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Molecular & Cellular Toxicology

, Volume 15, Issue 1, pp 75–83 | Cite as

Ethanolic extract of Melia azedarach L. induces melanogenesis through the cAMP-PKA-CREB signaling pathway

  • Mi-Ok Kim
  • Se Jung Park
  • See-Hyoung Park
  • Sae Woong Oh
  • Seung Eun Lee
  • Ju Ah Yoo
  • Kitae Kwon
  • Jangsoon Kim
  • Min Hee Kim
  • Jae Youl ChoEmail author
  • Jongsung LeeEmail author
Original Paper
  • 18 Downloads

Abstract

Backgrounds

Since the cause of hypopigmentary skin disorders (hair graying and vitiligo) is typically unknown, there is no known cure for these disorders. Melia azedarach L. is used in Southeast Asia across China and Japan as a traditional medicine, and it has been reported to have various pharmacological properties. However, there have been no reports to demonstrate the involvement of M. azedarach L. in pigmentation. This study was conducted to investigate the effect of ethanolic extract of M. azedarach L. (MAE) on melanogenesis and to elucidate its mechanism of action in B16F10 mouse melanoma cells and human epidermal melanocytes.

Methods

Effects of MAE on melanogenesis and its mechanism of action were investigated using several assays, including melanin content, cellular tyrosinase activity, real-time PCR analysis, Western blot analysis, and ELISAs for cyclic AMP (cAMP), protein kinase A (PKA), cAMP response element binding (CREB) protein, and mitogen-activated protein kinases (MAPKs).

Results

MAE increased the melanin content levels and cellular tyrosinase activity in B16F10 mouse melanoma cells and human epidermal melanocytes. In addition, the action mechanism of MAE-induced melanogenesis was examined in human epidermal melanocytes. It also upregulated the expressions of microphthalmia-associated transcription factor (MITF) gene and its downstream target genes, tyrosinase and tyrosinase-related protein (TRP) 1, but not TRP 2. MAE treatment increased the cAMP levels, PKA activity, and phosphorylation of CREB protein, its downstream signaling protein. However, MAE showed no effects on MAPKs (p42/44 MAPK, p38 MAPK, and c-Jun-N-terminal kinase (JNK)).

Conclusion

These findings indicate that MAE induces melanogenesis by upregulating the MITF gene through the cAMP-PKA-CREB signaling pathway, and they suggest its potential in the treatment of hypopigmentary skin diseases.

