FGIN-1-27 Inhibits Melanogenesis by Regulating Protein Kinase A/cAMP-Responsive Element-Binding, Protein Kinase C-β, and Mitogen-Activated Protein Kinase Pathways.

Jinpeng Lv,Ximei Zhang,Ying Yang,Songzhou Jiang,Rongyin Gao,Guoqiang Song,Yan Cao

doi:10.3389/fphar.2020.602889

Abstract

FGIN-1-27 is a synthetic mitochondrial diazepam binding inhibitor receptor (MDR) agonist that has demonstrated pro-apoptotic, anti-anxiety, and steroidogenic activity in various studies. Here we report, for the first time, the anti-melanogenic efficacy of FGIN-1-27 in vitro and in vivo. FGIN-1-27 significantly inhibited basal and α-melanocyte-stimulating hormone (α-MSH)-, 1-Oleoyl-2-acetyl-sn-glycerol (OAG)- and Endothelin-1 (ET-1)-induced melanogenesis without cellular toxicity. Mushroom tyrosinase activity assay showed that FGIN-1-27 did not directly inhibit tyrosinase activity, which suggested that FGIN-1-27 was not a direct inhibitor of tyrosinase. Although it was not capable of modulating the catalytic activity of mushroom tyrosinase in vitro, FGIN-1-27 downregulated the expression levels of key proteins that function in melanogenesis. FGIN-1-27 played these functions mainly by suppressing the PKA/CREB, PKC-β, and MAPK pathways. Once inactivated, it decreased the expression of MITF, tyrosinase, TRP-1, TRP-2, and inhibited the tyrosinase activity, finally inhibiting melanogenesis. During in vivo experiments, FGIN-1-27 inhibited the body pigmentation of zebrafish and reduced UVB-induced hyperpigmentation in guinea pig skin, but not a reduction of numbers of melanocytes. Our findings indicated that FGIN-1-27 exhibited no cytotoxicity and inhibited melanogenesis in both in vitro and in vivo models. It may prove quite useful as a safer skin-whitening agent.

Highlights

Melanogenesis is the most important function of melanocytes in the skin
Tyrosinase, tyrosinase-related protein 1 (TRP1), and TRP-2 are the key enzymes in melanogenesis, while α-melanocyte-stimulating hormone (α-MSH) and ET-1 promote pigmentation by increasing the expression of these three crucial melanogenic enzymes (Rzepka et al, 2016; Corre et al, 2004; Regazzetti et al, 2015)
Our results suggested that FGIN-1-27 suppressed α-MSH or ET-1-induced tyrosinase, TRP-1, and TRP-2 expression increase (Figures 2A,B)

Summary

Introduction

Melanogenesis is the most important function of melanocytes in the skin. Several critical factors involving in melanogenesis have been clarified (Raposo and Marks, 2007; Noguchi et al, 2014). The key enzyme that regulates melanogenesis is tyrosinase and it acts with tyrosinase-related protein 1 (TRP1) and tyrosinaserelated protein 2 (TRP2) to promote melanin synthesis (Zhu et al, 2015) Another important factor involved in pigmentation is microphthalmia-associated transcription factor (MITF), which regulates the proliferation and survival of melanocytes and regulates tyrosinase, TRP1 and TRP2 expression (Kawasaki et al, 2008; Levy and Fisher, 2011). Environmental stimuli, such as ultraviolet (UV) irradiation, play a crucial role in melanogenesis (Abdel-Naser et al, 2003). Endothelin-1 (ET1) induces melanogenesis in melanocytes via the activation of mitogen-activated protein kinase (MAPK) pathway (Park et al, 2015; Regazzetti et al, 2015)

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Conclusion