2. Academic Validation
  3. 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)

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)

  • Eur J Pharmacol. 2023 Aug 5;952:175734. doi: 10.1016/j.ejphar.2023.175734.
Shahid H Naikoo 1,  Haroon Rashid 2,  Sanjay Kumar 3,  Sajida Archoo 1,  Umar A Sheikh 1,  Nazir A Lone 1,  Parvinder P Singh 4,  Sheikh A Tasduq 5
Affiliations

Affiliations

  • 1 Pharmacology Division, Council of Scientific and Industrial Research-Indian Institute of Integrative Medicine, Canal Road, Jammu, Jammu and Kashmir, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
  • 2 Sher-e-Kashmir Institute of Medical Sciences, Soura, Srinagar, 190011, Jammu and Kashmir, India.
  • 3 Natural Product and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu Tawi, Jammu and Kashmir, India.
  • 4 Natural Product and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu Tawi, Jammu and Kashmir, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
  • 5 Pharmacology Division, Council of Scientific and Industrial Research-Indian Institute of Integrative Medicine, Canal Road, Jammu, Jammu and Kashmir, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India. Electronic address: [email protected].
PMID: 37080332 DOI: 10.1016/j.ejphar.2023.175734
Abstract

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.

Keywords

3-(1′-methyltetrahydropyridinyl)-2,4-6-trihydroxy acetophenone; Anti-melanogenesis; Aurones; CRTC1; UV-B; cAMP; α-MSH.

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