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Carbenoxolone blocks endotoxin-induced protein kinase R (PKR) activation and high mobility group box 1 (HMGB1)

Wei Li1, Jianhua Li, Andrew E Sama

  • 1The Feinstein Institute for Medical Research, Manhasset, New York, USA. wll2@nshs.edu

Molecular Medicine (Cambridge, Mass.)
|July 10, 2013
PubMed

Insights

Carbenoxolone (CBX), a licorice derivative, inhibits lipopolysaccharide (LPS)-induced high mobility group box 1 (HMGB1) release by blocking PKR activation. CBX treatment improved survival rates in a sepsis animal model, suggesting its therapeutic potential.

Area of Science:

  • Immunology
  • Molecular Biology
  • Pharmacology

Background:

  • Pathogen- and damage-associated molecular patterns activate protein kinase R (PKR) and inflammasomes, leading to high mobility group box 1 (HMGB1) release.
  • Extracellular adenosine triphosphate (ATP) activates P2X7 receptors (P2X7R) and pannexin-1 (panx-1) channels, contributing to inflammasome activation.
  • The role of panx-1 channel blockers in inhibiting lipopolysaccharide (LPS)-induced PKR activation and HMGB1 release remained unclear.

Purpose of the Study:

  • To investigate whether carbenoxolone (CBX), a panx-1 channel blocker and licorice derivative, can inhibit LPS-induced PKR activation and HMGB1 release in innate immune cells.
  • To evaluate the therapeutic efficacy of CBX in an animal model of polymicrobial sepsis.

Main Methods:

  • Dose-dependent inhibition of LPS-induced HMGB1 release by CBX in macrophage cultures.
  • Assessment of circulating and peritoneal HMGB1 levels and animal survival rates in a cecal ligation and puncture (CLP) sepsis model following CBX administration.
  • Evaluation of P2X7R/panx-1 channel activation and PKR phosphorylation in macrophages using Lucifer Yellow dye uptake and Western blotting.

Main Results:

  • CBX dose-dependently abrogated LPS-induced HMGB1 release in macrophages (IC50 ≈ 5 μmol/L).
  • Repetitive CBX administration in CLP-induced sepsis significantly reduced HMGB1 levels and increased animal survival.
  • CBX, similar to P2X7R antagonists, attenuated LPS-induced P2X7R/panx-1 channel activation and PKR phosphorylation.

Conclusions:

  • CBX inhibits LPS-induced HMGB1 release, likely by impairing PKR activation.
  • These findings support the involvement of PKR in regulating HMGB1 release.
  • CBX demonstrates therapeutic potential for sepsis treatment by modulating HMGB1 release and PKR activation.

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