ACTH: The forgotten therapy

• The melanocortin drug ACTH is an effective anti-inflammatory therapy.
• Glucocorticoid-related side effects limit its use as a first-choice drug.
• Melanocortin actions and receptors pharmacology are now better understood.
• Melanocortins exert glucocorticoid-independent pro-resolving actions.
• Improved and safer melanocortin drugs may be developed to treat inflammation.

Although anti-inflammatory drugs are among the most common class of marketed drugs, chronic inflammatory conditions such as rheumatoid arthritis, multiple sclerosis or inflammatory bowel disease still represent unmet needs. New first-in-class drugs might be discovered in the future but the repurpose and further development of old drugs also offers promise for these conditions. This is the case of the melanocortin adrenocorticotropin hormone, ACTH, used in patients since 1952 but regarded as the last therapeutic option when other medications, such as glucocorticoids, cannot be used. Better understanding on its physiological and pharmacological mechanisms of actions and new insights on melanocortin receptors biology have revived the interest on rescuing this old and effective drug. ACTH does not only induce cortisol production, as previously assumed, but it also exerts anti-inflammatory actions by targeting melanocortin receptors present on immune cells. The endogenous agonists for these receptors (ACTH, α-, β-, and γ-melanocyte stimulating hormones), are also produced locally by immune cells, indicating the existence of an endogenous anti-inflammatory tissue-protective circuit involving the melanocortin system. These findings suggested that new ACTH-like melanocortin drugs devoid of steroidogenic actions, and hence side effects, could be developed. This review summarizes the actions of ACTH and melanocortin drugs, their role as endogenous pro-resolving mediators, their current clinical use and provides an overview on how recent advances on GPCR functioning may lead to a novel class of drugs.