CEP-1347 inhibits caerulein-induced rat pancreatic JNK activation and ameliorates caerulein pancreatitis.
Pancreatic caerulein-induced activation of c-Jun NH(2)-terminal kinase (JNK) has been reported, and JNK has been proposed as a mediator during induction of hyperstimulated pancreatitis. CEP-1347 has recently been described as a specific JNK inhibitor. We tested whether CEP-1347 inhibits caerulein-induced pancreatic JNK activation in isolated acini and in vivo. CEP-1347 dose dependently inhibited acinar caerulein-induced JNK activation with nearly complete inhibition at 2 microM but had no effect on digestive enzyme release. For in vivo studies, rats were pretreated with CEP-1347 before caerulein hyperstimulation. For assessment of JNK activation and histological alterations, animals were killed 30 min or 2 and 4 h after caerulein hyperstimulation, respectively. Pancreatic wet weight, serum enzyme levels, and pancreatic activity of p38 and extracellular signal-regulated kinase (ERK) were also determined. Caerulein hyperstimulation strongly activated JNK, p38, and ERK. CEP-1347 pretreatment dose dependently reduced caerulein-induced pancreatic JNK activation without p38 or ERK inhibition. JNK inhibition also reduced pancreatic edema formation and reduced histological severity of pancreatitis. Thus we show that CEP-1347 inhibits JNK activation in vivo and ameliorates caerulein-induced pancreatitis.
Wagner
A C
AC
Department of Gastroenterology, University of Bern, CH-3010 Bern, Switzerland. awagner@dkf4.unibe.ch
Mazzucchelli
L
L
Miller
M
M
Camoratto
A M
AM
Göke
B
B
D000681:Amylases / Q000378:metabolism; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D002108:Ceruletide / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010179:Pancreas / Q000201:enzymology*; D010182:Pancreatic Diseases / Q000473:pathology; D010195:Pancreatitis / Q000188:drug therapy* / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; C106592:3,9-bis((ethylthio)methyl)-K-252a; D002108:Ceruletide; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D000681:Amylases