Protective effects of SP600125 a new inhibitor of c-jun N-terminal kinase (JNK) and extracellular-regulated kinase (ERK1/2) in an experimental model of cerulein-induced pancreatitis

Life Sci. 2004 Oct 29;75(24):2853-66. doi: 10.1016/j.lfs.2004.03.040.


Extracellular regulated kinases (ERK1/2) and c-Jun N-terminal Kinases (JNK), are generally considered to play a key role in signal transduction pathways activated by a wide range of stimuli. We studied the effects of SP600125, a novel inhibitor of both JNK and ERK1/2, in male C57/BL6 mice given with an hyper-stimulating dose of cerulein (50 microg/kg for each of four injections at hourly intervals) to elicit secretagogue-induced pancreatitis. A control group received four intra-peritoneal injections of 0.9% saline at hourly intervals. Animals were randomized to receive either SP600125 (15 mg/kg i.p. administered 2 h before and 30 min after the first injection of cerulein) or its vehicle (1 ml/kg of a 10% DMSO/NaCl solution). A group of animals was killed 30 minutes after the last cerulein injection to evaluate pancreatic JNK and ERK1/2 activation by Western Blot analysis. Another group was sacrificed 2 hours after the last cerulein injection to evaluate serum lipase and amylase levels, pancreas oedema, pancreatic content of Tumor Necrosis Factor-alpha (TNF-alpha) and Intercellular adhesion molecule-1 (ICAM-1) and the histological alterations. SP600125 inhibited almost totally JNK activation (90%) and partially ERK1/2 activation (45%), reduced the serum lipase and amylase levels and the degree of oedema, blunted the increased pancreatic content of TNF-alpha and ICAM-1 and protected against the histological damage. Our data confirm that both JNK and ERK1/2 activation plays a key role in acute pancreatitis and that SP600125 may represent a potential therapeutic approach to the treatment of patients at high risk of developing this life-threatening condition.

Publication types

  • Comparative Study

MeSH terms

  • Amylases / blood
  • Analysis of Variance
  • Animals
  • Anthracenes / pharmacology*
  • Blotting, Western
  • Ceruletide / toxicity
  • Disease Models, Animal
  • Edema / pathology*
  • Enzyme Activation / drug effects
  • Histological Techniques
  • Intercellular Adhesion Molecule-1 / metabolism
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Lipase / blood
  • MAP Kinase Kinase 4
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Oligonucleotides
  • Pancreas / pathology
  • Pancreatitis / chemically induced*
  • Pancreatitis / prevention & control*
  • Peroxidase / metabolism
  • RNA / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects*
  • Tumor Necrosis Factor-alpha / metabolism


  • Anthracenes
  • Oligonucleotides
  • Tumor Necrosis Factor-alpha
  • Intercellular Adhesion Molecule-1
  • pyrazolanthrone
  • RNA
  • Ceruletide
  • Peroxidase
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 3
  • MAP Kinase Kinase 4
  • Mitogen-Activated Protein Kinase Kinases
  • Lipase
  • Amylases