Metformin therapy attenuates pro-inflammatory Microglia by inhibiting NF-κB in cuprizone demyelinating mouse model of multiple Sclerosis

Abdi, Mahdad and Pasbakhsh, Parichehr and Shabani, Maryam and Nekoonam, Saied and Sadeghi, Asie and Fathi, Fardin and Abouzaripour, Morteza and Mohamed, Wael Mohamed Yousef and Zibara, Kazem and Kashani, Iraj Ragerdi and Zendedel, Adib (2021) Metformin therapy attenuates pro-inflammatory Microglia by inhibiting NF-κB in cuprizone demyelinating mouse model of multiple Sclerosis. Neurotoxi Research, 39. pp. 1732-1746. ISSN 1029-8428 E-ISSN 1476-3524

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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.

Item Type:	Article (Journal)
Uncontrolled Keywords:	Cuprizone; Metformin; Microglia activity; Multiple sclerosis; NF-κB; Neuroinflammation
Subjects:	R Medicine > R Medicine (General)
Kulliyyahs/Centres/Divisions/Institutes (Can select more than one option. Press CONTROL button):	Kulliyyah of Medicine Kulliyyah of Medicine > Department of Basic Medical
Depositing User:	Dr Wael Mohamed
Date Deposited:	14 Dec 2021 09:54
Last Modified:	14 Dec 2021 17:05
URI:	http://irep.iium.edu.my/id/eprint/94204

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