclear antigen-positive cells in the DG. These results indicate that donepezil enhances and scopolamine suppresses the survival of newborn neurons in the DG without affecting the proliferation of neural progenitor cell and the neuronal differentiation. We also found that chronic treatment of donepezil enhanced, and scopolamine suppressed phosphorylation of cAMP response element binding protein (CREB), which was involved in cell survival, in the DG. These results suggest that donepezil activates the central cholinergic transmission and enhances the survival of newborn neurons in the DG via CREB signaling.

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

References (33)

T. Kosasa et al.
Effect of donepezil hydrochloride (E2020) on basal concentration of extracellular acetylcholine in the hippocampus of rats
Eur. J. Pharmacol.
(1999)
T. Hagg
Molecular regulation of adult CNS neurogenesis: an integrated view
Trends Neurosci.
(2005)
K. Van der Borght et al.
Input from the medial septum regulates adult hippocampal neurogenesis
Brain Res. Bull.
(2005)
S. Kotani et al.
Pharmacological evidence of cholinergic involvement in adult hippocampal neurogenesis in rats
Neuroscience
(2006)
P. Mohapel et al.
Forebrain acetylcholine regulates adult hippocampal neurogenesis and learning
Neurobiol. Aging
(2005)
S. Finkbeiner et al.
CREB: a major mediator of neuronal neurotrophin responses
Neuron
(1997)
P.A. Lapchak et al.
Cholinergic regulation of hippocampal brain-derived neurotrophic factor mRNA expression: evidence from lesion and chronic cholinergic drug treatment studies
Neuroscience
(1993)
S.J. French et al.
Hippocampal neurotrophin and trk receptor mRNA levels are altered by local administration of nicotine, carbachol and pilocarpine
Brain Res. Mol. Brain Res.
(1999)
T.M. Madsen et al.
Arrested neuronal proliferation and impaired hippocampal function following fractionated brain irradiation in the adult rat
Neuroscience
(2003)
R. Rola et al.
Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice
Exp. Neurol.
(2004)

H. Ogura et al.

Comparison of inhibitory activities of donepezil and other cholinesterase inhibitors on acetylcholinesterase and butyrylcholinesterase in vitro

Methods Find. Exp. Clin. Pharmacol.

(2000)

H. Ogura et al.

Donepezil, a centrally acting acetylcholinesterase inhibitor, alleviates learning deficits in hypocholinergic models in rats

Methods Find. Exp. Clin. Pharmacol.

(2000)

P.J. Whitehouse et al.

Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain

Science

(1982)

J.T. Coyle et al.

Alzheimer's disease: a disorder of cortical cholinergic innervation

Science

(1983)

P.S. Eriksson et al.

Neurogenesis in the adult human hippocampus

Nat. Med.

(1998)

F.H. Gage

Mammalian neural stem cells

Science

(2000)

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Donepezil, an acetylcholinesterase inhibitor, enhances adult hippocampal neurogenesis

Abstract

Introduction

Section snippets

Animals

Drug treatment

Results

Discussion

Eur. J. Pharmacol.

Trends Neurosci.

Brain Res. Bull.

Neuroscience

Neurobiol. Aging

Neuron

Neuroscience

Brain Res. Mol. Brain Res.

Neuroscience

Exp. Neurol.

Comparison of inhibitory activities of donepezil and other cholinesterase inhibitors on acetylcholinesterase and butyrylcholinesterase in vitro

Methods Find. Exp. Clin. Pharmacol.

Donepezil, a centrally acting acetylcholinesterase inhibitor, alleviates learning deficits in hypocholinergic models in rats

Methods Find. Exp. Clin. Pharmacol.

Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain

Science

Alzheimer's disease: a disorder of cortical cholinergic innervation

Science

Neurogenesis in the adult human hippocampus

Nat. Med.

Mammalian neural stem cells

Science