Keywords

Ethanolic extract of Melia azedarach L. (MAE) Melanin cAMP PKA CREB 

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References

  1. 1.
    Valacchi, G. et al. Cutaneous responses to environmental stressors. Ann N Y Acad Sci 1271, 75–81 (2012).CrossRefGoogle Scholar
  2. 2.
    d’Ischia, M. et al. Melanins and melanogenesis: from pigment cells to human health and technological applications. Pigment Cell Melanoma Res 28, 520–544 (2015).CrossRefGoogle Scholar
  3. 3.
    Brenner, M. & Hearing, V. J. The protective role of melanin against UV damage in human skin. Photochem Photobiol 84, 539–549 (2008).CrossRefGoogle Scholar
  4. 4.
    Oode, C., Shimada, W., Yokota, M., Yamada, Y. & Nihei, K. I. Dihydroresveratrol cellobioside and xylobioside as effective melanogenesis activators. Carbohydr Res 436, 45–49 (2016).CrossRefGoogle Scholar
  5. 5.
    Dessinioti, C., Stratigos, A. J., Rigopoulos, D. & Katsambas, A. D. A review of genetic disorders of hypopigmentation: lessons learned from the biology of melanocytes. Exp Dermatol 18, 741–749 (2009).CrossRefGoogle Scholar
  6. 6.
    McDonough, P. H. & Schwartz, R. A. Premature hair graying. Cutis 89, 161–165 (2012).Google Scholar
  7. 7.
    Eby, J. M. et al. Immune responses in a mouse model of vitiligo with spontaneous epidermal de-and repigmentation. Pigment Cell Melanoma Res 27, 1075–1085 (2014).CrossRefGoogle Scholar
  8. 8.
    Videria, I. F. S., Moura, D. F. L. & Magina, S. Mechanisms regulating melanogenesis. An Bras Dermatol 88, 76–83 (2013).CrossRefGoogle Scholar
  9. 9.
    Gu, W. J. et al. Additive effect of heat on the UVB-induced tyrosinase activation and melanogenesis via ERK/p38/MITF pathway in human epidermal melanocytes. Arch Dermatol Res 306, 583–590 (2014).CrossRefGoogle Scholar
  10. 10.
    Jian, D. et al. Diethylstilbestrol enhances melanogenesis via cAMP-PKA-mediating up-regulation of tyrosinase and MITF in mouse B16 melanoma cells. Steroids 76, 1297–1304 (2011).CrossRefGoogle Scholar
  11. 11.
    Lin, M. et al. Ginsenosides Rb1 and Rg1 stimulate melanogenesis in human epidermal melanocytes via PKA/CREB/MITF signaling. Evid Based Complement Alternat Med 2014, 892073 (2014).Google Scholar
  12. 12.
    Lee, J., Kim, Y. S. & Park, D. Rosmarinic acid induces melanogenesis through protein kinase A activation signaling. Biochem Pharmacol 74, 960–968 (2007).CrossRefGoogle Scholar
  13. 13.
    Namba, T. in The Encyclopedia of Wakan-Yaku (Traditional Sino-Japanese Medicines) with Color Pictures Vol. I. Revised edition (Hoikusya Co. Ltd., Osaka, 1994).Google Scholar
  14. 14.
    Okada, M. in Newly Revised Illustrated Medicinal Plants of World (Hokuryukan Publishing Co. Ltd., Tokyo, 2002).Google Scholar
  15. 15.
    Vishnukanta, A. C. Rana. Melia azedarach: A phytopharmacological review. Pharmacogn Rev 2, 173–179 (2008).Google Scholar
  16. 16.
    Khan, M. F. et al. Bioactivity-guided chemical analysis of Melia azedarach L. (Meliaceae), displaying antidiabetic activity. Fitoterapia 98, 98–103 (2014).Google Scholar
  17. 17.
    Akihisa, T. et al. Nitric oxide production-inhibitory activity of limonoids from Azadirachta indica and Melia azedarach. Chem Biodivers 14, e1600468 (2017).CrossRefGoogle Scholar
  18. 18.
    Lucena, A. P. S. et al. Antioxidant activity and phenolics content of selected Brazilian wines. J Food Compos Anal 23, 30–36 (2010).CrossRefGoogle Scholar
  19. 19.
    Huh, S. et al. Mechanisms of melanogenesis inhibition by propafenone. Arch Dermatol Res 302, 561–565 (2010).CrossRefGoogle Scholar
  20. 20.
    Fu, Y. T., Lee, C. W., Ko, H. H. & Yen, F. L. Extracts of Artocarpus communis decrease α-melanocyte stimulating hormone-induced melanogenesis through activation of ERK and JNK signaling Pathways. Scientific WorldJournal 2014, 724314 (2014).Google Scholar
  21. 21.
    Kim, H. J., Kim, J. S., Woo, J. T., Lee, I. S. & Cha, B. Y. Hyperpigmentation mechanism of methyl 3,5-di-caffeoylquinate through activation of p38 and MITF induction of tyrosinase. Acta Biochim Biophys Sin 47, 548–556 (2015).CrossRefGoogle Scholar
  22. 22.
    Huang, H. C., Chang, S. J., Wu, C. Y., Ke, H. J. & Chang, T. M. [6]-Shogaol inhibits α-MSH-induced melanogenesis through the acceleration of ERK and PI3K/Akt-mediated MITF degradation. Biomed Res Int 2014, 842569 (2014).Google Scholar
  23. 23.
    Minamitsuji, Y., Toyofuku, K., Sugiyama, S., Yamada, K. & Jimbow, K. Sulfur containing tyrosine analogs can cause selective melanocytotoxicity involving tyrosinasemediated apoptosis. J Investig Dermatol Symp Proc 4, 130–136 (1999).CrossRefGoogle Scholar
  24. 24.
    Rad, H. H. et al. Tyrosinase-related proteins suppress tyrosinase-mediated cell death of melanocytes and melanoma cells. Exp Cell Res 298, 317–328 (2004).CrossRefGoogle Scholar
  25. 25.
    Alerico, G. C., Beckenkamp, A., Vignoli-Silva, M., Buffon, A. & von Poser, G. L. Proliferative effect of plants used for wound healing in Rio Grande do Sul state, Brazil. J Ethnopharmacol 176, 305–310 (2015).CrossRefGoogle Scholar
  26. 26.
    Sheth, V. M., Gunasekera, N. S., Silwal, S. & Qureshi, A. A. Development and pilot testing of a vitiligo screening tool. Arch Dermatol Res 307, 31–38 (2015).CrossRefGoogle Scholar
  27. 27.
    Ezzedine, K. et al. Vitiligo is not a cosmetic disease. J Am Acad Dermatol 73, 883–885 (2015).CrossRefGoogle Scholar
  28. 28.
    Ezzedine, K. et al. Revised classification/nomenclature of vitiligo and related issues: The Vitiligo Global Issues Consensus Conference. Pigment Cell Melanoma Res 25, E1–E13 (2012).CrossRefGoogle Scholar
  29. 29.
    Namazi, M. R. Neurogenic dysregulation, oxidative stress, autoimmunity, and melanocytorrhagy in vitiligo: Can they be interconnected? Pigment Cell Melanoma Res 20, 360–363 (2007).CrossRefGoogle Scholar
  30. 30.
    Schallreuter, K. U. et al. Vitiligo pathogenesis: Autoimmune disease, genetic defect, excessive reactive oxygen species, calcium imbalance, or what else? Exp Dermatol 17, 139–140 (2008).CrossRefGoogle Scholar
  31. 31.
    Pan, X. 1. et al. Cytotoxic and nitric oxide productioninhibitory activities of limonoids and other compounds from the leaves and bark of Melia azedarach. Chem Biodivers 11, 1121–1139 (2014).CrossRefGoogle Scholar

