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

Abstract

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-3beta 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 microg/kg). In the treatment group, the potent and selective GSK-3beta 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-kappaB activation (p < .01); the production of tumor necrosis factor-alpha and interleukin-1beta (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-3beta 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.

• Authors: Salvatore Cuzzocrea, Giuseppe Malleo, Tiziana Genovese, Emanuela Mazzon, Emanuela Esposito, Carmelo Muià, Maha Abdelrahman, Rosanna Di Paola, Cristoph Thiemermann
• Journal: Critical care medicine (Crit Care Med) Vol. 35 Issue 12 Pg. 2811-21 (Dec 2007) ISSN: 0090-3493 [Print] United States
• PMID: 18074481 (Publication Type: Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione
• Cell Adhesion Molecules
• Cytokines
• Enzyme Inhibitors
• NF-kappa B
• Thiadiazoles
• Ceruletide
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Glycogen Synthase Kinase 3

Topics

• Acute Disease
• Animals
• Cell Adhesion Molecules (drug effects)
• Ceruletide
• Cytokines (drug effects)
• Enzyme Inhibitors (immunology, pharmacology)
• Glycogen Synthase Kinase 3 (antagonists & inhibitors, immunology)
• Glycogen Synthase Kinase 3 beta
• Male
• Mice
• Mice, Inbred Strains
• NF-kappa B (drug effects)
• Neutrophil Activation (drug effects)
• Oxidative Stress (drug effects)
• Pancreatitis (immunology, pathology, prevention & control)
• Prospective Studies
• Random Allocation
• Survival Analysis
• Thiadiazoles (immunology, pharmacology)