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


METHODS
Prospective, randomized study.


METHODS
University-based research laboratory.


METHODS
One-hundred and sixty anesthetized male CD mice.


METHODS
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.


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.
Cuzzocrea
Salvatore
S
Department of Clinical, Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Italy. salvator@.unime.it
Malleo
Giuseppe
G
Genovese
Tiziana
T
Mazzon
Emanuela
E
Esposito
Emanuela
E
Muià
Carmelo
C
Abdelrahman
Maha
M
Di Paola
Rosanna
R
Thiemermann
Cristoph
C
D000208:Acute Disease; D000818:Animals; D015815:Cell Adhesion Molecules / Q000187:drug effects; D002108:Ceruletide; D016207:Cytokines / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000276:immunology / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000276:immunology; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D016328:NF-kappa B / Q000187:drug effects; D018375:Neutrophil Activation / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010195:Pancreatitis / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D011446:Prospective Studies; D011897:Random Allocation; D016019:Survival Analysis; D013830:Thiadiazoles / Q000276:immunology / Q000494:pharmacology*
C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; D015815:Cell Adhesion Molecules; D016207:Cytokines; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D013830:Thiadiazoles; D002108:Ceruletide; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3