Inhibitors of Intracellular Signaling Pathways that Lead to Stimulated Epidermal Pigmentation: Perspective of Anti-Pigmenting Agents

Abstract

Few anti-pigmenting agents have been designed and developed according to their known hyperpigmentation mechanisms and corresponding intracellular signaling cascades. Most anti-pigmenting agents developed so far are mechanistically involved in the interruption of constitutional melanogenic mechanisms by which skin color is maintained at a normal and unstimulated level. Thus, owing to the difficulty of confining topical application to a specific hyperpigmented skin area, potent anti-pigmenting agents capable of attenuating the natural unstimulated pigmentation process have the risk of leading to hypopigmentation. Since intracellular signaling pathways within melanocytes do not function substantially in maintaining normal skin color and are activated only by environmental stimuli such as UV radiation, specifically down-regulating the activation of melanogenesis to the constitutive level would be an appropriate strategy to develop new potent anti-pigmenting agents with a low risk of hypopigmentation. In this article, we review the hyperpigmentation mechanisms and intracellular signaling pathways that lead to the stimulation of melanogenesis. We also discuss a screening and evaluation system to select candidates for new anti-melanogenic substances by focusing on inhibitors of endothelin-1 or stem cell factor-triggered intracellular signaling cascades. From this viewpoint, we show that extracts of the herbs Withania somnifera and Melia toosendan and the natural chemicals Withaferin A and Astaxanthin are new candidates for potent anti-pigmenting substances that avoid the risk of hypopigmentation.

Advanced glycation end products (AGEs) promote melanogenesis through receptor for AGEs

“…Since repeated UV exposure is a culprit of pigmentary changes and skin cancers3637, mechanisms of UV damage and protective strategies have already been extensively researched38. UV irradiation induces oxidative stress, boosts proinflammatory cytokines and generates harmful AGEs in skin1739.…”

Effects of Ganodermanondiol, a New Melanogenesis Inhibitor from the Medicinal Mushroom Ganoderma lucidum

“…Melanogenic activation by binding stem cell factor (SCF) and endothelin-1 (EDN1) to c-kit and endothelin receptor type B (EDNRB) receptor, respectively, have been well studied in melanocytes [41]. Binding END1 to EDNRB activates protein kinase C (PKC) by released diacylglycerol (DAG) from the cell membrane.…”

A Novel Stilbene-Like Compound That Reduces Melanin through Inhibiting Melanocyte Differentiation and Proliferation without Inhibiting Tyrosinase

“…MAPK signaling pathway has been shown to positively regulate pigment formation (Imokawa and Ishida [9]). We performed Western blotting to examine how A11 and MEK-I influence MAPK activity to regulate pigment formation.…”

“…Unfortunately, those and our results do not quite agree with the current molecular mechanism for melanogenesis. In the review article by Imokawa and Ishida [9], UV light and α-MSH (melanocyte stimulating hormone) induce melanin synthesis by activating MAPK and PKC pathways but haginin A and gallic acid both activate MAPK and Akt to reduce melanin (Kim et al [10]). In our study, we show that MEK-I reduces pigment and inhibits MAPK at the same time in zebrafish embryo.…”

“…Among the several positive compounds that were identified in the last few years, A11 and MEK-I were also able to cause significant reduction of black pigment in the zebrafish embryos. Since MEK-I is a known inhibitor of the MEK (mitogen-activated protein kinase kinase) which functions in the MAPK pathway to promote melanin synthesis (reviewed in Imokawa and Ishida [9]), it is not so surprising to see MEK-I causing pigment reduction. A11, however, has a very different chemical structure than MEK-I and belongs to the stilbene family which has a characteristic C6-C2-C6 structure, similar to that in resveratrol ( Figure 1).…”