Metformin Therapy Attenuates Pro-inflammatory Microglia by Inhibiting NF-κB in Cuprizone Demyelinating Mouse Model of Multiple Sclerosis.
Animals
Blotting, Western
Cuprizone
/ pharmacology
Disease Models, Animal
Male
Metformin
/ therapeutic use
Mice
Mice, Inbred C57BL
Microglia
/ drug effects
Multiple Sclerosis
/ drug therapy
NF-kappa B
/ metabolism
Neuroinflammatory Diseases
/ drug therapy
Neuroprotective Agents
/ therapeutic use
Transcriptome
/ drug effects
Cuprizone
Metformin
Microglia activity
Multiple sclerosis
NF-κB
Neuroinflammation
Journal
Neurotoxicity research
ISSN: 1476-3524
Titre abrégé: Neurotox Res
Pays: United States
ID NLM: 100929017
Informations de publication
Date de publication:
Dec 2021
Dec 2021
Historique:
received:
14
06
2021
accepted:
13
09
2021
revised:
30
08
2021
pubmed:
28
9
2021
medline:
31
3
2022
entrez:
27
9
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34570348
doi: 10.1007/s12640-021-00417-y
pii: 10.1007/s12640-021-00417-y
doi:
Substances chimiques
NF-kappa B
0
Neuroprotective Agents
0
Cuprizone
5N16U7E0AO
Metformin
9100L32L2N
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1732-1746Subventions
Organisme : tehran university of medical sciences and health services
ID : 98-01-30- 41867
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
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