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).

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.

A Novel Molecule 3-(1'-Methyltetrahydropyridinyl)-2,4-6-Trihydroxy Acetophenone Alleviates Ultraviolet-B-Induced Photoaging in Human Dermal Fibroblasts and BALB/c Mice.

Ultraviolet radiation (UVR) is the major exogenous agent that disturbs tissue homeostasis and hastens the onset of age-related phenotypes (photoaging). Exposure to UV-B radiation promotes apoptosis in human skin cells via induction of Reactive Oxygen Species (ROS)-mediated Endoplasmic Reticulum (ER) stress by activating the PERK-eIF2α-CHOP pathway, which plays a major role in exacerbating skin photoaging. Alleviating the production of ROS and boosting the antioxidant capacity of cells is the foremost therapeutic strategy to avert the repercussions of ultraviolet radiation exposure. In this study, we investigated the role of 3-(1'-methyltetrahydropyridinyl)-2,4-6-trihydroxy acetophenone (IIIM-8) in thwarting the UV-B-induced photoaging. We observed that IIIM-8 ameliorates UV-B-induced oxidative stress, ER stress, Loss of Mitochondrial membrane potential, MAPK activation and Inflammation in irradiated skin cells. Ultraviolet radiation-related damage to fibroblasts within the dermis leads to collagen degradation-the hallmark of photoaging. IIIM-8 substantially restored the synthesis of collagen and prevented its degradation via the downregulation of matrix metalloproteinases. Topical application of IIIM-8 prevented BALB/c mice skin from UV-B-induced leukocyte infiltration, epidermal thickening and disruption of Extracellular matrix components. Implying that IIIM-8 has a strong photoprotective property and has potential to be developed as a topical therapeutic/cosmeceutical agent against UV-B-induced photoaging.