title: Metformin has adenosine-monophosphate activated protein kinase (AMPK)-independent effects on LPS-stimulated rat primary microglial cultures.
abstract: The results of recent studies suggest that metformin, in addition to its efficacy in treating type 2 diabetes, may also have therapeutic potential for the treatment of neuroinflammatory diseases in which reactive microglia play an essential role. However, the molecular mechanisms by which metformin exerts its anti-inflammatory effects remain largely unknown. Adenosine-monophosphate-activated protein kinase (AMPK) activation is the most well-known mechanism of metformin action; however, some of the biological responses to metformin are not limited to AMPK activation but are mediated by AMPK-independent mechanisms. In this paper, we attempted to evaluate the effects of metformin on unstimulated and LPS-activated rat primary microglial cell cultures. The presented evidence supports the conclusion that metformin-activated AMPK participates in regulating the release of TNF-α. Furthermore, the effects of metformin on the release of IL-1β, IL-6, IL-10, TGF-β, NO, and ROS as well as on the expression of arginase I, iNOS, NF-κB p65 and PGC-1α were not AMPK-dependent, because pretreatment of LPS-activated microglia with compound C, a pharmacological inhibitor of AMPK, did not reverse the effect of metformin. Based on the present findings, we propose that the shift of microglia toward alternative activation may underlie the beneficial effects of metformin observed in animal models of neurological disorders.
authors.affiliation: Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Medyków 18, PL40-752 Katowice, Poland. labuzek@rubikon.pl
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Łabuzek
authors.forename: Sebastian
authors.initials: S
authors.lastname: Liber
authors.forename: Bożena
authors.initials: B
authors.lastname: Gabryel
authors.forename: Bogusław
authors.initials: B
authors.lastname: Okopień
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001119:Arginase / Q000378:metabolism; D002478:Cells, Cultured; D020536:Enzyme Activators / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008687:Metformin / Q000494:pharmacology*; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009609:Nitrous Oxide / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D020536:Enzyme Activators; D007004:Hypoglycemic Agents; D008070:Lipopolysaccharides; D016328:NF-kappa B; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D011720:Pyrazoles; D011743:Pyrimidines; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; D012265:Ribonucleotides; D014157:Transcription Factors; C516138:dorsomorphin; D000620:Aminoimidazole Carboxamide; D008687:Metformin; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D055372:AMP-Activated Protein Kinases; D001119:Arginase; C542908:arginase I, rat; C031143:AICA ribonucleotide; D009609:Nitrous Oxide