Lipid peroxidation inhibition reduces NF-kappa B activation and attenuates cerulein-induced pancreatitis

Increased lipid peroxidation, enhanced nuclear factor kappa-B (NF-kappaB) activation and augmented tumor necrosis factor-alpha (TNF-alpha) production have been implicated in cerulein-induced pancreatitis. We investigated whether lipid peroxidation inhibition might reduce NF-kappaB activation and the inflammatory response in cerulein-induced pancreatitis. Male Sprague-Dawley rats of 230-250 g body weight received administration of cerulein (80 mug/kg s.c. for each of four injections at hourly intervals). A control group received four s.c. injections of 0.9% saline at hourly intervals. Animals were randomized to receive either raxofelast, an inhibitor of lipid peroxidation (20 mg/kg i.p. administered with the first cerulein injection) or its vehicle (1 ml/kg of a 10% DMSO/NaCl solution). All these rats were sacrificed 2 h after the last injection of either cerulein or its vehicle. Raxofelast administration (20 mg/kg i.p. with the first cerulein) significantly reduced malondialdehyde (MDA) levels, an index of lipid peroxidation (CER+DMSO=3.075+/-0.54 mumol/g; CER+raxofelast= 0.693+/-0.18 mumol/g; p < 0.001), decreased myeloperoxidase (MPO) activity (CER+DMSO=22.2+/-3.54 mU/g; CER+raxofelast=9.07+/-2.05 mU/g; p < 0.01 ), increased glutathione levels (GSH) (CER+DMSO= 5.21+/-1.79 mumol/g; CER+raxofelast=15.71+/-2.14 mumol/g; p < 0.001 ), and reduced acinar cell damage evaluated by means of histology and serum levels of both amylase (CER+DMSO=4063+/-707.9 U/l; CER+raxofelast=1198+/-214.4 U/l; p < 0.001 ), and lipase (CER+DMSO=1654+/-330 U/l; CER+raxofelast= 386+/-118.2 U/l; p < 0.001 ), Furthermore, raxofelast reduced pancreatic NF-κB activation and the TNF-α mRNA levels and tissue content of mature protein in the pancreas. Indeed, lipid peroxidation inhibition might be considered a potential therapeutic approach to prevent the severe damage in acute pancreatitis.