Glycogen synthase kinase 3β inhibition reduces the development of nonseptic shock induced by zymosan in mice

Salvatore Cuzzocrea, Rosanna Di Paola, Emanuela Mazzon, Concetta Crisafulli, Tiziana Genovese, Carmelo Muià, Maha Abdelrahman, Emanuela Esposito, Christoph Thiemermann

Research output: Contribution to journalArticle

Abstract

Glycogen synthase kinase 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 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8), a glycogen synthase kinase 3β inhibitor, on the development of nonseptic shock caused by zymosan (dose, 500 mg/kg i.p. suspension in saline) in mice. Organ failure and systemic inflammation in mice was assessed 18 h after administration of zymosan and/or TDZD-8; another group of mice was monitored for 12 days (for clinical score and mortality). Treatment of mice with TDZD-8 (dose, 10 mg/kg i.p., 1 and 6 h after zymosan administration) attenuated the peritoneal exudation and the migration of polymorphonuclear cells caused by zymosan. TDZD-8 also attenuated the lung, liver, and pancreatic injury, the renal dysfunction caused by zymosan, and the increase in myeloperoxidase activity caused by zymosan in the lung and in the intestine. Immunohistochemical analysis for inducible nitric oxide synthase, nitrotyrosine, poly(ADP-ribose), CD30, CD30 ligand, and Fas ligand revealed positive staining in lung and intestinal tissues obtained from zymosan-injected mice. The degree of staining for inducible nitric oxide synthase, nitrotyrosine, poly(ADP-ribose), CD30, CD30 ligand, and Fas ligand were markedly reduced in tissue sections obtained from zymosan-injected mice that had received TDZD-8. This study provides the first evidence that TDZD-8 attenuates the degree of zymosan-induced, nonseptic shock in mice.

Original languageEnglish
Pages (from-to)97-107
Number of pages11
JournalShock
Volume27
Issue number1
DOIs
Publication statusPublished - Jan 2007

Keywords

  • Cytokines
  • GSK-3β
  • Inducible nitric oxide synthase
  • Inflammation
  • Nitric oxide
  • TDZD-8
  • Zymosan-induced multiple-organ failure

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine
  • Physiology

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    Cuzzocrea, S., Di Paola, R., Mazzon, E., Crisafulli, C., Genovese, T., Muià, C., Abdelrahman, M., Esposito, E., & Thiemermann, C. (2007). Glycogen synthase kinase 3β inhibition reduces the development of nonseptic shock induced by zymosan in mice. Shock, 27(1), 97-107. https://doi.org/10.1097/01.shk.0000235084.56100.71