Cerulein-induced acute pancreatitis in the rat is significantly ameliorated by treatment with MEK1/2 inhibitors U0126 and PD98059.

Abstract

INTRODUCTION:

Both cerulein and cholecystokinin activate mitogen-activated protein (MAP) kinase (ERK1/2) in vivo and in isolated pancreatic acini.

AIMS AND METHODOLOGY:

ERK1/2 in pancreas homogenates was activated in rats rendered pancreatitic by subcutaneous injections of cerulein (5 microg/kg per hour). To determine if blocking ERK1/2 activity might rescue cerulein-induced acute pancreatitis, the "MAP kinase kinase" (also known as MEK1/2) inhibitors PD98059 and U0126 were administered in vivo.

RESULTS:

In rats pretreated with PD98059 (10 mg/kg per i.v. injection) or U0126 (5 mg/kg per i.v. injection) 30 minutes before and then together with hourly cerulein injections for 3 hours, pancreatitis was significantly attenuated on the basis of pancreatic wet weight and histology. Serum amylase concentration was significantly reduced when PD98059 was administered intraperitoneally (10 mg/kg per intraperitoneal injection). PD98059 also ameliorated pancreatitis over a 6-hour cerulein time course. The phosphorylation of pancreatic ERK1/2 was attenuated in PD98059- and U0126-treated animals at both 30 minutes and 3 hours after cerulein injection. Rats rendered neutropenic with vinblastine and pretreated with U0126 still showed attenuated manifestations of cerulein-induced acute pancreatitis, a finding suggesting that pancreatic ERK1/2 is mostly responsible for the effect, rather than infiltrating neutrophils.

CONCLUSIONS:

Inhibition of pancreatic ERK1/2 in vivo affords significant protection against inflammatory sequelae following cerulein-induced acute pancreatitis.

• Authors: Antoinette P Clemons, Deborah M Holstein, Aurelio Galli, Christine Saunders
• Journal: Pancreas (Pancreas) Vol. 25 Issue 3 Pg. 251-9 (Oct 2002) ISSN: 1536-4828 [Electronic] United States
• PMID: 12370536 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Butadienes
• Enzyme Inhibitors
• Flavonoids
• Nitriles
• U 0126
• Ceruletide
• Protein-Tyrosine Kinases
• Protein Serine-Threonine Kinases
• Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 1
• MAP Kinase Kinase 2
• Mitogen-Activated Protein Kinase Kinases
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

Topics

• Acute Disease
• Animals
• Butadienes (pharmacology)
• Ceruletide
• Enzyme Inhibitors (pharmacology)
• Flavonoids (pharmacology)
• MAP Kinase Kinase 1
• MAP Kinase Kinase 2
• Male
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors)
• Mitogen-Activated Protein Kinases (antagonists & inhibitors)
• Nitriles (pharmacology)
• Pancreatitis (chemically induced, drug therapy, enzymology, pathology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Rats
• Rats, Sprague-Dawley