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

 Kim E.  ;  Park M  ;  Jeong J.  ;  Kim H.  ;  Lee S.K.  ;  Lee E.  ;  Oh B.H.  ;  Namkoong K. 
 NEUROPSYCHOBIOLOGY, Vol.73(2) : 81-91, 2016 
Journal Title
Issue Date
AMP-Activated Protein Kinases/metabolism* ; Adenosine Triphosphate/metabolism ; Animals ; Cell Line, Tumor ; Cholinesterase Inhibitors/pharmacology* ; Dendrites/drug effects ; Dendrites/metabolism ; Dose-Response Relationship, Drug ; Female ; Hippocampus/drug effects* ; Hippocampus/metabolism ; Humans ; Indans/pharmacology* ; Male ; Mice, Inbred ICR ; Mitochondria/drug effects* ; Mitochondria/metabolism ; Nuclear Respiratory Factor 1/metabolism ; Organelle Biogenesis* ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; Piperidines/pharmacology* ; RNA, Messenger/metabolism ; Rats, Sprague-Dawley ; Tissue Culture Techniques
Donepezil ; AMP-activated protein kinase ; PGC-1α ; Mitochondria ; Neurometabolism
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.
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1. College of Medicine (의과대학) > Research Institute (부설연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Psychiatry (정신과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Eosu(김어수) ORCID logo https://orcid.org/0000-0001-9472-9465
Namkoong, Kee(남궁기) ORCID logo https://orcid.org/0000-0003-1400-8057
Park, Min Sun(박민선)
Oh, Byong Hoon(오병훈)
Lee, Eun(이은) ORCID logo https://orcid.org/0000-0002-7462-0144
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