Date of Graduation
Eberly College of Arts and Sciences
Steven G Kinsey
Melissa D Blank
Jefferson C Frisbee
Kevin T Larkin
David P Siderovski
Non-steroidal anti-inflammatory drugs (NSAIDs) are common analgesic drugs that also cause well-known, negative gastrointestinal (GI) side effects. The specific physiological mechanism(s) of NSAID-induced GI damage are unknown, and are likely due to multiple causes. The most studied components include: increased gastric acid secretions, inflammation of the gastric epithelium, and increased gastric motility. Currently, proton pump inhibitor (PPI) antacids are used by chronic NSAID users, with the expectation that decreasing gastric acid output will reduce gastric epithelial irritation. However, PPIs are associated with side effects like infection, gastric polyps, and dementia. Therefore, new gastroprotective treatments that prevent NSAID-induced gastropathy are needed. The endocannabinoid system has several possible targets to reduce NSAID-induced ulcers, including the endocannabinoid 2-AG (2-arachidonoylglycerol), and the primary enzyme that metabolizes 2-AG, monoacylglycerol lipase (MAGL). Blocking the MAGL enzyme increases stomach levels of 2-AG and reduces NSAID-induced ulcers in male mice. The present project was designed to determine which ulcerogenic effects of the NSAID diclofenac are reversed by MAGL inhibition. We hypothesized that MAGL inhibition would reverse the following effects of diclofenac: (1) increased gastric acid secretion; (2) increased gastric inflammation; and (3) increased gastric motility. Diclofenac induced gastric hemorrhages to a similar extent in both male and female mice. Diclofenac dose-dependently increased neutrophil infiltration in both male and female mice, indicating that diclofenac induces a cell-mediated inflammatory response. Gastric hemorrhage severity correlated with myeloperoxidase levels, an objective measure of immune cell infiltration, indicating its use as a potential biomarker of gastric damage. Diclofenac significantly increased inflammatory cytokines in male mice, whereas administration of JZL184, a MAGL inhibitor, prior to diclofenac had no effect in male mice and increased gastric inflammatory cytokine levels in female mice. Neither JZL184 nor diclofenac produced any changes on gastric acid secretions when evaluated during the gastric hemorrhage procedure. However, in the pentagastrin-stimulated acid model, JZL184 decreased gastric acid secretions in both basal and stimulated conditions. As hypothesized, JZL184 decreased gastric motility, although diclofenac, contrary to expectations, slowed gastric motility, indicating that diclofenac-induced ulcers most likely do not occur through increased gastric motility, at least not as measured in the present study. The present data indicate that MAGL inhibition may proffer gastroprotection through modulating the secretory pathway of gastric hemorrhage. These data underscore the importance of sampling multiple time points and using both sexes in research, in addition to multiple mechanistic targets, and contribute to the basic understanding of NSAID-induced gastric inflammation.
Crowe, Molly S., "Endocannabinoid modulation of secretory and inflammatory causes of gastric pathology" (2016). Graduate Theses, Dissertations, and Problem Reports. 5412.