Dimethyl Fumarate Prevents Acinar Damage From Rodent Chronic Pancreatitis Model With L-Arginine.

Abstract

Introduction: Nrf2 pathway is the master regulator of the antioxidant/antiinflammatory response, regulating the expression of numerous antioxidant enzymes. Dimethyl Fumarate (DMF) is an oral Nrf2 activator, which has been successfully used for clinical trials in patients with Multiple sclerosis. Purpose: Determine the effects of oral DMF on islet cells and non-endocrine tissue in rodent model of L-Arginine-induced chronic pancreatitis. Methods: Wister rats fed daily DMF (25mg/kg) or vehicle, were given injections of L-Arginine (500mg/100g) every three days for a total of 54 days. Rats were assessed with biweekly body weights and intra-peritoneal glucose tolerance tests (IPGTT, 2g/kg). At sacrifice, rat pancreases underwent islet isolation and assessment for islet count and equivalence (IC, IEQ) and islet viability with FACS. Results: Rat body weight remained similar between DMF and vehicle treated rats after 6 weeks; however, significant differences were seen in IPGTT during 90 and 120 minutes, with DMF treated animals returning to baseline glucose levels faster than control animals. At explant, vehicle treated control rats revealed evidence of pancreatic atrophy (p <0.05). After islet isolation, the remaining pellet containing non-endocrine tissue was significantly smaller in vehicle treated controls. Despite changes in acinar cell tissue, IC, IEQ and islet viability were not significantly different between the two groups. Conclusion: DMF ameliorated pancreatic atrophy and acinar cell destruction, while improving glucose response in vivo. Fortification of the antioxidant defense system by pharmacological activation of Nrf2 pathway in pancreas may be a strategy to improve the outcome in clinical auto islet transplantation for patients with chronic pancreatitis.Figure: No Caption available.