Dexamethasone: Therapeutic Applications, Targets and Translation

Dexamethasone is a synthetic corticosteroid that has historically been used to treat inflammation, such as from osteoarthritis, spinal cord injury and, more recently, COVID-19. The mechanism of action of dexamethasone is generally known to include attenuation of pro-inflammatory responses as well as upregulation of anti-inflammatory elements. A major issue with the use of dexamethasone is its delivery, as it is normally administered in large quantities via methods like bolus injection to attempt to maintain sufficient concentrations days or weeks after administration. In this review, we examine the mechanism of action of dexamethasone and its effects on three major cell types in the context of specific diseases: macrophages in the context of COVID, chondrocytes in the context of osteoarthritis, and astrocytes in the context of neuro-inflammatory disease. From this, we identify the key proinflammatory cytokines interleukin-1 (IL-1) and Tumor Necrosis Factor alpha (TNF-a) as universal effectors of inflammation that should be targeted alongside dexamethasone administration. Additionally, we review current extended release dosing mechanisms for dexamethasone to act over periods of weeks and months. We suggest that dual treatment of dexamethasone with IL-1 and/or TNF-a monoclonal antibodies will be an effective immediate treatment for inflammation, while the addition of fully developed dexamethasone extended release mechanisms will allow for effective long-term control of inflammatory disease.