CEP-1347 inhibits caerulein-induced rat pancreatic JNK activation and ameliorates caerulein pancreatitis

Pancreatic caerulein-induced activation of c-Jun NH2-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-indu ced pancreatic JNK activation in isolated acini and in vivo. CEP-1347 dose dependently inhibited acinar caerulein-induced JNK activation with nearly c omplete inhibition at 2 mu M but had no effect on digestive enzyme release. For in vivo studies, rats were pretreated with CEP-1347 before caerulein h yperstimulation. For assessment of JNK activation and histological alterati ons, animals were killed 30 min or 2 and 4 h after caerulein hyperstimulati on, respectively. Pancreatic wet weight, serum enzyme levels, and pancreati c activity of p38 and extracellular signal-regulated kinase (ERK) were also determined. Caerulein hyperstimulation strongly activated JNK, p38, and ER K. CEP-1347 pretreatment dose dependently reduced caerulein-induced pancrea tic JNK activation without p38 or ERK inhibition. JNK inhibition also reduc ed pancreatic edema formation and reduced histological severity of pancreat itis. Thus we show that CEP-1347 inhibits JNK activation in vivo and amelio rates caerulein-induced pancreatitis.