Metformin-induced AMPK activation stimulates remyelination through induction of neurotrophic factors, downregulation of NogoA and recruitment of Olig2+ precursor cells in the cuprizone murine model of multiple sclerosis

Daru. 2019 Dec;27(2):583-592. doi: 10.1007/s40199-019-00286-z. Epub 2019 Oct 16.

Abstract

Purpose: Oligodendrocytes (OLGs) damage and myelin distraction is considered as a critical step in many neurological disorders especially multiple sclerosis (MS). Cuprizone (cup) animal model of MS targets OLGs degeneration and frequently used to the mechanistic understanding of de- and remyelination. The aim of this study was exploring the effects of metformin on the OLGs regeneration, myelin repair and profile of neurotrophic factors in the mice brain after cup-induced acute demyelination.

Methods: Mice (C57BL/6 J) were fed with chow containing 0.2% cup for 5 weeks to induce specific OLGs degeneration and acute demyelination. Next, the cup was withdrawn to allow one-week recovery (spontaneous remyelination). At the end of this period, mature OLGs markers, myelin-associated neurite outgrowth inhibitor protein A (NogoA), premature specific OLGs transcription factor (Olig2), anti-apoptosis marker (survivin), neurotrophic factors, and AMPK activation were monitored in the presence or absence of metformin (50 mg/kg body weight/day) in the corpus callosum (CC).

Results: Our finding indicated that consumption of metformin during the recovery period potentially induced an active form of AMPK (p-AMPK) and promoted repopulation of mature OLGs (MOG+ cells, MBP+ cells) in CC through up-regulation of BDNF, CNTF, and NGF as well as down-regulation of NogoA and recruitment of Olig2+ precursor cells.

Conclusions: This study for the first time reveals that metformin-induced AMPK, a master regulator of energy homeostasis, activation following toxic demyelination could potentially accelerate regeneration and supports spontaneous demyelination. These findings suggest the development of new therapeutic strategies based on AMPK activation for MS in the near future. Graphical abstract An overview of the possible molecular mechanisms of action of metformin-mediated remyelinationa.

Keywords: AMPK; Cuprizone; Metformin; Multiple sclerosis; Remyelination.

MeSH terms

  • AMP-Activated Protein Kinases / genetics*
  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • Cuprizone / adverse effects*
  • Disease Models, Animal
  • Down-Regulation
  • Enzyme Activation / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Male
  • Metformin / administration & dosage*
  • Metformin / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Multiple Sclerosis / chemically induced
  • Multiple Sclerosis / drug therapy*
  • Multiple Sclerosis / enzymology
  • Multiple Sclerosis / genetics
  • Nerve Growth Factors / genetics*
  • Nerve Growth Factors / metabolism
  • Oligodendrocyte Transcription Factor 2 / genetics*
  • Oligodendrocyte Transcription Factor 2 / metabolism

Substances

  • Nerve Growth Factors
  • Olig2 protein, mouse
  • Oligodendrocyte Transcription Factor 2
  • Cuprizone
  • Metformin
  • AMP-Activated Protein Kinases