Date of Completion

Spring 5-1-2014

Thesis Advisor(s)

Arlene Albert

Honors Major

Molecular and Cell Biology

Disciplines

Digestive System Diseases | Gastroenterology | Medical Molecular Biology

Abstract

Acute pancreatitis is an inflammatory disease that is initiated by the activation and retention of digestive zymogens inside pancreatic acinar cells (acini). It is proposed that adenosine monophosphate-activated protein kinase (AMPK) regulates early responses of acute pancreatitis in acini. A recent study shows that induction of experimental pancreatitis in isolated rat acini with supraphysiologic cerulein (orthologue of cholecystokinin) increases intracellular zymogen activation, but decreases AMPK levels. Furthermore, in vitro pharmacologic stimulation of AMPK reduces zymogen activation, having a protective effect. In this study, the effectiveness of two AMPK activators was examined in two separate in vivo pancreatitis models. In the first model, rats received a pre-treatment of the AMPK activator metformin via intraperitoneal (IP) injection. A second injection of cerulein was administered one hour later. The pancreata were harvested after an additional hour, and the following markers of pancreatitis were assessed: intracellular zymogen activation, edema, and histological damage. In the second model, mice received a pre-treatment of either metformin or salicylate. For each of the six hours following, mice received an injection of cerulein. At the seventh hour, the pancreata were harvested. The same parameters were assessed. In both models, AMPK activators displayed a marked decrease in zymogen activation. Edema data obtained through percentage wet weight measurements were insignificant. Histological staining of pre-treated sections demonstrated a considerable decrease in edema and pyknotic nuclei in rats. These results strongly suggest that metformin and salicylate could be used as prophylactic or therapeutic treatments for patients early in the course of acute pancreatitis.

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