Treatment with a novel poly(ADP-ribose) glycohydrolase inhibitor reduces development of septic shock-like syndrome induced by zymosan in mice

Tiziana Genovese, Rosanna Di Paola, Paolo Catalano, Jia He Li, Weizheng Xu, Edmond Massuda, Achille P. Caputi, Jie Zhang, Salvatore Cuzzocrea

Research output: Contribution to journalArticle

Abstract

Objective: Poly(ADP-ribose) is synthesized from nicotinamide adenine dinucleotide by poly(ADP-ribose) polymerase (PARP) and degraded by poly(ADP-ribose) glycohydrolase (PARG). The activation of the PARP/PARG pathway has been found in a variety of animal models of diseases, including septic shock-like syndrome. We have previously demonstrated that PARP inhibition by 3-aminobenzamlde or GPI 6150 ameliorates multiple organ dysfunctions induced by zymosan. In the present study, we investigated whether similar effect could be achieved, through PARG inhibition to break the cycle of poly(ADP-ribose) turnaround. Design: Experimental study. Setting: University laboratory. Subjects: Male CD mice (20-22 g). Interventions: We tested the effects of GPI 18214 (40 mg/kg intraperitoneally bolus), a novel and potent PARG inhibitor, at 1 and 6 hr after zymosan (500 mg/kg, administered intraperitoneally as a suspension in saline) on the development of septic shock-like syndrome in mice. Organ failure and systemic inflammation in mice were assessed 18 hrs after administration of zymosan and/or GPI 18214 and monitored for 12 days (for loss of body weight and mortality). Measurements and Main Results: At 18 hrs after zymosan administration, we found a significant increase of peritoneal exudates, leukocyte infiltration in peritoneal cavity as well as an infiltration of neutrophils in lung and ileum tissues and subsequent lipid peroxidation, and increased production of plasma tumor necrosis factor-α and interleukin-1β. Furthermore, zymosan administration induced significant liver, lung, pancreas, intestine, and kidney dysfunction as well as a systemic toxicity and significant loss of body weight. At the end of observation period (12 days), 90% of zymosan-treated mice were dead. GPI 18214 (40 mg/kg intraperitoneally, 1 and 6 hrs after zymosan) treatment significantly reduced peritoneal exudates, inflammatory cell infiltration, and organ injury and mortality rate in zymosan-treated mice. Conclusions: This study supports early studies that show efficacy from blocking the poly(ADP-rlbose) pathway in septic stock-like syndrome model. It provides evidence that GPI 18214, a PARG inhibitor, attenuates the degree of zymosan-induced nonseptic shock in mice, suggesting that PARG may be an alternative therapeutic target for shock treatment.

Original languageEnglish (US)
Pages (from-to)1365-1374
Number of pages10
JournalCritical Care Medicine
Volume32
Issue number6
DOIs
StatePublished - Jun 2004
Externally publishedYes

Fingerprint

Zymosan
Septic Shock
Poly(ADP-ribose) Polymerases
Poly Adenosine Diphosphate Ribose
Therapeutics
Exudates and Transudates
Shock
Body Weight
poly ADP-ribose glycohydrolase
Animal Disease Models
Lung
Neutrophil Infiltration
Mortality
Peritoneal Cavity
Interleukin-1
Ileum
NAD
Adenosine Diphosphate
Lipid Peroxidation
Intestines

Keywords

  • Neytrophil infiltration
  • Organ injury
  • Poly(ADP-ribose) glycohydrolase inhibitor
  • Zymosan-induced multiple organ failure

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Treatment with a novel poly(ADP-ribose) glycohydrolase inhibitor reduces development of septic shock-like syndrome induced by zymosan in mice. / Genovese, Tiziana; Di Paola, Rosanna; Catalano, Paolo; Li, Jia He; Xu, Weizheng; Massuda, Edmond; Caputi, Achille P.; Zhang, Jie; Cuzzocrea, Salvatore.

In: Critical Care Medicine, Vol. 32, No. 6, 06.2004, p. 1365-1374.

