Imperatorin Positively Regulates Melanogenesis through Signaling Pathways Involving PKA/CREB, ERK, AKT, and GSK3β/β-Catenin

Abstract

The present study investigated the melanogenic effects of imperatorin and isoimperatorin and the underlying mechanisms of imperatorin using a mouse melanoma B16F10 model. Interestingly, treatment with 25 μM of either imperatorin or isoimperatorin, despite their structural differences, did not produce differences in melanin content and intracellular tyrosinase activity. Imperatorin also activated the expression of melanogenic enzymes, such as tyrosinase (TYR) and tyrosinase-related proteins TYRP-1 and TYRP-2. Mechanistically, imperatorin increases melanin synthesis through the cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA)/cAMP-responsive element-binding protein (CREB)-dependent upregulation of microphthalmia-associated transcription factor (MITF), which is a key transcription factor in melanogenesis. Furthermore, imperatorin exerted melanogenic effects by downregulating extracellular signal-regulated kinase (ERK) and upregulating phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT)/glycogen synthesis kinase-3β (GSK-3β). Moreover, imperatorin increased the content of β-catenin in the cell cytoplasm and nucleus by reducing the content of phosphorylated β-catenin (p-β-catenin). Finally, we tested the potential of imperatorin in topical application through primary human skin irritation tests. These tests were performed on the normal skin (upper back) of 31 volunteers to determine whether 25 or 50 µM of imperatorin had irritation or sensitization potential. During these tests, imperatorin did not induce any adverse reactions. Taken together, these findings suggest that the regulation of melanogenesis by imperatorin can be mediated by signaling pathways involving PKA/CREB, ERK, AKT, and GSK3β/β-catenin and that imperatorin could prevent the pathogenesis of pigmentation diseases when used as a topical agent.

A 7-Hydroxy 4-Methylcoumarin Enhances Melanogenesis in B16-F10 Melanoma Cells

“…Natural coumarins and their derivatives have always provided an invaluable source for the discovery of novel melanogenic and/or tanning agents. Natural coumarins, such as imperatorin, 7,8-dimethoxycoumarin, and psoralen derivatives, as well as several coumarin-containing plant extracts, have been reported to activate the melanogenesis process in B16-F10 cell lines [ 8 , 9 , 10 , 11 ].…”

“…From the use of our screening strategy for multi-targeting agents, our laboratory re-ported attractive results that elucidate the functionalities of various psoralens and coumarins in terms of their anti-inflammatory and melanogenesis-stimulating effects [ 8 , 9 , 10 , 11 , 12 , 13 ]. In this study, we aimed to verify the efficacy of the 7-hydroxy coumarin derivatives and systematically applied this to skin-related diseases using four 7-hydroxy coumarin derivatives: 7-hydroxy 5,6-dimethoxycoumain (7H-5,6DM), 7-hydroxy 6,8-dimethoxycoumain (7H-6,8DM), 7-hydroxy 6-methoxycoumain (7H-6M), and 7-hydroxy 4-methlycoumarin (7H-4M) ( Figure 1 ).…”

“…In B16-F10 cells, Schisandrin B inhibited melanin production by decreasing the phosphorylation levels of ERK [ 36 ]. In contrast, two studies have proven that increased P-ERK levels suppress melanogenesis [ 8 , 9 ]. These conflicting results, due to the complexity of melanin synthesis regulation, are often explained in relation to the process of inducing the ubiquitin proteasome-dependent degradation of MITF.…”

“…Coumarin derivatives, which are natural products containing benzopyrone structures, have been widely found as secondary metabolites in plants. These natural coumarins have been shown to exhibit various bioactivities, and have as anti-inflammatory, antitumor, neuroprotective, melanogenic, and anti-melanogenic effects [ 6 , 7 , 8 , 9 ]. In view of this, the coumarin derivatives have been widely utilized in the cosmetics, agricultural, and medicine sectors.…”

New Mechanistic Insights of Melasma

“…Activation of GSK3β phosphorylates MITF, thereby enhancing transcriptional activation of tyrosinase-related genes and melanogenesis. 39,64 The activation of the PI3K/Akt signaling pathway connects intracellular cAMP to GSK3β activity.…”