Simvastatin and eugenol restore autophagic flux and alleviate oxidative, inflammatory, and fibrotic perturbations in an arginine-induced chronic pancreatitis rat model

Abstract

Chronic pancreatitis (CP), a progressive inflammatory disease characterized by pancreatic tissue destruction and fibrosis, is considered a challenging health burden due to insufficiencies of current management procedures. Autophagy impairment has emerged as a major triggering event in pancreatitis, raising interest in exploring the potential of targeting autophagy as a possible interventional strategy. This study aimed to evaluate the possible ameliorative effect of two autophagy modulators, simvastatin and eugenol, on CP-related perturbations in an arginine-induced rat model. Repeated l-arginine administration (5 g/kg divided into 2 doses with a 1 h interval, given intraperitoneally every 3rd day for a total of 10 times) provoked CP features, demonstrated by acinar damage, oxidative stress, inflammation, and fibrosis. Arginine-triggered pancreatitis was accompanied by hampered pancreatic autophagic flux, evidenced by overexpression of pancreatic p62 and LC3-Ⅱ and downregulation of pancreatic AMPK and LAMP-1 mRNA expression. Treatment with simvastatin (20 mg/kg, intraperitoneally 24 h, before each arginine dose) and eugenol (50 mg/kg/day orally for 30 days) achieved significant anti-oxidative, anti-inflammatory, and anti-fibrotic effects, and reversed the arginine-instigated autophagic blockade, with superior ameliorative effects attained by eugenol. Altogether, simvastatin and eugenol provide a promising interventional approach for CP, at least partly, by restoring the impaired autophagic flux associated with CP.