Research output: Contribution to journalArticle

Genovese, T, Di Paola, R, Catalano, P, Li, JH, Xu, W, Massuda, E, Caputi, AP, Zhang, J & Cuzzocrea, S 2004, 'Treatment with a novel poly(ADP-ribose) glycohydrolase inhibitor reduces development of septic shock-like syndrome induced by zymosan in mice', Critical Care Medicine, vol. 32, no. 6, pp. 1365-1374. https://doi.org/10.1097/01.CCM.0000127775.70867.0C
Genovese, Tiziana ; Di Paola, Rosanna ; Catalano, Paolo ; Li, Jia He ; Xu, Weizheng ; Massuda, Edmond ; Caputi, Achille P. ; Zhang, Jie ; Cuzzocrea, Salvatore. / Treatment with a novel poly(ADP-ribose) glycohydrolase inhibitor reduces development of septic shock-like syndrome induced by zymosan in mice. In: Critical Care Medicine. 2004 ; Vol. 32, No. 6. pp. 1365-1374.
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abstract = "Objective: Poly(ADP-ribose) is synthesized from nicotinamide adenine dinucleotide by poly(ADP-ribose) polymerase (PARP) and degraded by poly(ADP-ribose) glycohydrolase (PARG). The activation of the PARP/PARG pathway has been found in a variety of animal models of diseases, including septic shock-like syndrome. We have previously demonstrated that PARP inhibition by 3-aminobenzamlde or GPI 6150 ameliorates multiple organ dysfunctions induced by zymosan. In the present study, we investigated whether similar effect could be achieved, through PARG inhibition to break the cycle of poly(ADP-ribose) turnaround. Design: Experimental study. Setting: University laboratory. Subjects: Male CD mice (20-22 g). Interventions: We tested the effects of GPI 18214 (40 mg/kg intraperitoneally bolus), a novel and potent PARG inhibitor, at 1 and 6 hr after zymosan (500 mg/kg, administered intraperitoneally as a suspension in saline) on the development of septic shock-like syndrome in mice. Organ failure and systemic inflammation in mice were assessed 18 hrs after administration of zymosan and/or GPI 18214 and monitored for 12 days (for loss of body weight and mortality). Measurements and Main Results: At 18 hrs after zymosan administration, we found a significant increase of peritoneal exudates, leukocyte infiltration in peritoneal cavity as well as an infiltration of neutrophils in lung and ileum tissues and subsequent lipid peroxidation, and increased production of plasma tumor necrosis factor-α and interleukin-1β. Furthermore, zymosan administration induced significant liver, lung, pancreas, intestine, and kidney dysfunction as well as a systemic toxicity and significant loss of body weight. At the end of observation period (12 days), 90{\%} of zymosan-treated mice were dead. GPI 18214 (40 mg/kg intraperitoneally, 1 and 6 hrs after zymosan) treatment significantly reduced peritoneal exudates, inflammatory cell infiltration, and organ injury and mortality rate in zymosan-treated mice. Conclusions: This study supports early studies that show efficacy from blocking the poly(ADP-rlbose) pathway in septic stock-like syndrome model. It provides evidence that GPI 18214, a PARG inhibitor, attenuates the degree of zymosan-induced nonseptic shock in mice, suggesting that PARG may be an alternative therapeutic target for shock treatment.",
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author = "Tiziana Genovese and {Di Paola}, Rosanna and Paolo Catalano and Li, {Jia He} and Weizheng Xu and Edmond Massuda and Caputi, {Achille P.} and Jie Zhang and Salvatore Cuzzocrea",
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AU - Genovese, Tiziana

AU - Di Paola, Rosanna

AU - Catalano, Paolo

AU - Li, Jia He

AU - Xu, Weizheng

AU - Massuda, Edmond

AU - Caputi, Achille P.

