New approaches in melasma treatment and In Vitro evaluation of possible toxic effects

Melasma is a chronic, acquired disease that results in the accumulation of brown or gray-brown melanin pigment in the epidermis layer and/or dermis layer, especially in areas where the body is more exposed to sunlight, such as the face, due to the increase in the number and activity of melanocytes that produce the melanin pigment. Although many factors play a role in the etiology of melasma, such as genetic predisposition, exposure to UV rays, oral contraceptives, pregnancy, thyroid dysfunctions, cosmetics, drugs that cause photosensitivity, the exact cause is unknown. Melasma treatment is difficult and complex due to its multifactorial etiology. Topical treatment options may provide temporary relief, but the disease often recurs. Among the different treatment options, studies have shown that the combination of corticosteroid, retinoid derivatives and hydroquinone is the most effective treatment option in the treatment of hyperpigmentation. Since it is known that hydroquinone, which is frequently preferred in treatment, can have serious side effects, research have been carried out in recent years for the use of drugs with low toxicity and high efficiency in the treatment of melasma. Studies have shown that metformin and ascorbic acid, which are used in the treatment of different diseases, can also be used in different areas with "drug repositioning". It is thought that metformin may inhibit the expression of genes involved in melanin synthesis via cyclic AMP (cAMP) pathway, thus reducing the amount of melanin in melanocytes. It is known that ascorbic acid inhibits tyrosinase activity by interacting with the copper ion in the structure of the tyrosinase enzyme. Within the scope of this thesis, the effects of ascorbic acid, metformin and ascorbic acid on melanin formation, cAMP formation, L-3,4-dihydroxyphenylalanine (L-DOPA) levels, tyrosinase gene expression and levels, cytotoxicity and oxidative stress on MNT-1 human melanoma cell line. effects were evaluated. It was determined that ascorbic acid applied at non-cytotoxic concentrations did not significantly change the measured parameters. Metformin, on the other hand, was found to significantly increase intracellular ROS levels and tyrosinase levels. With the combined application, intracellular ROS levels and tyrosinase levels increased significantly. Considering especially tyrosinase levels and gene expression, combined application may not be beneficial in the treatment of melasma; it can be said that individual applications of ascorbic acid or metformin may provide limited benefit. However, extensive in vivo studies are needed on this topic.