Metformin, a diabetic drug attenuated autoimmune inflammatory disease of CNS in animal models of multiple sclerosis
Abstract
Metformin is the most widely prescribed oral anti‐diabetic and hypoglycemic drug. Here we examined the efficacy of metformin in relapsing/remitting (SJL) and chronic (C57BL/6) models of EAE. Administration of metformin restricted the infiltration of mononuclear cells in central nervous system (CNS), thereby; downregulated the expression of proinflammatory cytokines (IFN‐gamma, TNF‐alpha, IL‐6, IL‐17 and iNOS), CAMs, MMP9 and chemokine (Rantes) in CNS of treated animals. Metformin treatment restored the lipids alterations (total phospholipids and in free fatty acid) in CNS during EAE suggest a possible involvement of AMP‐activated protein kinase (AMPK) which acts as cellular energy sensor in cells. Activation of AMPK with metformin was observed in macrophages and inhibits phospholipids and neutral lipid biosynthesis. Further it down regulated the expression of pro‐inflammatory mediators (iNOS and Cox2) induced with LPS/IFN‐gamma. It also downregulated recall responses, Th1 as well as Th17 cytokines and induced IL‐10 production in total spleen cells of treated and untreated EAE animals. Together, these findings reveal that metformin may have possible therapeutic value for the treatment of multiple sclerosis and other inflammatory diseases. Grants: RG 3810‐A‐1, PP1283 from National Multiple Sclerosis Society (SG) and NS‐22576, NS‐34741, NS‐37766 and NS‐40810 from NIH (IS).
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