Figure 8: The possible mechanism of action of Metf and LOV in immune and CNS cells in EAE.
LOV inhibits mevalonate pathway via inhibition of HMG-CoA reductase and lowers levels of cholesterol and isoprenoids. The depletion of isoprenoids affects Rho family GTPases functions that are reported to regulate PPARs activity in cells. Metformin (Metf) activates AMPK which in turn, regulates PPARs activity in cells. The observed targeting of PPARs by LOV and Metf in combination may inhibit Th1/Th17 cell expansion, but enhance Th2 cells generation that eventually inhibit CNS inflammation and demyelination in EAE.