Exercise-mimetic AICAR transiently benefits brain function

Oncotarget. 2015 Jul 30;6(21):18293-313. doi: 10.18632/oncotarget.4715.


Exercise enhances learning and memory in animals and humans. The role of peripheral factors that may trigger the beneficial effects of running on brain function has been sparsely examined. In particular, it is unknown whether AMP-kinase (AMPK) activation in muscle can predict enhancement of brain plasticity. Here we compare the effects of running and administration of AMPK agonist 5-Aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR, 500 mg/kg), for 3, 7 or 14 days in one-month-old male C57BL/6J mice, on muscle AMPK signaling. At the time-points where we observed equivalent running- and AICAR-induced muscle pAMPK levels (7 and 14 days), cell proliferation, synaptic plasticity and gene expression, as well as markers of oxidative stress and inflammation in the dentate gyrus (DG) of the hippocampus and lateral entorhinal cortex (LEC) were evaluated. At the 7-day time-point, both regimens increased new DG cell number and brain-derived neurotrophic factor (BDNF) protein levels. Furthermore, microarray analysis of DG and LEC tissue showed a remarkable overlap between running and AICAR in the regulation of neuronal, mitochondrial and metabolism related gene classes. Interestingly, while similar outcomes for both treatments were stable over time in muscle, in the brain an inversion occurred at fourteen days. The compound no longer increased DG cell proliferation or neurotrophin levels, and upregulated expression of apoptotic genes and inflammatory cytokine interleukin-1β. Thus, an exercise mimetic that produces changes in muscle consistent with those of exercise does not have the same sustainable positive effects on the brain, indicating that only running consistently benefits brain function.

Keywords: AICAR; AMPK; Gerotarget; hippocampus; muscle; running.

Publication types

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

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Aminoimidazole Carboxamide / analogs & derivatives*
  • Aminoimidazole Carboxamide / pharmacology
  • Animals
  • Brain / drug effects*
  • Brain / metabolism
  • Brain / physiology
  • Brain-Derived Neurotrophic Factor / genetics
  • Brain-Derived Neurotrophic Factor / metabolism
  • Cytokines / metabolism
  • Dentate Gyrus / drug effects
  • Dentate Gyrus / metabolism
  • Dentate Gyrus / physiology
  • Hypoglycemic Agents / pharmacology
  • Immunoblotting
  • Male
  • Mice, Inbred C57BL
  • Muscles / drug effects
  • Muscles / enzymology
  • Neuronal Plasticity / drug effects*
  • Neuronal Plasticity / physiology
  • Olfactory Cortex / drug effects
  • Olfactory Cortex / metabolism
  • Olfactory Cortex / physiology
  • Oligonucleotide Array Sequence Analysis
  • Oxidative Stress / drug effects
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ribonucleotides / pharmacology*
  • Running / physiology*
  • Time Factors
  • Transcriptome / drug effects
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism


  • Brain-Derived Neurotrophic Factor
  • Cytokines
  • Hypoglycemic Agents
  • Ribonucleotides
  • Vascular Endothelial Growth Factor A
  • Aminoimidazole Carboxamide
  • AMP-Activated Protein Kinases
  • AICA ribonucleotide