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

Abstract

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.

• Authors: Xuemei Li, Junwu Su, Xizhong Cui, Yan Li, Amisha Barochia, Peter Q Eichacker
• Journal: Expert opinion on investigational drugs (Expert Opin Investig Drugs) Vol. 18 Issue 8 Pg. 1047-60 (Aug 2009) ISSN: 1744-7658 [Electronic] England
• PMID: 19555300 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Review)

Chemical References

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

Topics

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