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

103 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 (US)
Pages (from-to)1373-1382
Number of pages10
JournalBiochemical Pharmacology
Volume65
Issue number8
DOIs
StatePublished - Apr 15 2003
Externally publishedYes

Fingerprint

Proto-Oncogene Proteins c-akt
Poly(ADP-ribose) Polymerases
Septic Shock
Endotoxins
Lipopolysaccharides
Liver
Animals
Phosphatidylinositol 3-Kinase
Coagulants
Oxidative stress
NF-kappa B
Blood vessels
Enzyme Inhibitors
Magnetic resonance
Oxidants
Critical Illness
Knockout Mice
Small Intestine
Blood Vessels
Oxidative Stress

Keywords

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

ASJC Scopus subject areas

  • Pharmacology

Cite this

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

In: Biochemical Pharmacology, Vol. 65, No. 8, 15.04.2003, p. 1373-1382.

Research output: Contribution to journalArticle

Veres, Balazs ; Gallyas, Ferenc ; Varbiro, Gabor ; Berente, Zoltan ; Osz, Erzsebet ; Szekeres, Gyorgy ; Szabo, Csaba ; Sumegi, Balazs. / 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. In: Biochemical Pharmacology. 2003 ; Vol. 65, No. 8. pp. 1373-1382.
@article{e301a9d98d3d481a8cf514d5409dd1ba,
title = "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",
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.",
keywords = "Akt/protein kinase B, Lipopolysaccharide, MRI, Poly-(ADP-ribose) polymerase, Septic shock",
author = "Balazs Veres and Ferenc Gallyas and Gabor Varbiro and Zoltan Berente and Erzsebet Osz and Gyorgy Szekeres and Csaba Szabo and Balazs Sumegi",
year = "2003",
month = "4",
day = "15",
doi = "10.1016/S0006-2952(03)00077-7",
language = "English (US)",
volume = "65",
pages = "1373--1382",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier Inc.",
number = "8",

}

TY - JOUR

T1 - 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

AU - Veres, Balazs

AU - Gallyas, Ferenc

AU - Varbiro, Gabor

AU - Berente, Zoltan

AU - Osz, Erzsebet

AU - Szekeres, Gyorgy

AU - Szabo, Csaba

AU - Sumegi, Balazs

PY - 2003/4/15

Y1 - 2003/4/15

N2 - 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.

AB - 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.

KW - Akt/protein kinase B

KW - Lipopolysaccharide

KW - MRI

KW - Poly-(ADP-ribose) polymerase

KW - Septic shock

UR - http://www.scopus.com/inward/record.url?scp=0037446371&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037446371&partnerID=8YFLogxK

U2 - 10.1016/S0006-2952(03)00077-7

DO - 10.1016/S0006-2952(03)00077-7

M3 - Article

C2 - 12694878

AN - SCOPUS:0037446371

VL - 65

SP - 1373

EP - 1382

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 8

ER -