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Selected Publication:
Stancic, A.
The endocannabinoid system in intestinal inflammation and colon cancer: role of G protein-coupled receptor 55 and monoacylglycerol lipase
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2015. pp.
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- Authors Med Uni Graz:
- Jacan Angela
- Advisor:
- Schicho Rudolf
- Schuligoi Rufina
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- Abstract:
- Endocannabinoids, such as anandamide and 2-arachidonoylglycerol (2-AG), are thought to play an important role in intestinal inflammation. They exert their actions via cannabinoid receptors 1 and 2 (CB1 and CB2) and probably via G protein-coupled receptor 55 (GPR55), which are part of the endocannabinoid system. Monoacylglycerol lipase (MAGL) is also part of the endocannabinoid system and is the key enzyme responsible for degrading 2-AG and is expressed not only in the brain, but also throughout the digestive tract. GPR55 is an atypical cannabinoid receptor and has been shown to be implicated in several pathophysiologic functions. However, its main agonist is the phospholipid lysophosphatidylinositol (LPI), which is not a cannabinoid, but some endocannabinoids were shown to exert their actions also via the GPR55 receptor. GPR55-/- knockout mice have no evident phenotype but inhibition of GPR55 is thought to be protective in models of neuroinflammation. Here, I investigated the effects of the MAGL inhibitor (JZL184) as well as a GPR55 antagonist (CID16020046) in mouse models of experimental colitis and colitis-associated cancer. In addition, I used MAGL-/- and GPR55-/- knockout mice. The GPR55 antagonist was able to reduce the severity of dextrane sulphate sodium (DSS) and 2,4,6-trinitrobenzenesulfonic acid (TNBS) induced colitis, as well as to reduce leukocyte recruitment into the lamina propria of the colon. GPR55-/- mice were also protected from severe intestinal inflammation. Cytokine expression was reduced in the selective GPR55 antagonist treated group. Incubation of mouse macrophage cell line J774.1 with the GPR55 antagonist decreased C5a-induced migration and CD11b expression. Chemotaxis of human neutrophils was also inhibited by GPR55 antagonist treatment. The MAGL inhibitor JZL184 decreased the extent of inflammation in the DSS-induced colitis at a high dose of 32mg/kg, as well as it reduced total tumor area in a model of colitis-driven colon cancer at a low dose. MAGL-/- mice had significantly less tumors and less severe intestinal inflammation compared to wild-type mice. Unlike the cannabinoid receptors, GPR55 plays a proinflammatory role in experimental colitis, and genetic and pharmacological inhibition of MAGL improved the course of the colitis and may therefore represent interesting therapeutic targets for inflammatory bowel diseases.