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Metformin accelerates myelin recovery and ameliorates behavioral deficits in the animal model of multiple sclerosis via adjustment of AMPK/Nrf2/mTOR signaling and maintenance of endogenous oligodendrogenesis during brain self-repairing period

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Abstract

Background

Multiple sclerosis (MS) is a devastating autoimmune disorder characterized by oligodendrocytes (OLGs) loss and demyelination. In this study, we have examined the effects of metformin (MET) on the oligodendrogenesis, redox signaling, apoptosis, and glial responses during a self-repairing period (1-week) in the animal model of MS.

Methods

For induction of demyelination, C57BL/6 J mice were fed a 0.2% cuprizone (CPZ) for 5 weeks. Thereafter, CPZ was removed for 1-week and molecular and behavioral changes were monitored in the presence or absence of MET (50 mg/kg body weight/day).

Results

MET remarkably increased the localization of precursor OLGs (NG2+/O4+ cells) and subsequently the renewal of mature OLGs (MOG+ cells) in the corpus callosum via AMPK/mammalian target of rapamycin (mTOR) pathway. Moreover, we observed a significant elevation in the antioxidant responses, especially in mature OLGs (MOG+/nuclear factor erythroid 2-related factor 2 (Nrf2+) cells) after MET intervention. MET also reduced brain apoptosis markers and lessened motor dysfunction in the open-field test. While MET was unable to decrease active astrogliosis (GFAP mRNA), it reduced microgliosis by down-regulation of Mac-3 mRNA a marker of pro-inflammatory microglia/macrophages. Molecular modeling studies, likewise, confirmed that MET exerts its effects via direct interaction with AMPK.

Conclusions

Altogether, our study reveals that MET effectively induces lesion reduction and elevated molecular processes that support myelin recovery via direct activation of AMPK and indirect regulation of AMPK/Nrf2/mTOR pathway in OLGs. These findings facilitate the development of new therapeutic strategies based on AMPK activation for MS in the near future.

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Acknowledgements

We are grateful to Dr. M. Baeiri from the Institute of Pharmaceutical Sciences (TIPS) at TUMS for her technical support.

Funding

This work was supported by the Iran University of Medical Sciences and University of Zabol (UOZ-GR-9618-5).

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Authors and Affiliations

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

    Nima Sanadgol

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

    Mahmood Barati

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

    Fariba Houshmand

  4. Toxicology and Diseases Group, Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran

    Shokoufeh Hassani

  5. Institute of Neuroanatomy, Faculty of Medicine, RWTH Aachen University, 52074, Aachen, Germany

    Tim Clarner

  6. Nano Drug Delivery Research Center, School of Pharmacy, Kermanshah University of Medical Science, Kermanshah, Iran

    Mohsen shahlaei

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

    Fereshteh Golab

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Contributions

NS, FG, and FH, conceived and designed the study. All authors contributed to performing the relevant experiments. NS, MB, FG, and FH, analyzed the data. NS, and FG, wrote the paper. All authors contributed to reviewing and editing the manuscript and also read and approved the manuscript.

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Correspondence to Fereshteh Golab.

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Sanadgol, N., Barati, M., Houshmand, F. et al. Metformin accelerates myelin recovery and ameliorates behavioral deficits in the animal model of multiple sclerosis via adjustment of AMPK/Nrf2/mTOR signaling and maintenance of endogenous oligodendrogenesis during brain self-repairing period. Pharmacol. Rep 72, 641–658 (2020). https://doi.org/10.1007/s43440-019-00019-8

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