Inhibition of glycogen synthase kinase-3β attenuates the development of carrageenan-induced lung injury in mice

S. Cuzzocrea, C. Crisafulli, E. Mazzon, E. Esposito, C. Muià, M. Abdelrahman, R. Di Paola, C. Thiemermann

Research output: Contribution to journalArticle

Abstract

Background and purpose: Glycogen synthase kinase-3 (GSK-3) is a ubiquitous serine-threonine protein kinase that participates in a multitude of cellular processes and has recently been implicated in the pathophysiology of a number of diseases. The aim of this study was to investigate the effects of GSK-3β inhibition in a model of acute inflammation. Here, we have investigated the effects of TDZD-8, a potent and selective GSK-3β inhibitor, in a mouse model of carrageenan-induced pleurisy. Experimental approach: Injection of carrageenan into the pleural cavity of mice elicited an acute inflammatory response characterized by: accumulation of fluid containing a large number of neutrophils (PMNs) in the pleural cavity, infiltration of PMNs in lung tissues and subsequent lipid peroxidation, and increased production of nitrite/nitrate (NOx), prostaglandin E 2 (PGE 2), tumour necrosis factor-α, (TNF-α) and interleukin-1β (IL-1β). Furthermore, carrageenan induced an upregulation of the adhesion molecules ICAM-1 and P-selectin, iNOS, COX-2 as well as nitrotyrosine as determined by immunohistochemical analysis of lung tissues. Key results: Administration of TDZD-8 (1, 3 or 10 mg kg -1, i.p.), 30 min prior to injection of carrageenan, caused a dose-dependent reduction in all the parameters of inflammation measured. Conclusions and Implications: Thus, based on these findings we propose that inhibitors of the activity of GSK-3β, such as TDZD-8, may be useful in the treatment of various inflammatory diseases.

Original languageEnglish
Pages (from-to)687-702
Number of pages16
JournalBritish Journal of Pharmacology
Volume149
Issue number6
DOIs
Publication statusPublished - Nov 3 2006

Keywords

  • Acute inflammation
  • Glycogen synthase kinase-3β
  • NF-κB
  • Polymorphonuclear leukocytes

ASJC Scopus subject areas

  • Pharmacology

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    Cuzzocrea, S., Crisafulli, C., Mazzon, E., Esposito, E., Muià, C., Abdelrahman, M., Di Paola, R., & Thiemermann, C. (2006). Inhibition of glycogen synthase kinase-3β attenuates the development of carrageenan-induced lung injury in mice. British Journal of Pharmacology, 149(6), 687-702. https://doi.org/10.1038/sj.bjp.0706902