Decrease of the inflammatory response and induction of the Akt/protein kinase B pathway by poly-(ADP-ribose) polymerase 1 inhibitor in endotoxin-induced septic shock

Balazs Veres, Ferenc Gallyas, Gabor Varbiro, Zoltan Berente, Erzsebet Osz, Gyorgy Szekeres, Csaba Szabo, Balazs Sumegi

Research output: Contribution to journalArticle

107 Citations (Scopus)

Abstract

The lack of efficacy of anti-inflammatory drugs, anti-coagulants, anti-oxidants, etc. in critically ill patients has shifted interest towards developing alternative treatments. Since inhibitors of the nuclear enzyme poly-(ADP-ribose) polymerase (PARP) were found to be beneficial in many pathophysiological conditions associated with oxidative stress and PARP-1 knock-out mice proved to be resistant to bacterial lipopolysaccharide (LPS)-induced septic shock, PARP inhibitors are candidates for such a role. In this study, the mechanism of the protective effect of a potent PARP-1 inhibitor, PJ34 was studied in LPS-induced (20mg/kg, i.p.) septic shock in mice. We demonstrated a significant inflammatory response by magnetic resonance imaging in the dorsal subcutaneous region, in the abdominal regions around the kidneys and in the inter-intestinal cavities. We have found necrotic and apoptotic histological changes as well as obstructed blood vessels in the liver and small intestine. Additionally, we have detected elevated tumor necrosis factor-α levels in the serum and nuclear factor kappa B activation in liver of LPS-treated mice. Pre-treating the animals with PJ34 (10mg/kg, i.p.), before the LPS challenge, besides rescuing the animals from LPS-induced death, attenuated all these changes presumably by activating the phosphatidylinositol 3-kinase-Akt/protein kinase B cytoprotective pathway.

Original languageEnglish
Pages (from-to)1373-1382
Number of pages10
JournalBiochemical Pharmacology
Volume65
Issue number8
DOIs
Publication statusPublished - Apr 15 2003

Keywords

  • Akt/protein kinase B
  • Lipopolysaccharide
  • MRI
  • Poly-(ADP-ribose) polymerase
  • Septic shock

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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