Prolonged treatment of fair‐skinned mice with topical forskolin causes persistent tanning and UV protection

Abstract

We previously reported that topical application of forskolin to the skin of fair-skinned MC1R-defective mice with epidermal melanocytes resulted in accumulation of eumelanin in the epidermis and was highly protective against UV-mediated cutaneous injury. In this report, we describe the long-term effects of chronic topical forskolin treatment in this animal model. Forskolin-induced eumelanin production persisted through 3 months of daily applications, and forskolin-induced eumelanin remained protective against UV damage as assessed by minimal erythematous dose (MED). No obvious toxic changes were noted in the skin or overall health of animals exposed to prolonged forskolin therapy. Body weights were maintained throughout the course of topical forskolin application. Topical application of forskolin was associated with an increase in the number of melanocytes in the epidermis and thickening of the epidermis due, at least in part, to an accumulation of nucleated keratinocytes. Together, these data suggest in this animal model, short-term topical regular application of forskolin promotes eumelanin induction and that over time, topical forskolin treatment is associated with persistent melanization, epidermal cell accumulation, and skin thickening.

Pharmacologic Induction of Epidermal Melanin and Protection Against Sunburn in a Humanized Mouse Model

“…Skin darkening, which is due to eumelanin induction in the epidermis, lasts for as long as topical forskolin treatments are continued. Even chronic application (through three months) seemed well-tolerated by the mice 49 . The increase in skin darkening is due to melanin synthesis rather than proliferation of melanocytes in the epidermis.…”

“…The increase in skin darkening is due to melanin synthesis rather than proliferation of melanocytes in the epidermis. 49 . Once topical treatments are discontinued, the skin gradually fades back to its baseline fair complexion (over 2-3 weeks) as epidermal melanin is lost with normal keratinocyte renewal.…”

“…In contrast, genetically matched K14-Scf C57BL/6 animals that harbor a mutant inactive Mc1r have almost no eumelanin in the epidermis. Instead, these "extension" animals (Mc1r e/e ) have a fair skin complexion caused by deposition of pheomelanin pigment ( Figure 1A) and are much more UV-sensitive [48][49] .…”

International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases

“…The local use of FSK for treatment of glaucoma is being explored, too (Majeed et al, 2015). Moreover, the dermatological application of FSK to protect the skin against ultraviolet light and induce persistent tanning is under investigation (Spry et al, 2009;Scott et al, 2012;Sikora et al, 2015). Furthermore, FSK derivatives are explored as anticancer compounds (Ponnam et al, 2014).…”

Melanocyte Pygmentation – Friend or Foe on the Route to Melanoma

“…Topical application of forskolin to K14-stem cell factor transgenic mice with Mclr e/e background (producing mostly pheomelanin) resulted in a dramatic shift to eumelanogenesis (Spry et al, 2009). In normal and malignant melanocytes, interleukin (IL-1α, IL-1 , endothelin-1, adult T-cell leukemia-derived factor/thioredoxin (ADF/TRX), interferons (IFN-α, IFN-, IFN-), dibutyryl cAMP, and the hormones MSH and ACTH can stimulate expression of the MC-1 gene and of functional cell surface MSH receptors (Slominski et al, 2004).…”