Effects of glycogen synthase kinase-3β inhibition on the development of cerulein-induced acute pancreatitis in mice

Objective: Glycogen synthase kinase (GSK)-3 is a 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-3 beta 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 anesthetized male CD mice. Interventions: Pancreatitis was induced by intraperitoneal injection of cerulein (hourly x5, 50 mu g/kg). In the treatment group, the potent and selective GSK-3 beta inhibitor 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) was administered 1 hr and 6 hrs after the first injection of cerulein (10 mg/kg, intraperitoneally). Sham groups were treated with vehicle (0.1 mL of 0.9% NaCl, intraperitoneally) and TDZD-8. 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 < .01); nuclear factor-kappa B activation (p < .01); the production of tumor necrosis factor-alpha and interleukin-10 (p < .01); the expression of adhesion molecules and neutrophil accumulation (p < .01); the formation of oxygen and nitrogen-derived radicals (p < .01); the degree of lipid peroxidation (p < .01); the expression of transforming growth factor-beta and vascular endothelial growth factor (p < .01); and-ultimately-the mortality rate (p < .01). Conclusions: Inhibition of GSK-3 beta reduces the degree of cerulein-induced acute pancreatitis and the associated mortality rate in mice. Blocking protein kinase activity may be a novel approach to treatment of this inflammatory condition.