Dimethyl Fumarate Ameliorates L-arginine Induced Acute and Chronic Pancreatitis

Lourdes Y Robles, MD, Nosratola Vaziri, MD, MACP, Shiri Li, MD, PhD, Chie Takasu, MD, PhD, Kelly Vo, Michael Stamos, MD, Hirohito Ichii, MD, PhD. University of California, Irvine.

Introduction: The objective of this study was to examine the effects of an oral Nrf2-keap 1 pathway activator, Dimethyl fumarate (DMF) on experimental acute and chronic pancreatitis induced by L-Arginine. Nrf2-keap 1 pathway is the master regulator of hundreds of genes, encoding antioxidant, cytoprotective, and detoxifying molecules. DMF is a potent oral Nrf2 activator which exerts its protective effects by attenuation of oxidative stress and inhibition of NF-?B. The main hypothesis of this study is that DMF will protect the rats from oxidative stress-mediated pancreatic injury induced by L-Arginine.

Methods: Rats were treated with daily DMF (25mg/kg) or vehicle prior to induction of acute or chronic pancreatitis by L-Arginine. Acute pancreatitis was induced by two injections of L-arginine (350mg/100g) one hour apart, after which animals were monitored for 72 hours prior to sacrifice. Chronic pancreatitis was induced by daily L-Arginine (400 mg/100g) injections for 28 days. Objective assessments for both acute and chronic pancreatitis included serum amylase level, body weight, pancreas size, pellet size after collagenase digestion, and pancreas histology.

Results: Fixed pancreas samples from DMF treated rats revealed a decrease in the level of pancreatic inflammation, edema, and acinar cell destruction compared to vehicle treated rats (p <0.001). Likewise, average serum amylase levels of the DMF treated rats was reduced at 2000 U/L compared to the vehicle treated rats at 4,015 U/L (control rats 700 U/L) (p <0.05). With chronic L-Arginine stimulation, the DMF rats were able to maintain their body weight and gain weight similar to control rats over the 4 week study period. In contrast, placebo treated rats had sluggish weight gain and a significant change in body weight compared to baseline. At sacrifice, the pancreases of the DMF rats were significantly larger and weighed more than the vehicle treated controls (1.12g versus 0.77g). The pancreases were dissociated after extraction and pellet size was measured and noted to be significantly smaller in the placebo treated rats (p <0.05). Histologically, 22% of vehicle treated controls had evidence of severe chronic pancreatitis. In contrast, all of the DMF rats had normal pancreases.

Conclusion: Treatment with DMF, a Nrf2 activator, significantly ameliorates experimental acute and chronic pancreatitis. DMF has also recently become FDA approved for the treatment of Multiple Sclerosis as clinical trials revealed a significant improvement in patients receiving the drug. This study may indicate that DMF may be useful in other inflammatory conditions as well.

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