Metformin protects the brain against ischemia/reperfusion injury through PI3K/Akt1/JNK3 signaling pathways in rats

Physiol Behav. 2017 Mar 1;170:115-123. doi: 10.1016/j.physbeh.2016.12.021. Epub 2016 Dec 23.


Although Metformin, a first-line antidiabetic drug, can ameliorate ischemia/reperfusion (I/R) induced brain damage, but how metformin benefits injured hippocampus and the mechanisms are still largely unknown. Therefore, the aim of this study was to investigate the neuroprotective mechanisms of metformin against ischemic brain damage induced by cerebral I/R and to explore whether the Akt-mediated down-regulation of the phosphorylation of JNK3 signaling pathway contributed to the protection provided by metformin. Transient global brain ischemia was induced by 4-vessel occlusion in adult male Sprague-Dawley rats. The open field tasks and Morris water maze were used to assess the effect of metformin on anxiety-like behavioral and cognitive impairment after I/R. Cresyl Violet staining was used to examine the survival of hippocampal CA1 pyramidal neurons. Immunoblotting was performed to measure the phosphorylation of Akt1, JNK3, c-Jun and the expression of cleaved caspase-3. Through ischemia/reperfusion (I/R) rat model, we found that metformin could attenuate the deficits of hippocampal related behaviors and inhibit cell apoptosis. The western blot data showed that metformin could promote the activation of Akt1 and reduce the phosphorylation of JNK3 and c-Jun as well as elevation of cleaved caspase-3 in I/R brains. PI3K inhibitor reversed all the protective effects, further indicating that metformin protect hippocampus from ischemic damage through PI3K/Akt1/JNK3/c-Jun signaling pathway.

Keywords: Akt; Caspase-3; Ischemia/reperfusion; JNK3; Metformin.

MeSH terms

  • Animals
  • Anxiety / drug therapy
  • Anxiety / enzymology
  • Anxiety / etiology
  • Anxiety / pathology
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Brain Ischemia / complications
  • Brain Ischemia / drug therapy*
  • Brain Ischemia / enzymology*
  • Brain Ischemia / pathology
  • CA1 Region, Hippocampal / drug effects
  • CA1 Region, Hippocampal / enzymology
  • CA1 Region, Hippocampal / pathology
  • Caspase 3 / metabolism
  • Cognition Disorders / drug therapy
  • Cognition Disorders / enzymology
  • Cognition Disorders / etiology
  • Cognition Disorders / pathology
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Male
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Metformin / pharmacology*
  • Mitogen-Activated Protein Kinase 10 / metabolism
  • Neuroprotective Agents / pharmacology*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyramidal Cells / drug effects
  • Pyramidal Cells / enzymology
  • Pyramidal Cells / pathology
  • Rats, Sprague-Dawley
  • Reperfusion Injury / complications
  • Reperfusion Injury / drug therapy*
  • Reperfusion Injury / enzymology*
  • Reperfusion Injury / pathology
  • Signal Transduction / drug effects


  • Enzyme Inhibitors
  • Neuroprotective Agents
  • Phosphoinositide-3 Kinase Inhibitors
  • Metformin
  • Mitogen-Activated Protein Kinase 10
  • Akt1 protein, rat
  • Proto-Oncogene Proteins c-akt
  • Casp3 protein, rat
  • Caspase 3