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-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 anesthetized male CD mice. INTERVENTIONS: Pancreatitis was induced by intraperitoneal injection of cerulein (hourly ×5, 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 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-κB activation (p <.01); the production of tumor necrosis factor-α and interleukin-1β (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-β and vascular endothelial growth factor (p <.01); and-ultimately-the mortality rate (p <.01). CONCLUSIONS: Inhibition of GSK-3β 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.
| Original language | English |
|---|---|
| Pages (from-to) | 2811-2821 |
| Number of pages | 11 |
| Journal | Critical Care Medicine |
| Volume | 35 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - Dec 2007 |
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Keywords
- Acute pancreatitis
- Adhesion molecules
- Cytokines
- Leukocytes
- Oxidative stress
- Protein kinase
ASJC Scopus subject areas
- Critical Care and Intensive Care Medicine
Cite this
Effects of glycogen synthase kinase-3β inhibition on the development of cerulein-induced acute pancreatitis in mice. / Cuzzocrea, Salvatore; Malleo, Giuseppe; Genovese, Tiziana; Mazzon, Emanuela; Esposito, Emanuela; Muià, Carmelo; Abdelrahman, Maha; Di Paola, Rosanna; Thiemermann, Cristoph.
In: Critical Care Medicine, Vol. 35, No. 12, 12.2007, p. 2811-2821.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Effects of glycogen synthase kinase-3β inhibition on the development of cerulein-induced acute pancreatitis in mice
AU - Cuzzocrea, Salvatore
AU - Malleo, Giuseppe
AU - Genovese, Tiziana
AU - Mazzon, Emanuela
AU - Esposito, Emanuela
AU - Muià, Carmelo
AU - Abdelrahman, Maha
AU - Di Paola, Rosanna
AU - Thiemermann, Cristoph
PY - 2007/12
Y1 - 2007/12
N2 - 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-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 anesthetized male CD mice. INTERVENTIONS: Pancreatitis was induced by intraperitoneal injection of cerulein (hourly ×5, 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 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-κB activation (p <.01); the production of tumor necrosis factor-α and interleukin-1β (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-β and vascular endothelial growth factor (p <.01); and-ultimately-the mortality rate (p <.01). CONCLUSIONS: Inhibition of GSK-3β 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.
AB - 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-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 anesthetized male CD mice. INTERVENTIONS: Pancreatitis was induced by intraperitoneal injection of cerulein (hourly ×5, 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 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-κB activation (p <.01); the production of tumor necrosis factor-α and interleukin-1β (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-β and vascular endothelial growth factor (p <.01); and-ultimately-the mortality rate (p <.01). CONCLUSIONS: Inhibition of GSK-3β 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.
KW - Acute pancreatitis
KW - Adhesion molecules
KW - Cytokines
KW - Leukocytes
KW - Oxidative stress
KW - Protein kinase
UR - http://www.scopus.com/inward/record.url?scp=36448996691&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=36448996691&partnerID=8YFLogxK
U2 - 10.1097/01.CCM.0000295303.62996.9F
DO - 10.1097/01.CCM.0000295303.62996.9F
M3 - Article
VL - 35
SP - 2811
EP - 2821
JO - Critical Care Medicine
JF - Critical Care Medicine
SN - 0090-3493
IS - 12
ER -