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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 Publisher Pubmed



Sanadgol N1 ; Barati M2 ; Houshmand F3 ; Hassani S4 ; Clarner T5 ; Shahlaei M6 ; Golab F7
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Authors Affiliations
  1. 1. Department of Biology, Faculty of Sciences, University of Zabol, Zabol, Iran
  2. 2. Department of Biotechnology, Faculty of Allied Medicine, Iran University of Medical Science, Tehran, Iran
  3. 3. Department of Physiology, School of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
  4. 4. Toxicology and Diseases Group, Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
  5. 5. Institute of Neuroanatomy, Faculty of Medicine, RWTH Aachen University, Aachen, 52074, Germany
  6. 6. Nano Drug Delivery Research Center, School of Pharmacy, Kermanshah University of Medical Science, Kermanshah, Iran
  7. 7. Cellular and Molecular Research Center, Iran University of Medical Science, P.O. Box 14155-6451, Tehran, Iran

Source: Pharmacological Reports Published:2020


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. © 2019, Maj Institute of Pharmacology Polish Academy of Sciences.
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