Suppression of melanogenesis by a newly synthesized compound, MHY966 via the nitric oxide/protein kinase G signaling pathway in murine skin.

Abstract

BACKGROUND:

Ultraviolet B (UVB) radiation is the main physiological stimulus for skin pigmentation. Nitric oxide (NO) and the NO/PKG signaling pathway play an important role in UVB-induced melanogenesis, which is related to the induction of expression of tyrosinase. In an attempt to find a novel anti-melanogenic agent, we synthesized a new compound, 2-bromo-4-(5-chloro-benzo[d]thiazol-2-yl) phenol (MHY966).

OBJECTIVE:

The purpose of this study was to investigate the action of MHY966 on NO and the NO-mediated signaling pathway using in vitro and in vivo models of melanogenesis.

METHODS:

NO generation, melanin synthesis, and the expression of tyrosinase and PKG were measured in B16F10 melanoma cells to verify the anti-melanogenic effect of MHY966 in vitro. Next, melanin-possessing hairless mice were pre-treated with MHY966 and then irradiated with UVB repeatedly. Morphological, histological, and biochemical analyses including the expressions of PKG, tryosinase and nuclear MITF, and productions of nitric oxide, peroxynitrite and ROS were conducted.

RESULTS:

MHY966 effectively inhibited NO generation and subsequent melanin synthesis induced by sodium nitroprusside, an NO donor, and suppressed the expression of tyrosinase and PKG. Topical application of MHY966 dose-dependently attenuated UVB-induced pigmentation in a mouse model. This hypopigmentation effect induced by MHY966 treatment was mediated by the down-regulation of tyrosinase, PKG, and nuclear MITF, which was accompanied by decreased NO and NO-related oxidative stress.

CONCLUSION:

The novel compound, MHY966 had an inhibitory effect on NO generation and the NO-mediated signaling pathway leading to the down-regulation of tyrosinase. The significance of the present study is the finding of a promising anti-melanogenic agent targeting the NO/PKG signaling pathway.

• Authors: Yeon Ja Choi, Yohei Uehara, Ji Young Park, Ki Wung Chung, Young Mi Ha, Ji Min Kim, Yu Min Song, Pusoon Chun, June Whan Park, Hyung Ryong Moon, Hae Young Chung
• Journal: Journal of dermatological science (J Dermatol Sci) Vol. 68 Issue 3 Pg. 164-71 (Dec 2012) ISSN: 1873-569X [Electronic] Netherlands
• PMID: 23088959 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Benzothiazoles
• Enzyme Inhibitors
• Free Radical Scavengers
• MHY966
• Melanins
• Phenols
• Nitric Oxide
• Monophenol Monooxygenase
• Cyclic GMP-Dependent Protein Kinases

Topics

• Animals
• Benzothiazoles (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Cyclic GMP-Dependent Protein Kinases (metabolism)
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Free Radical Scavengers (chemical synthesis, chemistry, pharmacology)
• Male
• Melanins (biosynthesis)
• Melanocytes (drug effects, metabolism)
• Melanoma, Experimental (metabolism)
• Mice
• Mice, Hairless
• Monophenol Monooxygenase (antagonists & inhibitors)
• Nitric Oxide (metabolism)
• Oxidation-Reduction
• Phenols (chemical synthesis, chemistry, pharmacology)
• Signal Transduction (drug effects)
• Skin (drug effects, metabolism)
• Skin Pigmentation (drug effects, physiology, radiation effects)
• Ultraviolet Rays