Prophylactic but not therapeutic administration of N-acetylcysteine (NAC) decreases the severity of experimental acute pancreatitis

Abstract

Background: Inflammation and oxidative stress occur in the pancreas during the early stages of acute pancreatitis. NAC is a thiol compound and can act as a direct scavenger of reactive oxygen species leading to decrease the inflammatory process. Aim: To assess the prophylactic as well as the therapeutic effect of NAC on the early course of acute necrotizing pancreatitis in mice. Methods: Acute pancreatitis (AP) was induced through 4 i.p. injections of 50 }ag/kg cerulein. Mice were assigned to receive either, Group 1: NAC given orally during one week + 1000 mg/kg i.p. one hour before AP induction then every 3 hours for 2 doses, or Group 2:1000 mg/kg i.p. one hour before AP induction then every 3 hours, or Group 3:1000 mg/kg i.p. one hour after AP induction then every 3 hours or Group 4: only saline before AP induction. Severity of AP was assessed in terms of Serum amylase/lipase levels, histological changes (edema, inflammation, necrosis), systemic release of TNF-a and IL-6, intrapancreatic levels of TNF-a and IL-6 and pancreatic glutathione content. Results: Prophylactic administration of NAC (Groups 1 and 2) dramatically decreased the severity (histologically and amylase/lipase levels at 3 and 6 hours after induction) of AP as compared to Group 3 (therapeutic administration) and Group 4 (controls) whose severity was similar. Interestingly, no significant difference was found between group 1 and 2 (NAC given orally as pretreatment or not). Prophylactic administration of NAC led to a significant decrease of systemic IL-6 release (TNF-ct not detectable in this model) and of intrapancreatic IL-6 and TNF-ct levels as compared to therapeutic administration or controls (3 and 6 hours after induction). However, this effect was not dose-dependent (300 mg/kg i.p. = 600 mg/kg = 1000 mg/kg). No significant differences in total pancreatic gluthatione content were found in mice treated with NAC before AP induction compared with those in mice treated with NAC after induction or with controls. Conclusions: NAC administered only in a prophylactic protocol limits the severity of cerulein-induced AP in mice despite no change on pancreatic glutathione content. This suggests that oxidative stress occurs very early in the course of AP and probably triggers the inflammatory process through cytokines induction. This approach may substantiate the prophylactic use of NAC in preventing post-ERCP pancreatitis.