TY - JOUR
T1 - Inhibition of glycogen synthase kinase-3β attenuates the development of carrageenan-induced lung injury in mice
AU - Cuzzocrea, S.
AU - Crisafulli, C.
AU - Mazzon, E.
AU - Esposito, E.
AU - Muià, C.
AU - Abdelrahman, M.
AU - Di Paola, R.
AU - Thiemermann, C.
PY - 2006/11/3
Y1 - 2006/11/3
N2 - 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.
AB - 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.
KW - Acute inflammation
KW - Glycogen synthase kinase-3β
KW - NF-κB
KW - Polymorphonuclear leukocytes
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U2 - 10.1038/sj.bjp.0706902
DO - 10.1038/sj.bjp.0706902
M3 - Article
C2 - 17016509
AN - SCOPUS:33751012990
VL - 149
SP - 687
EP - 702
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
SN - 0007-1188
IS - 6
ER -