Copyright information

© The Korean Society of Toxicogenomics and Toxicoproteomics and Springer Nature B.V. 2019

Authors and Affiliations

  • Mi-Ok Kim
    • 1
  • Se Jung Park
    • 1
  • See-Hyoung Park
    • 2
  • Sae Woong Oh
    • 1
  • Seung Eun Lee
    • 1
  • Ju Ah Yoo
    • 1
  • Kitae Kwon
    • 1
  • Jangsoon Kim
    • 1
  • Min Hee Kim
    • 3
  • Jae Youl Cho
    • 4
    Email author
  • Jongsung Lee
    • 1
    Email author
  1. 1.Molecular Dermatology Laboratory and Biocosmetics Research Center, Department of Integrative Biotechnology, College of Biotechnology and BioengineeringSungkyunkwan UniversitySuwon, Gyeonggi-doRepublic of Korea
  2. 2.Department of Bio and Chemical EngineeringHongik UniversitySejongRepublic of Korea
  3. 3.Department of Physical Therapy, College of Health ScienceEulji UniversitySeongnam, Gyeonggi-doRepublic of Korea
  4. 4.Molecular Immunology Laboratory, Department of Integrative Biotechnology, College of Biotechnology and BioengineeringSungkyunkwan UniversitySuwon, Gyeonggi-doRepublic of Korea

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