Metformin attenuated the autoimmune disease of the central nervous system 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).

Novel synthetic small‐molecule activators of AMPK as enhancers of autophagy and amyloid‐β peptide degradation

“…In summary, this work describes the identification and characterization of novel small-molecule activators of AMPK that potently inhibit mTOR signaling, activate autophagy, and trigger A␤ clearance by the lysosomal system. AMPK is a key target for drug discovery mostly because of its broad spectrum of functions in energy metabolism and cell growth, but also in neuroprotection in the CNS (57)(58)(59)(60). Our results strengthen the notion that small-molecule indirect and potent activators of AMPK can be identified and thus may offer new therapeutic perspectives in disorders where AMPK, mTOR, and autophagy are involved.…”

Multiple Sclerosis: Molecular Mechanisms and Therapeutic Opportunities

“…Euphol (alcohol tetracyclic triterpene) not only attenuates the progression and severity of EAE, most likely by suppressing myelin-specific Th17 cells infiltration and cytokine production, but also attenuates NF-jB-regulated iNOS and COX2 expression in the CNS (125). Very similar effects in an EAE model were observed for metformin (antidiabetic drug) (339). Some studies showed that the application of selective iNOS inhibitor aminoguanidine leads to a significant decrease in the clinical expression of EAE (58,278,402,493), implying that iNOS inhibition may represent an important component of MS treatment.…”

Protective Effect of Metformin against Acute Inflammation and Oxidative Stress in Rat

“…Metformin, a first-line drug used for the treatment of type 2 diabetes, exhibits pleiotropic effects of which its anti-inflammatory effects are noteworthy [Hattori et al, 2015]. It has been reported to inhibit inflammation in various preclinical studies on chronic diseases like rheumatoid arthritis, encephalomyelitis, endotoxin-induced uveitis, non-alcoholic steatohepatitis, peritonitis-induced sepsis, and colitis-associated colon cancer [Nath et al, 2009;Kalariya et al, 2012;Kita et al, 2012;Kang et al, 2013;Park et al, 2013;Koh et al, 2014]. It has been shown to reduce the levels of inflammatory mediators like TNF-a and IL-6 in a rat model of obesity and metabolic syndrome and to attenuate the expression of adhesion molecules [Hattori et al,2006;Desai et al, 2013].…”