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

• Published in: Biochemical pharmacology 2003-04, Vol.65 (8), p.1373-1382
• Main Authors: Veres, Balazs, Gallyas, Ferenc, Varbiro, Gabor, Berente, Zoltan, Osz, Erzsebet, Szekeres, Gyorgy, Szabo, Csaba, Sumegi, Balazs
• Format: Article
• Language: English
• Subjects: Akt/protein kinase B; Animals; Base Sequence; Binding Sites; Biological and medical sciences; Consensus Sequence; Endotoxins - toxicity; Enzyme Inhibitors - pharmacology; Escherichia coli; Inflammation - physiopathology; Inflammation - prevention & control; Lipopolysaccharide; Lipopolysaccharides - toxicity; Medical sciences; Mice; Mice, Inbred BALB C; MRI; NF-kappa B - metabolism; Phenanthrenes - pharmacology; Poly(ADP-ribose) Polymerase Inhibitors; Poly-(ADP-ribose) polymerase; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Sepsis - enzymology; Sepsis - pathology; Sepsis - physiopathology; Septic shock; Shock, Septic - enzymology; Shock, Septic - pathology; Shock, Septic - physiopathology
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(03)00077-7

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 (20 mg/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 (10 mg/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.