Inhibition of melanogenesis by 3-(1′-methyltetrahydropyridinyl)-2,4-6-trihydroxy acetophenone via suppressing the activity of cAMP response element-binding protein (CREB) and nuclear exclusion of CREB-regulated transcription coactivator 1 (CRTC1)

• Published in: European journal of pharmacology 2023-08, Vol.952, p.175734-175734, Article 175734
• Main Authors: Naikoo, Shahid H., Rashid, Haroon, Kumar, Sanjay, Archoo, Sajida, Sheikh, Umar A., Lone, Nazir A., Singh, Parvinder P., Tasduq, Sheikh A.
• Format: Article
• Language: English
• Subjects: 3-(1′-methyltetrahydropyridinyl)-2,4-6-trihydroxy acetophenone; Anti-melanogenesis; Aurones; cAMP; CRTC1; UV-B; α-MSH
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2023.175734

Exposure to Ultraviolet radiation or α-melanocyte-stimulating hormone (α-MSH) stimulates the Cyclic Adenosine Monophosphate/Protein Kinase A signalling pathway, which leads to the synthesis and deposition of melanin granules in the epidermis. Skin pigmentation is the major physiological defence against inimical effects of sunlight. However, excessive melanin production and accumulation can cause various skin hyperpigmentation disorders. The present study involved the identification of 3-(1′-methyltetrahydropyridinyl)-2,4-6-trihydroxy acetophenone (IIIM-8) as an inhibitor of melanogenesis, IIIM-8 significantly inhibited pigment production both in vitro and in vivo without incurring any cytotoxicity in Human Adult Epidermal Melanocytes (HAEM). IIIM-8 repressed melanin synthesis and secretion both at basal levels and in α-MSH stimulated cultured HAEM cells by decreasing the levels of Cyclic Adenosine Monophosphate (cAMP) and inhibiting the phosphorylation of cAMP response element-binding (CREB) protein, coupled with restoring the phosphorylation of CREB-regulated transcription coactivator 1 (CRTC1) and its nuclear exclusion in HAEM cells. This impeding effect correlates with diminished expression of master melanogenic proteins including microphthalmia-associated transcription factor (MITF), Tyrosinase (TYR), Tyrosinase related protein 1 (TRP1), and Tyrosinase related protein 2 (TRP2). Additionally, topical application of IIIM-8 induced tail depigmentation in C57BL/6J mice. Furthermore, IIIM-8 efficiently mitigated the effect of ultraviolet-B radiation on melanin synthesis in the auricles of C57BL/6J mice. This study demonstrates that IIIM-8 is an active anti-melanogenic agent against ultraviolet radiation-induced melanogenesis and other hyperpigmentation disorders. [Display omitted] •Exposure to UV radiations and α-MSH leads to melanin pigment synthesis.•IIIM-8 inhibits α-MSH induced melanin synthesis in HAEM cells and alleviates UV-B induced melanogenesis in auricles of C57BL/6J mice.•Topical application of IIIM-8 induces tail depigmentation in C57BL/6J mice.•IIIM-8 inhibits melanin synthesis Via suppressing CREB activity and inhibiting the CRTC1 nuclear translocation.