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


METHODS
Experimental study.


METHODS
University laboratory.


METHODS
Male CD mice (20-22 g).


METHODS
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).


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-alpha and interleukin-1 beta. 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-ribose) pathway in septic shock-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.
Genovese
Tiziana
T
Department of Clinical and Experimental Medicine and Pharmacology, Torre Biologica, Policlinico Universitario, Messina, Italy.
Di Paola
Rosanna
R
Catalano
Paolo
P
Li
Jia-He
JH
Xu
Weizheng
W
Massuda
Edmond
E
Caputi
Achille P
AP
Zhang
Jie
J
Cuzzocrea
Salvatore
S
D000208:Acute Disease; D000577:Amides / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors*; D007375:Interleukin-1 / Q000096:biosynthesis; D008297:Male; D008315:Malondialdehyde / Q000032:analysis; D051379:Mice; D008815:Mice, Inbred Strains; D009102:Multiple Organ Failure / Q000188:drug therapy; D010538:Peritonitis / Q000139:chemically induced; D009195:Peroxidase / Q000378:metabolism; D012772:Shock, Septic / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D013634:Tannins / Q000008:administration & dosage / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015054:Zymosan
D000577:Amides; D007375:Interleukin-1; D013634:Tannins; D014409:Tumor Necrosis Factor-alpha; D008315:Malondialdehyde; D015054:Zymosan; D009195:Peroxidase; D006026:Glycoside Hydrolases; C022407:poly ADP-ribose glycohydrolase