Inhibitory mechanism of MMP-9 gene expression by ethyl pyruvate in lipopolysaccharide-stimulated BV2 microglial cells

Neurosci Lett. 2011 Apr 8;493(1-2):38-43. doi: 10.1016/j.neulet.2011.02.016. Epub 2011 Feb 21.

Abstract

Ethyl pyruvate (EP) is a stable derivative of pyruvate and has been identified as a therapeutic agent for various inflammatory diseases. In the present study, we showed that EP and sodium pyruvate (SP) inhibited the production of TNF-α, nitric oxide (NO), or reactive oxygen species (ROS) in LPS-stimulated BV2 microglial cells. The inhibitory effects of EP were more potent than SP. Because matrix metalloproteinase-9 (MMP-9) plays a key role in neuroinflammation, as well as in neuronal cell death, we examined the effect of EP on MMP-9 expression. RT-PCR and Western blot analyses revealed that EP inhibits MMP-9 expression at mRNA and protein levels in LPS-stimulated BV2 cells. In addition, EP suppressed MMP-9 secretion, as demonstrated by gelatin zymography analysis. In contrast, SP did not affect MMP-9 expression at an equivalent concentration of EP. Further mechanistic studies revealed that EP inhibits MMP-9 promoter activity by reducing the binding of NF-κB and AP-1 to its cognitive binding sites. In addition, EP suppressed LPS-induced phosphorylation of p38 MAPK, ERK, and Akt, which are upstream signaling molecules in MMP-9 gene expression. Taken together, our data suggest that the inhibition of MMP-9 may be one of the factors contributing to anti-inflammatory activity of EP in LPS-stimulated microglia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Cell Line, Transformed
  • Gene Expression Regulation, Enzymologic / drug effects*
  • Gene Expression Regulation, Enzymologic / physiology
  • Inflammation Mediators / pharmacology*
  • Lipopolysaccharides / pharmacology
  • Matrix Metalloproteinase 9 / genetics*
  • Matrix Metalloproteinase 9 / metabolism
  • Matrix Metalloproteinase Inhibitors*
  • Mice
  • Microglia / drug effects*
  • Microglia / enzymology
  • Microglia / pathology*
  • Protease Inhibitors / pharmacology*
  • Pyruvates / pharmacology*
  • RNA, Messenger / antagonists & inhibitors
  • RNA, Messenger / metabolism

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Inflammation Mediators
  • Lipopolysaccharides
  • Matrix Metalloproteinase Inhibitors
  • Protease Inhibitors
  • Pyruvates
  • RNA, Messenger
  • ethyl pyruvate
  • Matrix Metalloproteinase 9