Date of Graduation
Eberly College of Arts and Sciences
Steven G Kinsey
Melissa D Blank
Christina L Duncan
Lisa J Robinson
Cole Vonder Haar
Rheumatoid arthritis (RA, Table 1) is the most common type of inflammatory arthritis, and is characterized by swelling, inflammation, pain, and destruction of the synovial joints (i.e., knees, elbows, wrists, hips, and fingers). Glucocorticoid receptor agonists are a type of steroid hormone and are among the most common treatments for inflammatory arthritis because of their powerful anti-inflammatory effects. However, harmful side effects are associated with these glucocorticoids (GCs), including increasing patients' vulnerability to infections. Cannabinoids (i.e., cannabis-like signaling molecules) exert anti-inflammatory and analgesic effects with limited side effects compared to traditional immunosuppressants making them excellent targets for the development of new arthritic therapeutics. For example, in mice, selective inhibition of the cannabinoid enzyme monoacylglycerol lipase (MAGL) reduces acute inflammatory pain and edema. Dual administration of drugs are promising novel treatments because it allows lower doses of drugs to attenuate pain and inflammation, while limiting side effects. Combined administration of an endocannabinoid enzyme inhibitor and nonsteroidal anti-inflammatory drug reduces neuropathic and acute pain. Similarly, inflammatory arthritis is reduced by a GC administered with an anti-inflammatory cytokine (i.e., immune system signaling molecule) in mice. Given the anti-inflammatory properties of MAGL inhibition, it is plausible that MAGL inhibition will increase the analgesic and anti-inflammatory effects of a steroid treatment, perhaps reducing the negative side effects of the steroid. Therefore, the goals of the present studies were to determine the analgesic and anti-inflammatory efficacy of (1) the MAGL inhibitor JZL184; (2) the glucocorticoid steroid dexamethasone (DEX); and (3) the combined administration of both JZL184 and DEX. To these ends, we used the collagen-induced arthritis (CIA) mouse model. We found that, although both JZL184 and DEX significantly attenuated proinflammatory cytokine levels in the paws of CIA mice, only DEX decreased pain-related behaviors and paw swelling. Combined administration of a sub-effective dose both drugs was ineffective overall.
Nass, Sara R., "Inhibiting the Cannabinoid Catabolic Enzyme MAGL to Potentiate the Anti-Arthritic Properties of the Synthetic Glucocorticoid Dexamethasone" (2017). Graduate Theses, Dissertations, and Problem Reports. 6298.