title: Cholinesterase Inhibitor Donepezil Increases Mitochondrial Biogenesis through AMP-Activated Protein Kinase in the Hippocampus.
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.
authors.affiliation: Department of Psychiatry, Institute of Behavioral Science in Medicine, Laboratory for Alzheimers Molecular Psychiatry, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Eosu
authors.initials: E
authors.lastname: Kim
authors.forename: Minsun
authors.initials: M
authors.lastname: Park
authors.forename: Jihyeon
authors.initials: J
authors.lastname: Jeong
authors.forename: Hyunjeong
authors.initials: H
authors.lastname: Kim
authors.forename: Su Kyoung
authors.initials: SK
authors.lastname: Lee
authors.forename: Eun
authors.initials: E
authors.lastname: Lee
authors.forename: Byoung Hoon
authors.initials: BH
authors.lastname: Oh
authors.forename: Kee
authors.initials: K
authors.lastname: Namkoong
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007189:Indans / Q000494:pharmacology*; D008297:Male; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D051266:Nuclear Respiratory Factor 1 / Q000378:metabolism; D001678:Organelle Biogenesis; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D046509:Tissue Culture Techniques
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; C495633:NRF1 protein, human; C495634:Nrf1 protein, mouse; D051266:Nuclear Respiratory Factor 1; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010880:Piperidines; C485290:Ppargc1a protein, mouse; D012333:RNA, Messenger; D000255:Adenosine Triphosphate; D000077265:Donepezil; D055372:AMP-Activated Protein Kinases