• S Cuzzocrea, C Crisafulli, E Mazzon, E Esposito, C Muià, M Abdelrahman, R Di Paola, and C Thiemermann.
• Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Messina, Italy. salvator@unime.it
• Br. J. Pharmacol. 2006 Nov 1; 149 (6): 687-702.

Background And PurposeGlycogen 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-3beta inhibition in a model of acute inflammation. Here, we have investigated the effects of TDZD-8, a potent and selective GSK-3beta inhibitor, in a mouse model of carrageenan-induced pleurisy.Experimental ApproachInjection 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 E2 (PGE2), tumour necrosis factor-alpha, (TNF-alpha) and interleukin-1beta (IL-1beta). 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 ResultsAdministration 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 ImplicationsThus, based on these findings we propose that inhibitors of the activity of GSK-3beta, such as TDZD-8, may be useful in the treatment of various inflammatory diseases.

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