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Original Paper

Cholinesterase Inhibitor Donepezil Increases Mitochondrial Biogenesis through AMP-Activated Protein Kinase in the Hippocampus

Kim E.a, b · Park M.a · Jeong J.a, b · Kim H.a, b · Lee S.K.a · Lee E.a · Oh B.H.a · Namkoong K.a

Author affiliations

aDepartment of Psychiatry, Institute of Behavioral Science in Medicine, Laboratory for Alzheimers Molecular Psychiatry, and bBrain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea

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Neuropsychobiology 2016;73:81-91

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Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: April 28, 2015
Accepted: October 05, 2015
Published online: March 23, 2016
Issue release date: April 2016

Number of Print Pages: 11
Number of Figures: 6
Number of Tables: 0

ISSN: 0302-282X (Print)
eISSN: 1423-0224 (Online)

For additional information: http://www.karger.com/NPS

Abstract

Objective: Donepezil, a widely prescribed drug for Alzheimer's disease (AD), is now considered to have multimodal actions beyond cholinesterase inhibition. We aimed to see whether donepezil enhances mitochondrial biogenesis and relevant signaling pathways since mitochondrial dysfunction is a key feature of the hypometabolic AD brain. Methods: As a metabolic gauge, AMP-activated protein kinase (AMPK) was investigated as a tentative mediator of neurometabolic action of donepezil. Changes in phospho-AMPK levels, mitochondrial biogenesis, and ATP levels were measured upon donepezil treatment using neuroblastoma cells, primary cultured neurons and ex vivo hippocampal tissue of adult mice. Results: Donepezil dose-dependently increased mitochondrial biogenesis and ATP levels as well as expression of PGC-1α and NRF-1 in neuroblastoma cells. Donepezil dose-dependently activated AMPK; however, inhibition of AMPK abolished the observed effects of donepezil, indicating that AMPK is a key mediator of donepezil's action. Notably, mitochondrial biogenesis upon donepezil treatment was mainly observed within dendritic regions of primary cultured hippocampal neurons. Levels of synaptic markers were also increased by donepezil. Finally, AMPK- dependent mitochondrial biogenesis by donepezil was confirmed in organotypic hippocampal tissue. Conclusions: Our findings indicate that AMPK/PGC-1α signaling is involved in beneficial actions of donepezil on neurometabolism. Pharmacological activation of AMPK might be a promising approach to counteract AD pathogenesis associated with brain hypometabolism.

© 2016 S. Karger AG, Basel


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: April 28, 2015
Accepted: October 05, 2015
Published online: March 23, 2016
Issue release date: April 2016

Number of Print Pages: 11
Number of Figures: 6
Number of Tables: 0

ISSN: 0302-282X (Print)
eISSN: 1423-0224 (Online)

For additional information: http://www.karger.com/NPS


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