Objective. Glycogen synthase kinase-3 (GSK-3) is an ubiquitous serine-threonine protein kinase that participates in a multitude of cellular processes and signal transduction pathways. It also plays an important role in the pathophysiology of a number of diseases characterized by an enhanced or unregulated inflammatory response. Here we investigate the effects of GSK-3β inhibition on the development of experimental acute pancreatitis induced by cerulein in mice. Design. Prospective, randomized study. Setting. University-based research laboratory. Subjects. One-hundred and sixty anhestetized male CD mice. Interventions. Pancreatitis was induced by intraperitoneal injection of cerulein (hourly x5, 50 μg/kg). In the treatment group, the potent and selective GSK-3β inhibitor 4-Benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) was administered one and six hours after the first injection of cerulein (10 mg/kg, intraperitoneally). Sham groups were treated with vehicle (0.1 mL 0.9% NaCl, intraperitoneally) and TDZD-8 respectively. In another set of experiments, mice were monitored for 24 days to determine their mortality rate. Measurements and Main Results. The injection of cerulein resulted in acute necrotizing pancreatitis. TDZD-8 significantly reduced the degree of pancreas injury, amylase and lipase serum levels (p <0.01), NF-B activation (p <0.01), the production of TNF-α and IL-1β (p <0.01), the expression of adhesion molecules and neutrophil accumulation (p <0.01), the formation of oxygen and nitrogen-derived radicals (p <0.01), the degree of lipid peroxidation (p <0.01), the expression of TGF-β and VEGF (p <0.01), and – ultimately – the mortality rate (p <0.01). Conclusions. Inhibition of GSK-3β reduces the degree and the mortality rate of cerulein-induced acute pancreatitis in mice. Blocking protein-kinases activity may represent a novel approach for the therapy of this inflammatory condition
Effects of glycogen synthase kinase-3 beta inhibition on the development of cerulein-induced acute pancreatitis in mice
CUZZOCREA, Salvatore;GENOVESE, TIZIANA;ESPOSITO, EMANUELA;DI PAOLA, ROSANNA
2007-01-01
Abstract
Objective. Glycogen synthase kinase-3 (GSK-3) is an ubiquitous serine-threonine protein kinase that participates in a multitude of cellular processes and signal transduction pathways. It also plays an important role in the pathophysiology of a number of diseases characterized by an enhanced or unregulated inflammatory response. Here we investigate the effects of GSK-3β inhibition on the development of experimental acute pancreatitis induced by cerulein in mice. Design. Prospective, randomized study. Setting. University-based research laboratory. Subjects. One-hundred and sixty anhestetized male CD mice. Interventions. Pancreatitis was induced by intraperitoneal injection of cerulein (hourly x5, 50 μg/kg). In the treatment group, the potent and selective GSK-3β inhibitor 4-Benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) was administered one and six hours after the first injection of cerulein (10 mg/kg, intraperitoneally). Sham groups were treated with vehicle (0.1 mL 0.9% NaCl, intraperitoneally) and TDZD-8 respectively. In another set of experiments, mice were monitored for 24 days to determine their mortality rate. Measurements and Main Results. The injection of cerulein resulted in acute necrotizing pancreatitis. TDZD-8 significantly reduced the degree of pancreas injury, amylase and lipase serum levels (p <0.01), NF-B activation (p <0.01), the production of TNF-α and IL-1β (p <0.01), the expression of adhesion molecules and neutrophil accumulation (p <0.01), the formation of oxygen and nitrogen-derived radicals (p <0.01), the degree of lipid peroxidation (p <0.01), the expression of TGF-β and VEGF (p <0.01), and – ultimately – the mortality rate (p <0.01). Conclusions. Inhibition of GSK-3β reduces the degree and the mortality rate of cerulein-induced acute pancreatitis in mice. Blocking protein-kinases activity may represent a novel approach for the therapy of this inflammatory conditionPubblicazioni consigliate
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