Pyruvic acid is a three-
carbon alpha-ketocarboxylic
acid that plays a central role in intermediary metabolism, being the final product of glycolysis and the starting substrate for the tricarboxylic acid cycle.
Ethyl pyruvate, which is a simple aliphatic
ester derived from
pyruvic acid, has been shown to improve survival and ameliorate organ system dysfunction in mice with
peritonitis induced by cecal
ligation and perforation, even when treatment is started as late as 12-24 hours after the onset of
sepsis. In studies using
lipopolysaccharide-stimulated RAW 264.7 murine macrophage-like cells,
ethyl pyruvate inhibits activation of the pro-inflammatory
transcription factor,
NF-kappaB, and down-regulates secretion of a number of pro-inflammatory
cytokines, such as TNF. In this reductionist in vitro system,
ethyl pyruvate also blocks secretion of the late-appearing pro-inflammatory
cytokine-like molecule, high mobility group B1 (
HMGB1). In murine models of
endotoxemia or
sepsis, treatment with
ethyl pyruvate decreases circulating levels of TNF and
HMGB1. While the molecular events responsible for the salutary effects of
ethyl pyruvate remain to be elucidated, one mechanism may involve covalent modification of a critical
thiol residue in the p65 component of
NF-kappaB.
Ethyl pyruvate warrants evaluation as a therapeutic agent for the treatment of
sepsis in humans.