IM156, a new AMPK activator, ameliorates polymicrobial sepsis by regulating inflammatory responses

Abstract

Abstract IM156, a biguanide with a higher potency of AMP-activated protein kinase (AMPK) activation than metformin, exhibits inhibitory activity against angiogenesis and cancer. In this study, we explored the anti-inflammatory effects of IM156 against polymicrobial sepsis. Administration of IM156 significantly improved the survival rate and tissue damage in cecal ligation and puncture (CLP)-induced sepsis. Mechanistically, IM156 markedly reduced the number of bacterial cells in the peritoneal fluid and peripheral blood in a CLP-induced sepsis model. IM156 also inhibited splenocyte apoptosis and the production of inflammatory cytokines, including IL-1β, IL-6, and IL-10, in CLP mice. Furthermore, IM156 strongly inhibited the reactive oxygen species (ROS) generation by enhancing antioxidative effects, which can lead to reduced neutrophil extracellular trap (NET) formation in response to lipopolysaccharide. In conclusion, these findings collectively indicate that IM156 can suppress the inflammatory response and provide protection against polymicrobial sepsis. These results suggest the potential of IM156 as a novel therapeutic agent for sepsis control.