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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

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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 Next, the cup was withdrawn to allow one-week recovery (spontaneous remyelination).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.

An overview of the possible molecular mechanisms of action of metformin-mediated remyelinationa

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Data availability

Materials described in the manuscript, including all relevant raw data, will be freely available to any scientist wishing to use them for non-commercial purposes, without breaching.

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Funding

This study was supported by the Shahrekord University of Medical Sciences, Shahrekord, Iran (Grant number: 1393-01-87-2325) and University of Zabol, Zabol, Iran (Grant number: 9618–5).

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Authors and Affiliations

  1. Department of Physiology, School of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran

    Fariba Houshmand

  2. Department of Biotechnology, Faculty of Allied Medicine, Iran University of Medical Science, Tehran, Iran

    Mahmood Barati

  3. Cellular and Molecular Research Center, Iran University of Medical Science, P.O. Box 14155-6451, Tehran, Iran

    Fereshteh Golab, Sara Tanbakooie, Mahsa Tabatabaei & Masoomeh Amiri

  4. Department of Biology, Faculty of Basic Sciences, Razi University, Kermanshah, Iran

    Samaneh Ramezani-sefidar

  5. Department of Biology, Faculty of Sciences, University of Zabol, Zabol, Iran

    Nima Sanadgol

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  1. Fariba Houshmand
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  2. Mahmood Barati
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  3. Fereshteh Golab
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  5. Sara Tanbakooie
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  8. Nima Sanadgol
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Contributions

Golab F. and Sanadgol N. conceived and designed this study. Houshmand F. and Barati M. analyzed data. Tanbakooie S. and Tabatabaei M. wrote the manuscript. All the authors contributed to conducting different experiments, read and approved the manuscript.

Corresponding authors

Correspondence to Fereshteh Golab or Nima Sanadgol.

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The animal study was approved by the Animal Ethics Committee of the Shahrekord University of Medical Sciences, Shahrekord, Iran.

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Houshmand, F., Barati, M., Golab, F. et al. 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 J Pharm Sci 27, 583–592 (2019). https://doi.org/10.1007/s40199-019-00286-z

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  • DOI: https://doi.org/10.1007/s40199-019-00286-z

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