Can we predict the effects of NF-kappaB inhibition in sepsis? Studies with parthenolide and ethyl pyruvate

Expert Opin Investig Drugs. 2009 Aug;18(8):1047-60. doi: 10.1517/13543780903018880.


Background: Based partially on encouraging findings from preclinical models, interest has grown in therapeutic inhibition of NF-kappaB to limit inflammatory injury during sepsis. However, NF-kappaB also regulates protective responses, and predicting the net survival effects of such inhibition may be difficult.

Objectives: To highlight the caution necessary with this therapeutic approach, we review our investigations in a mouse sepsis model with parthenolide and ethyl pyruvate, two NF-kappaB inhibitors proposed for clinical study.

Results: Consistent with published studies, parthenolide decreased NF-kappaB binding activity and inflammatory cytokine release from lipopolysaccharide (LPS) stimulated RAW 264.7 cells in vitro. In LPS-challenged mice (C57BL/6J), however, while both agents decreased lung and kidney NF-kappaB binding activity and plasma cytokines early (1-3 h), these measures were increased later (6-12 h) in patterns differing significantly over time. Furthermore, despite studying several doses of parthenolide (0.25-4.0 mg/kg) and ethyl pyruvate (0.1-100 mg/kg), each produced small but consistent decreases in survival which overall were significant (p < or = 0.04 for each agent).

Conclusion: While NF-kappaB inhibitors hold promise for inflammatory conditions such as sepsis, caution is necessary. Clear understanding of the net effects of NF-kappaB inhibitors on outcome will be necessary before such agents are used clinically.

Publication types

  • Research Support, N.I.H., Intramural
  • Review

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / adverse effects
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
  • Disease Models, Animal
  • Humans
  • Mice
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / physiology
  • Pyruvates / adverse effects
  • Pyruvates / pharmacology
  • Pyruvates / therapeutic use*
  • Sepsis / drug therapy*
  • Sepsis / immunology
  • Sepsis / metabolism
  • Sesquiterpenes / adverse effects
  • Sesquiterpenes / pharmacology
  • Sesquiterpenes / therapeutic use*


  • Anti-Inflammatory Agents, Non-Steroidal
  • NF-kappa B
  • Pyruvates
  • Sesquiterpenes
  • ethyl pyruvate
  • parthenolide