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Metformin Therapy Attenuates Pro-inflammatory Microglia by Inhibiting NF-κB in Cuprizone Demyelinating Mouse Model of Multiple Sclerosis

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Abstract

Multiple sclerosis (MS) is a chronic disorder characterized by reactive gliosis, inflammation, and demyelination. Microglia plays a crucial role in the pathogenesis of MS and has the dynamic plasticity to polarize between pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes. Metformin, a glucose-lowering drug, attenuates inflammatory responses by activating adenosine monophosphate protein kinase (AMPK) which suppresses nuclear factor kappa B (NF-κB). In this study, we indirectly investigated whether metformin therapy would regulate microglia activity in the cuprizone (CPZ)-induced demyelination mouse model of MS via measuring the markers associated with pro- and anti-inflammatory microglia. Evaluation of myelin by luxol fast blue staining revealed that metformin treatment (CPZ + Met) diminished demyelination, in comparison to CPZ mice. In addition, metformin therapy significantly alleviated reactive microgliosis and astrogliosis in the corpus callosum, as measured by Iba-1 and GFAP staining. Moreover, metformin treatment significantly downregulated the expression of pro-inflammatory associated genes (iNOS, H2-Aa, and TNF-α) in the corpus callosum, whereas expression of anti-inflammatory markers (Arg1, Mrc1, and IL10) was not promoted, compared to CPZ mice. Furthermore, protein levels of iNOS (pro-inflammatory marker) were significantly decreased in the metformin group, while those of Trem2 (anti-inflammatory marker) were increased. In addition, metformin significantly increased AMPK activation in CPZ mice. Finally, metformin administration significantly reduced the activation level of NF-κB in CPZ mice. In summary, our data revealed that metformin attenuated pro-inflammatory microglia markers through suppressing NF-κB activity. The positive effects of metformin on microglia and remyelination suggest that it could be used as a promising candidate to lessen the incidence of inflammatory neurodegenerative diseases such as MS.

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Availability of Data and Material

Data and material supporting the published claims and complying with field standards will be made available upon request.

Code Availability

In this study, we used ImageJ (ImageJ, RRID:SCR_003070) and GraphPad Prism (GraphPad Prism, RRID:SCR_002798) software. We also used anti-Iba-1 (Abcam Cat# ab178847, RRID:AB_2832244), anti-GFAP (Abcam Cat# ab7260, RRID:AB_305808), anti-iNOS (Abcam Cat# ab115819, RRID:AB_10898933), anti-Trem2 (Antibodies-Online Cat# ABIN749678, RRID:AB_11182784), anti-NFkB p65 (Abcam Cat# ab16502, RRID:AB_443394), anti-p-NFκB p65 (Santa Cruz Biotechnology Cat# sc-136548, RRID:AB_10610391), anti-p-AMPK (Santa Cruz Biotechnology Cat# sc-33524, RRID:AB_2169714), and anti-AMPK (Santa Cruz Biotechnology Cat# sc-74461, RRID:AB_1118940).

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Funding

The current study was supported by a grant (number 98–01‐30‐41867) to Parichehr Pasbakhsh from the Tehran University of Medical Sciences and Health Services, Tehran, Iran.

Author information

Authors and Affiliations

  1. Department of Anatomy, school of medicine, Tehran University of Medical Sciences, Tehran, Iran

    Mahdad Abdi, Parichehr Pasbakhsh, Saied Nekoonam & Iraj Ragerdi Kashani

  2. Department of Clinical Biochemistry, Tehran University of Medical Sciences, Tehran, Iran

    Maryam Shabani

  3. Department of Clinical Biochemistry, Faculty of medicine, Kerman University of Medical Sciences, Kerman, Iran

    Asie Sadeghi

  4. Cellular and Molecular Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran

    Fardin Fathi

  5. Department of Anatomy, Kurdistan University of Medical Sciences, Sanandaj, Iran

    Morteza Abouzaripour

  6. Basic Medical Science Department, International Islamic University Malaysia, Pahang, Malaysia

    Wael Mohamed

  7. Clinical Pharmacology Department, Menoufia Medical School, Menoufia University, Shebin El Kom, Egypt

    Wael Mohamed

  8. PRASE and Biology Department, Faculty of Sciences-I, Lebanese University, Beirut, Lebanon

    Kazem Zibara

  9. Institute of Neuroanatomy, RWTH University Hospital Aachen, Aachen, Germany

    Adib Zendedel

Authors
  1. Mahdad Abdi
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  2. Parichehr Pasbakhsh
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  3. Maryam Shabani
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  4. Saied Nekoonam
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  5. Asie Sadeghi
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  6. Fardin Fathi
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  7. Morteza Abouzaripour
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  8. Wael Mohamed
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  9. Kazem Zibara
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  10. Iraj Ragerdi Kashani
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  11. Adib Zendedel
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Contributions

MA, MS, SN, AS, FF, and MA performed experiments. MA, PP, WM, KZ, IRK, and AZ analyzed experiments. MA and KZ wrote the manuscript. PP and AZ designed the study with help of KZ and IRJ. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Parichehr Pasbakhsh or Kazem Zibara.

Ethics declarations

Ethical Approval

This article does not contain any studies with human participants performed by any of the authors. However, research and animal care were approved by the Institutional Animal Care and Use Committee (IACUC) and Ethics Committees of Tehran University of Medical Science (TUMS), Tehran, Iran (IR.TUMS.MEDICINE.REC.1398.224). Animals were kept in quarantine for approx. 1 week prior to use. All applicable international, national, and institutional guidelines for the care and use of animals were followed. All animals were kept in standard conditions with unlimited access to food and water. Surgical procedures were performed under deep anesthesia. Housing of animals and experimental procedures were carried out in accordance with the guidelines of the Iranian Agriculture Ministry and of the European Communities Council Directive (86/609/EEC).

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Not applicable, as no human material was used.

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Not applicable.

Conflict of Interest

The authors declare no competing interests.

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Abdi, M., Pasbakhsh, P., Shabani, M. et al. Metformin Therapy Attenuates Pro-inflammatory Microglia by Inhibiting NF-κB in Cuprizone Demyelinating Mouse Model of Multiple Sclerosis. Neurotox Res 39, 1732–1746 (2021). https://doi.org/10.1007/s12640-021-00417-y

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  • DOI: https://doi.org/10.1007/s12640-021-00417-y

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