Send Orders for Reprints to [email protected] Current Pharmaceutical Design, 2019, 25, 1-21 1 REVIEW ARTICLE Depigmentation and Anti-aging Treatment by Natural Molecules Abdelnaser Zaid* and Rowa’ Al Ramahi Pharmacy Department, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine Abstract: Natural molecules are becoming more accepted choices as cosmetic agents, many products in the mar- ket today claim to include natural components. Plants include many substances that could be of a value in the whitening of the skin and working as anti-aging agents. A wide range of articles related to natural skin whitening and anti-aging agents have been reviewed. Many plant-derived and natural molecules have shown to affect mela- nin synthesis by different mechanisms, examples include Arbutin, Ramulus mori extract, Licorice extract, A R T I C L E H I S T O R Y Glabridin, Liquiritin, Kojic acid, Methyl gentisate, Aloesin, Azelaic acid, Vitamin C, Thioctic acid, Soya bean extracts, Niacinamide, α and β-hydroxy acids, Lactic acid, Chamomile extract, and Ellagic acid. Some of the Received: April 29, 2019 widely used natural anti-aging products as natural antioxidants, collagen, hyaluronic acid, and coenzyme Q can Accepted: June 20, 2019 counteract the effects of reactive oxygen species in skin cells and have anti-aging properties on the skin. It was concluded that many natural products including antioxidants can prevent UV-induced skin damage and have DOI: whitening and anti-aging effects. It is very important to develop and stabilize appropriate methods for the evalua- 10.2174/1381612825666190703153730 tion of the whitening and anti-aging capacity of natural products and their exact mechanism of action to ensure real efficacy based on evidence-based studies. The attention should be oriented on the formulations and the de- velopment of an appropriate vehicle to ensure suitable absorption of these natural products in addition to evaluat- ing the suitable concentration of these molecules required having the desired effects without causing harmful side effects. Keywords: Natural products, antioxidants, skin whitening, photoaging, anti-aging, formulation. 1. INTRODUCTION Melanin is produced from tyrosine and takes two forms: (i) eumelanin; gives a brown-black color and is the more common The achieved advancement in dermatological studies and the form and (ii) pheomelanin which produces a yellow or red color improvements in the quality of life consequently resulted in a (Fig. 1). This last one also has an important protective function marked increase in the use of cosmetic preparations especially from the ultra-violate (UV) radiations [2, 3]. among women. Indeed, consumers of cosmetics could be classified Melanin is synthesized by the melanocytes that are found in the into two categories; those who prefer the use of decorative cosmet- basal layer of the epidermis. These cells represent 13% of the cellu- ics such as makeup, while the second category prefers the use of lar population of the epidermis. Particularly in the part of the skin functional cosmetics (cosmeceuticals) such as whitening and anti- 2 exposed to the sun rays like hand and face (2000-2500/mm ), while aging products that inhibit skin pigmentations and prevent prema- 2 in the remaining part of the skin, they are near 1000-1500 mm [4]. ture wrinkles. Skin anti-aging strategies are highly demanded all Normally, black skin has the same number of melanocytes as blond, over the world. Some methods are even invasive and require surger- red and white skin, but the black skin melanocytes are greatly more ies or injections [1]. The dermatologic studies- taking in considera- active in the synthesis of melanin. Another difference is that the tion the market demand- were oriented toward an accurate compre- melanin granules are present in the corneal layer, while in the blond hension of the physiology and biochemistry of the complete pig- skin, they are found in the basal layer of the epidermis only [3]. The mentation process of the skin and skin aging, for a better under- number of melanocytes depends on the age. In fact, the number standing of the mechanism of action of the whitening and anti- decreases 10-20% every 10 years. The genetic factor influences the aging agents of the skin. Great efforts are done to reach safe and number and type of the produced melanosomes rather than the less invasive methods and products. number of melanocytes [5]. Also, certain hormones can influence Natural molecules are a major target in this field due to the idea these parameters [5]. The melanocytes stimulating hormone (MSH) among people that natural products are safe. Natural products in- produced by the adenohypophysis accelerates melanin synthesis. β- clude molecules either from plant sources or animal sources. FGF (fibroblast growth factor), HGF (Hepatocytes Growth Factor) The color of the skin depends on three factors: the keratin