GLYCOGEN SYNTHASE KINASE-3?? INHIBITION REDUCES THE DEVELOPMENT OF NON-SEPTIC SHOCK INDUCED BY ZYMOSAN IN MICE

Abstract

Glycogen synthase kinase-3 (GSK-3) has recently been identified as a ubiquitous serine-threonine protein kinase that participates in a multitude of cellular processes and plays an important role in the pathophysiology of a number of diseases. In the present study, we have investigated the effects of TDZD-8, a GSK-3β inhibitor, on the development of non-septic shock caused by zymosan (500 mg/kg, administered i.p. as a suspension in saline) in mice. Organ failure and systemic inflammation in mice was assessed 18 hours after administration of zymosan and/or TDZD-8; an other group of mice was monitored for 12 days (for clinical score and mortality). Treatment of mice with TDZD-8 (10 mg/kg i.p., 1 and 6 hours after zymosan) attenuated the peritoneal exudation and the migration of polymorphonuclear cells (PMNs) caused by zymosan, TDZD-8 also attenuated the lung, liver and pancreatic injury and renal dysfunction caused by zymosan as well as the increase in myeloperoxidase (MPO) activity caused by zymosan in the lung and intestine. Immunohistochemical analysis for inducible nitric oxide synthase (iNOS), nitrotyrosine, poly(ADP-ribose) (PAR), CD30, CD30-ligand and FAS-ligand revealed positive staining in lung and intestine tissues obtained from zymosan-treated mice. The degree of staining for nitrotyrosine, iNOS, PAR, CD30, CD30-ligand and FAS-ligand were markedly reduced in tissue sections obtained from zymosan-treated mice, which had received TDZD-8. This study provides the first evidence that TDZD-8 attenuates the degree of zymosan-induced, non-septic shock in mice.