IM156, a new AMPK activator, protects against polymicrobial sepsis

Area of Science:

• Pharmacology
• Immunology
• Sepsis Research

Background:

• Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection.
• Current treatments for sepsis have limitations, necessitating the development of novel therapeutic agents.
• IM156, a potent AMP-activated protein kinase activator, has demonstrated anti-cancer and anti-angiogenic properties.

Purpose of the Study:

• To investigate the therapeutic potential of IM156 in a murine model of polymicrobial sepsis.
• To elucidate the mechanisms underlying IM156's effects on sepsis progression and host defense.

Main Methods:

• Polymicrobial sepsis was induced using the caecal ligation and puncture (CLP) model in mice.
• Survival rates, bacterial burden, organ damage, splenocyte apoptosis, cytokine production, reactive oxygen species (ROS) generation, and neutrophil extracellular traps (NETs) were assessed.
• IM156 was administered to evaluate its protective effects.

Main Results:

• IM156 administration significantly increased survival rates in CLP-induced sepsis.
• IM156 markedly reduced bacterial burden in peritoneal fluid and peripheral blood.
• IM156 attenuated organ damage, inhibited splenocyte apoptosis, and decreased inflammatory cytokine production (IL-1β, IL-6, IL-10).
• IM156 strongly inhibited ROS generation and subsequent NET formation in neutrophils.

Conclusions:

• IM156 demonstrates significant protective effects against polymicrobial sepsis in mice.
• The therapeutic benefits of IM156 are attributed to its ability to reduce bacterial load, attenuate organ damage, and modulate inflammatory responses.
• IM156 shows promise as a novel therapeutic candidate for treating sepsis.