Repository of Research and Investigative Information

Repository of Research and Investigative Information

Kurdistan University of Medical Sciences

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

(2021) Metformin Therapy Attenuates Pro-inflammatory Microglia by Inhibiting NF-kappaB in Cuprizone Demyelinating Mouse Model of Multiple Sclerosis. Neurotoxicity research.

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Official URL: https://www.ncbi.nlm.nih.gov/pubmed/34570348

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-kappaB). 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-alpha) 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-kappaB in CPZ mice. In summary, our data revealed that metformin attenuated pro-inflammatory microglia markers through suppressing NF-kappaB 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.

Item Type: Article
Keywords: Animals Blotting, Western Cuprizone/pharmacology Disease Models, Animal Male Metformin/*therapeutic use Mice Mice, Inbred C57BL Microglia/*drug effects Multiple Sclerosis/*drug therapy/metabolism NF-kappa B/*metabolism Neuroinflammatory Diseases/*drug therapy Neuroprotective Agents/*therapeutic use Transcriptome/drug effects Cuprizone Metformin Microglia activity Multiple sclerosis NF-kappaB Neuroinflammation
Page Range: pp. 1732-1746
Journal or Publication Title: Neurotoxicity research
Volume: 39
Number: 6
Depositing User: مهندس مهدی شریفی
URI: http://eprints.muk.ac.ir/id/eprint/5335

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