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

    106 Scopus citations

    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 (US)
    Pages (from-to)1373-1382
    Number of pages10
    JournalBiochemical Pharmacology
    Volume65
    Issue number8
    DOIs
    StatePublished - 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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