Effect of Metformin on Adult Hippocampal Neurogenesis: Comparison with Donepezil and Links to Cognition

J Mol Neurosci. 2017 May;62(1):88-98. doi: 10.1007/s12031-017-0915-z. Epub 2017 Apr 4.


Recent studies have uncovered evidence suggesting that interference with hippocampal adult neurogenesis contributes to neurodegeneration in Alzheimer's disease (AD). Evidence supporting that AD is a metabolic disease with derangements in brain glucose utilization implies the use of anti-diabetics as an alternate therapeutic strategy. The present study drew comparison between the pro-neurogenic potential of metformin and donepezil in AlCl3-induced mouse model of neurodegeneration. Morris water maze task and subsequent immunohistochemical evaluation for NeuN was conducted. Expression of neurogenesis markers and hippocampal proteome analysis was determined by qRT-PCR and SDS-PAGE, respectively, followed by ESI-QTOFF MS/MS identification. The results demonstrated impaired spatial memory and differential expression of eight proteins in the AlCl3 group as compared to the controls. Interestingly, treatment with metformin normalized the proteome profile and expression levels of neurogenesis markers along with improvement in the spatial memory. Moreover, as compared to donepezil, metformin-treated mice exhibited an enhanced number of post-mitotic NeuN-positive neurons. It is suggested that underlying molecular mechanisms of metformin-mediated adult hippocampal neurogenesis may have implications in treatment of neurodegenerative disorders.

Keywords: Alzheimer’s disease; Donepezil; Metformin; Neurogenesis; Type III diabetes.

MeSH terms

  • Animals
  • Cholinesterase Inhibitors / adverse effects
  • Cholinesterase Inhibitors / pharmacology*
  • Cognition
  • Donepezil
  • Hippocampus / drug effects*
  • Hippocampus / growth & development
  • Hippocampus / physiology
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / pharmacology*
  • Indans / adverse effects
  • Indans / pharmacology*
  • Male
  • Maze Learning
  • Metformin / adverse effects
  • Metformin / pharmacology*
  • Mice
  • Mice, Inbred BALB C
  • Neurogenesis*
  • Piperidines / adverse effects
  • Piperidines / pharmacology*


  • Cholinesterase Inhibitors
  • Hypoglycemic Agents
  • Indans
  • Piperidines
  • Donepezil
  • Metformin