AU - Zhang, Jie

AU - Cuzzocrea, Salvatore

PY - 2004/6

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N2 - Objective: Poly(ADP-ribose) is synthesized from nicotinamide adenine dinucleotide by poly(ADP-ribose) polymerase (PARP) and degraded by poly(ADP-ribose) glycohydrolase (PARG). The activation of the PARP/PARG pathway has been found in a variety of animal models of diseases, including septic shock-like syndrome. We have previously demonstrated that PARP inhibition by 3-aminobenzamlde or GPI 6150 ameliorates multiple organ dysfunctions induced by zymosan. In the present study, we investigated whether similar effect could be achieved, through PARG inhibition to break the cycle of poly(ADP-ribose) turnaround. Design: Experimental study. Setting: University laboratory. Subjects: Male CD mice (20-22 g). Interventions: We tested the effects of GPI 18214 (40 mg/kg intraperitoneally bolus), a novel and potent PARG inhibitor, at 1 and 6 hr after zymosan (500 mg/kg, administered intraperitoneally as a suspension in saline) on the development of septic shock-like syndrome in mice. Organ failure and systemic inflammation in mice were assessed 18 hrs after administration of zymosan and/or GPI 18214 and monitored for 12 days (for loss of body weight and mortality). Measurements and Main Results: At 18 hrs after zymosan administration, we found a significant increase of peritoneal exudates, leukocyte infiltration in peritoneal cavity as well as an infiltration of neutrophils in lung and ileum tissues and subsequent lipid peroxidation, and increased production of plasma tumor necrosis factor-α and interleukin-1β. Furthermore, zymosan administration induced significant liver, lung, pancreas, intestine, and kidney dysfunction as well as a systemic toxicity and significant loss of body weight. At the end of observation period (12 days), 90% of zymosan-treated mice were dead. GPI 18214 (40 mg/kg intraperitoneally, 1 and 6 hrs after zymosan) treatment significantly reduced peritoneal exudates, inflammatory cell infiltration, and organ injury and mortality rate in zymosan-treated mice. Conclusions: This study supports early studies that show efficacy from blocking the poly(ADP-rlbose) pathway in septic stock-like syndrome model. It provides evidence that GPI 18214, a PARG inhibitor, attenuates the degree of zymosan-induced nonseptic shock in mice, suggesting that PARG may be an alternative therapeutic target for shock treatment.

AB - Objective: Poly(ADP-ribose) is synthesized from nicotinamide adenine dinucleotide by poly(ADP-ribose) polymerase (PARP) and degraded by poly(ADP-ribose) glycohydrolase (PARG). The activation of the PARP/PARG pathway has been found in a variety of animal models of diseases, including septic shock-like syndrome. We have previously demonstrated that PARP inhibition by 3-aminobenzamlde or GPI 6150 ameliorates multiple organ dysfunctions induced by zymosan. In the present study, we investigated whether similar effect could be achieved, through PARG inhibition to break the cycle of poly(ADP-ribose) turnaround. Design: Experimental study. Setting: University laboratory. Subjects: Male CD mice (20-22 g). Interventions: We tested the effects of GPI 18214 (40 mg/kg intraperitoneally bolus), a novel and potent PARG inhibitor, at 1 and 6 hr after zymosan (500 mg/kg, administered intraperitoneally as a suspension in saline) on the development of septic shock-like syndrome in mice. Organ failure and systemic inflammation in mice were assessed 18 hrs after administration of zymosan and/or GPI 18214 and monitored for 12 days (for loss of body weight and mortality). Measurements and Main Results: At 18 hrs after zymosan administration, we found a significant increase of peritoneal exudates, leukocyte infiltration in peritoneal cavity as well as an infiltration of neutrophils in lung and ileum tissues and subsequent lipid peroxidation, and increased production of plasma tumor necrosis factor-α and interleukin-1β. Furthermore, zymosan administration induced significant liver, lung, pancreas, intestine, and kidney dysfunction as well as a systemic toxicity and significant loss of body weight. At the end of observation period (12 days), 90% of zymosan-treated mice were dead. GPI 18214 (40 mg/kg intraperitoneally, 1 and 6 hrs after zymosan) treatment significantly reduced peritoneal exudates, inflammatory cell infiltration, and organ injury and mortality rate in zymosan-treated mice. Conclusions: This study supports early studies that show efficacy from blocking the poly(ADP-rlbose) pathway in septic stock-like syndrome model. It provides evidence that GPI 18214, a PARG inhibitor, attenuates the degree of zymosan-induced nonseptic shock in mice, suggesting that PARG may be an alternative therapeutic target for shock treatment.

KW - Neytrophil infiltration

KW - Organ injury

KW - Poly(ADP-ribose) glycohydrolase inhibitor

KW - Zymosan-induced multiple organ failure

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