Oligoprotective effect of metformin through the AMPK-dependent on restoration of mitochondrial hemostasis in the cuprizone-induced multiple sclerosis model

J Mol Histol. 2019 Jun;50(3):263-271. doi: 10.1007/s10735-019-09824-0. Epub 2019 Apr 23.


Oxidative stress with mitochondrial defects has a central role in the development and deterioration of Multiple sclerosis (MS). According to new findings of the effects of metformin on mitochondrial function, has attracted a lot of attention. Furthermore, it is suggested that metformin exerts its beneficial influence through AMP-activated protein kinase (AMPK) pathway. In the current study, we investigated the possible protective effects of metformin on oxidative stress and mitochondrial function by activating the AMPK pathway in the cuprizone-induced demyelination. Mice were fed with cuprizone for 6 weeks. Animals simultaneously received metformin. After sacrificing animals, myelinations, and gliosis, changes in transcription factor and biochemical analysis were assessed. Transmission electron microscopy and luxol fast blue staining revealed that the myelinated axons within corpus callosum of cuprizone-induced demyelination animals increased after administration of metformin. Metformin also upregulated the expression of mitochondrial biogenesis genes. Furthermore, the biochemical analysis demonstrated that metformin ameliorated the oxidative stress induced by cuprizone. Immunohistochemistry analysis showed that astrogliosis and microgliosis were decreased after metformin administration while it enhanced the number of oligodendrocytes. Our data implicated that metformin exerts its therapeutic effects on MS by AMPK signaling improved mitochondrial homeostasis and protected oligodendrocytes.

Keywords: AMP-activated protein kinase (AMPK); Cuprizone; Metformin; Mitochondria; Multiple sclerosis; Oxidative stress.

MeSH terms

  • Animals
  • Axons / drug effects
  • Axons / pathology
  • Cuprizone / toxicity
  • Demyelinating Diseases / chemically induced
  • Demyelinating Diseases / drug therapy
  • Demyelinating Diseases / pathology
  • Disease Models, Animal
  • Hemostasis / drug effects
  • Hemostasis / genetics
  • Humans
  • Metformin / administration & dosage*
  • Mice
  • Mitochondria / drug effects*
  • Mitochondria / genetics
  • Multiple Sclerosis / chemically induced
  • Multiple Sclerosis / drug therapy*
  • Multiple Sclerosis / pathology
  • Oligodendroglia / drug effects
  • Oxidative Stress / drug effects
  • Protein Kinases / genetics*
  • Signal Transduction / drug effects


  • Cuprizone
  • Metformin
  • Protein Kinases
  • AMP-activated protein kinase kinase