layer, activate tyrosine kinase receptors [5]. Also, estrogen and progester- which gives a yellow to white foundation color depending on the one increase melanin production, especially in women’s face, ab- thickness of the keratin layer; the superficial blood circulation, domen, genitals and the areola of the mammalian which remain which gives reddish to bluish color where its intensity depends on irreversibly hyperpigmented after first pregnancy [5, 6]. Also, ex- the number, dilation, and deepness of the blood vessels. But the posure to UV light determines the modification of skin color caus- most important factor in the determination of skin color is given by ing an immediate photo-oxidation of the melanin which is stored in the presence and ratio of several chromophores in the skin [2]. the melanosomes of the most superficial layer [6]. Oxyhaemoglobin (bright red), reduced hemoglobin (bluish red) and In fact, the prolonged exposure to the UV light causes also an bilirubin (yellow) are found in the blood capillaries of the dermis. activation of the synthesis process of melanin and acceleration of its transformation to keratinocytes [7]. Historically, during the past *Address correspondence to this author at Department of Pharmacy, Faculty centuries, many substances were involved in the cosmetic field to of Medicine and Health Sciences, An-Najah National University, P.O.Box produce bleaching effect to the human skin, such as the milk of 7, Nablus -, Palestine; Tel: 0097292345113; Fax: 0097292345982; goats used by Cleopatra and the milk of the donkeys used by Pop- E-mail: [email protected] 1381-6128/19 $58.00+.00 © 2019 Bentham Science Publishers 2 Current Pharmaceutical Design, 2019, Vol. 25, No. 00 Zaid and Al Ramahi O H O H N O NH OH R 2 N N R O H R S HO S R O H N N HO H R N S O R O N H B A H 2 N O H R R = COOH or H denotes where the polymer continue Fig. (1). Chemical structures of eumelanin (A) and pheumelanin (B). pea [8]. In these two cases, the whitening agent involved is the agents may interfere with one or more steps of this process. They lactic acid which is present in the milk. In the Mediterranean region may affect (a) the transcription and activity of tyrosinase including which is rich of citrus fruits, lemon juice which is rich of citric acid tyrosinase-related protein-1 (TRP-1), tyrosinase-related protein-2 and vitamin C has been used to eliminate the black spots without (TRP-2), and/or peroxidase enzymes; (b) the uptake and distribu- knowing that Vitamin C is responsible for this activity. Nowadays, tion of melanosomes in recipient keratinocytes and (c) degradation many typical whitening agents in the market target the melanocytes. of melanin and melanosome further to the pigmented keratinocytes. Regarding skin aging, it happens due to many factors such as 2.1. Old Generation Whitening Agents the biologic progression of cells with years, in addition to external factors as excessive exposure to UV radiation, tobacco smoking, 2.1.1. Mercury nutritional deficiencies, pollution and hormonal imbalances that Red mercuric oxide, mercuric chloride and ammoniated mer- lead to the degradation of skin cells [9]. One of the major factors cury have depigmentation activity. These salts were used for many that participate in skin aging is exposure to sunlight (UV radiations) years as bleaching agents due to their high capacity and low cost. which is called photoaging. Free radicals attach skin structures and These salts are still used as ancient skin–bleaching products in destroy collagen and elastic fibers. Free radicals and inflammation some countries [13]. The red mercury oxide and mercury chloride weaken repair mechanisms and result in collagen and elastic fiber were the first whitening agent to be employed, but the majority of breakdown. Aging of skin causes skin roughness, wrinkling, pig- the formulations included mercury chloride and ammoniated mer- mentation change, loss of elasticity, and decreased firmness [9, 10]. cury. Mercury chloride was formulated as a lotion, but it caused These changes are mainly apparent in the face because aging is exfoliative effect to the skin. The ammoniated mercury is a white accelerated in areas subjected more to the sun. Reactive Oxygen powder, insoluble in water and alcohol. It has good chemical stabil- Species (ROS) type free radicals are related not only to skin aging ity and it inhibits tyrosinase enzyme possibly by the replacement of but also to skin cancer. So, any natural molecule with antioxidant the copper ion which is required for the tyrosinase activity or by effect may have a possible role in fighting skin aging and cancer, combining with the protein structure of the tyrosinase enzyme, thousands of products have been tested for their antioxidant effects. causing inhibition of melanin synthesis. Mercury is absorbed According to the “mitochondrial theory of aging” being the main transcutaneously.