Metformin Attenuated the Autoimmune Disease of the Central Nervous System in Animal Models of Multiple Sclerosis

Abstract

Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated autoimmune disease of the CNS. Metformin is the most widely used drug for diabetes and mediates its action via activating AMP-activated protein kinase (AMPK). We provide evidence that metformin attenuates the induction of EAE by restricting the infiltration of mononuclear cells into the CNS, down-regulating the expression of proinflammatory cytokines (IFN-γ, TNF-α, IL-6, IL-17, and inducible NO synthase (iNOS)), cell adhesion molecules, matrix metalloproteinase 9, and chemokine (RANTES). Furthermore, the AMPK activity and lipids alterations (total phospholipids and in free fatty acids) were restored by metformin treatment in the CNS of treated EAE animals, suggesting the possible involvement of AMPK. Metformin activated AMPK in macrophages and thereby inhibited biosynthesis of phospholipids as well as neutral lipids and also down-regulated the expression of endotoxin (LPS)-induced proinflammatory cytokines and their mediators (iNOS and cyclooxygenase 2). It also attenuated IFN-γ and IL-17-induced iNOS and cyclooxygenase 2 expression in RAW267.4 cells, further supporting its anti-inflammatory property. Metformin inhibited T cell-mediated immune responses including Ag-specific recall responses and production of Th1 or Th17 cytokines, while it induced the generation of IL-10 in spleen cells of treated EAE animals. Altogether these findings reveal that metformin may have a possible therapeutic value for the treatment of multiple sclerosis and other inflammatory diseases.

AMP-activated protein kinase is activated in adipose tissue of individuals with type 2 diabetes treated with metformin: a randomised glycaemia-controlled crossover study

“…Furthermore, there is a significant increase in HSL phosphorylation (at an AMPK-specific site) in 3T3-L1 adipocytes and a tendency towards phosphorylation at that site in human adipose, whereas metformin is without effect on the levels of FAS, PPARγ or GLUT4 protein in either adipose biopsies from individuals with type 2 diabetes or 3T3-L1 adipocytes. We cannot dismiss the possibility that the observed increase in AMPK activity in human adipose was occurring in the stromal/vascular fraction rather than in adipocytes themselves, as metformin has been reported to activate AMPK in human vascular endothelial cells [44] and a macrophage cell line [45]. As metformin also stimulated AMPK Fig.…”

“…Furthermore, as stimulation of AMPK in vascular cells and macrophages has been demonstrated to elicit antiinflammatory effects that would also be beneficial in type 2 diabetes [28,45,47,48], stimulation of adipose AMPK in both the adipocyte and stromal/vascular cell fractions of adipose may explain some of the beneficial metabolic effects of metformin in patients with type 2 diabetes.…”

AMP-activated Protein Kinase Suppresses Matrix Metalloproteinase-9 Expression in Mouse Embryonic Fibroblasts

“…Previous experimental inflammation animal models and cancer cell lines have been used to show that the broad and nonspecific AMPK activators metformin and AICAR decrease MMP-9 expression; however, base-line MMP-9 expression in these artificial models was already up-regulated, and metformin and AICAR can have many off-target effects (39,40). Similarly, here we found that the activity of AMPK was partially responsible for the regulation of basal MMP-9 levels.…”

TCEAL7, a putative tumor suppressor gene, negatively regulates NF-κB pathway

“…Real-time analysis for target genes was performed as described before (Nath et al, 2009): Cox2, IL-6, IL-8 and CyclinD1 primers were purchased from SA Biosciences (Frederick, MD, USA).…”