Prolonged metformin treatment leads to reduced transcription of Nrf2 and neurotrophic factors without cognitive impairment in older C57BL/6J mice

Behav Brain Res. 2016 Mar 15;301:1-9. doi: 10.1016/j.bbr.2015.12.012. Epub 2015 Dec 14.


Long-term use of anti-diabetic agents has become commonplace as rates of obesity, metabolic syndrome and diabetes continue to escalate. Metformin, a commonly used anti-diabetic drug, has been shown to have many beneficial effects outside of its therapeutic regulation of glucose metabolism and insulin sensitivity. Studies on metformin's effects on the central nervous system are limited and predominantly consist of in vitro studies and a few in vivo studies with short-term treatment in relatively young animals; some provide support for metformin as a neuroprotective agent while others show evidence that metformin may be deleterious to neuronal survival. In this study, we examined the effect of long-term metformin treatment on brain neurotrophins and cognition in aged male C57Bl/6 mice. Mice were fed control (C), high-fat (HF) or a high-fat diet supplemented with metformin (HFM) for 6 months. Metformin decreased body fat composition and attenuated declines in motor function induced by a HF diet. Performance in the Morris water maze test of hippocampal based memory function, showed that metformin prevented impairment of spatial reference memory associated with the HF diet. Quantitative RT-PCR on brain homogenates revealed decreased transcription of BDNF, NGF and NTF3; however protein levels were not altered. Metformin treatment also decreased expression of the antioxidant pathway regulator, Nrf2. The decrease in transcription of neurotrophic factors and Nrf2 with chronic metformin intake, cautions of the possibility that extended metformin use may alter brain biochemistry in a manner that creates a vulnerable brain environment and warrants further investigation.

Keywords: BDNF; Metformin; NGF; Neurotrophin 3; Nrf2; Water maze.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Adipose Tissue / drug effects
  • Aging / drug effects*
  • Aging / physiology
  • Aging / psychology
  • Animals
  • Blood Glucose / drug effects
  • Brain / drug effects*
  • Brain / metabolism
  • Brain-Derived Neurotrophic Factor / metabolism
  • Cognition / drug effects*
  • Cognition / physiology
  • Diet, High-Fat / adverse effects
  • Hypoglycemic Agents / adverse effects*
  • Male
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Metformin / adverse effects*
  • Mice, Inbred C57BL
  • Motor Activity / drug effects
  • NF-E2-Related Factor 2 / metabolism*
  • Nerve Growth Factor / metabolism
  • Neurotrophin 3 / metabolism
  • RNA, Messenger / metabolism
  • Random Allocation


  • Blood Glucose
  • Brain-Derived Neurotrophic Factor
  • Hypoglycemic Agents
  • NF-E2-Related Factor 2
  • Neurotrophin 3
  • Nfe2l2 protein, mouse
  • RNA, Messenger
  • Nerve Growth Factor
  • Metformin
  • AMP-Activated Protein Kinases