Фармакологические свойства меланина

Sunscreening and radioprotective effects of melanin

Melanin from natural sources has reported to possess a broad spectrum of biological activities, which include protection against UV radiation, enzymatic lysis, damage by oxidants, resistance to drugs by pathogens, protection of insects against bacteria and antiviral protection 3-6. Additionally, melanin has been shown to chelate metal ions and to act as a physiological redox buffer 7, 8. The use of melanin in cosmetics and sunscreens has been adopted by many manufacturers in an attempt to mimic the natural role of these molecules in the skin. The protective effect of sunscreen is rated using the Sun Protection Factor (SPF) scale, and it is thought that a higher SPF value indicates a better protective capacity. In 2011, Huang et al. 9 demonstrated that the SPF value of gel formulations increased with the addition of melanin extracts from the berry of Cinnamomum burmannii and Osmanthus fragrans. Revskaya et al. (2012) 10 investigated the possibility of creating an efficient oral radioprotectant based on melanin using edible black mushrooms prior to administration of 9 Gy total-body irradiation in mice. The location of the mushroom-derived melanin in the body before irradiation was determined by in vivo fluorescent imaging. Ingestion of black mushrooms protected 80% of mice from the lethal dose, whereas control mice, or those given mushrooms lacking melanin, died from a gastrointestinal syndrome. Notably, mice that were given white mushrooms supplemented with melanin survived at the same rate as mice that were given black mushrooms. The authors concluded that melanin-containing mushrooms can provide significant protection against radiation and could be developed into oral radioprotectants. Similarly, Kunwar A et al. (2012) 11 studied the probable mechanism of the radioprotective action of extracellular melanin (isolated from the fungus Gliocephalotrichum) in mice after exposure to 7 Gy whole-body irradiation. They found that administration of melanin at an effective dose of 50 mg/kg of body-weight increased the survival of mice by 100%. Mice that received melanin displayed reversion of radiation-induced reduction in extracellular signal-regulated kinase phosphorylation in splenic tissue. The authors suggest that this mechanism is a key feature that mediates melanin's radioprotective effects. In some diseases, the excess free radicals that are created by UV radiation in the skin are suggested to be involved in UV-induced photocarcinogenesis. Valavanidis et al. 12 used electron spin resonance (ESR) to carry out in vivo studies of free radicals' mechanisms in UV-induced skin photocarcinogenesis.

Interaction of melanin with drugs and metals and its related pharmacological properties

In 1993, Larsson conducted extensive pharmacological and physiochemical studies on the interaction of melanin with metals and drugs 6. This work showed that various drugs and other chemicals, such as organic amines, metals and polycyclic aromatic hydrocarbons, readily bind to melanin and are retained in pigmented tissues for long periods. The physiological significance of this metallic-binding property of melanin is not clear, but one suggestion is that melanin protects pigmented cells and adjacent tissues by adsorbing potentially harmful substances, which are then slowly released in non-toxic concentrations. However, Larsson also mentioned that long-term chemical exposure may lead to build-up of high levels of noxious chemicals in melanin, which may ultimately cause cellular degeneration and secondary lesions in surrounding tissue 6. Melanins may thus act as scavengers of toxic material in foods and may contribute to the regulation of some metals (such as iron and copper) that are of importance in metabolic and physiological processes. More recently, Karlsson and Lindquist 13, 14 have reviewed the toxicological implications of melanin's and neuromelanin's binding of drugs and chemicals. Many studies suggest that specific retention of drugs and metals by melanin protects the cells initially but also serves as a depot that slowly releases accumulated compounds and may cause toxicity on overexposure. Compounds with high neuromelanin affinity have been implicated in the development of adverse drug reactions in the central nervous system (CNS) as well as in the aetiology of Parkinson's disease (PD).

In addition, melanin could also interact with orally administered drugs and be used as a vehicle for drug delivery. For example, Lei et al. (2008) 15 conducted an interesting study on the use of a melanin–iron complex to induce remission of iron-deficiency anaemia. Treatment with the melanin complex led to higher bioavailability of iron and fewer side effects than did treatment with standard drugs. The melanin–iron complex significantly reduced symptoms, suggesting that melanin–iron complexes might help improve haematopoietic function and could be exploited as a safe, efficient new iron tonic. Seniuk et al. (2011) 16 reported various favourable effects of melanin complexes on pure cultures of Helicobacter pylori, Candida albicans, Herpes vulgaris I and HIV-1, both in in vitro and in vivo animal models. The authors concluded that these melanin complexes could be used as a source of biopolymers for the creation of new agents with wide applications in infectious pathology.

Antioxidant effects of melanin

Melanins from various sources exhibit significant antioxidant activity 8, 17, 18. The role of melanin as a scavenging or quenching molecule on superoxide anions, and singlet oxygen species has been discussed by Tada M et al. (2010) 19 who used ESR and spectrophotometric methods to show that melanin potently interacts with reactive oxygen species that are generated in certain physiological reactions.

These antioxidant melanins include extracts from the berry of Cinnamomum burmannii and Osmanthus fragrans, which also have concentration-dependent metal-chelating activities. Hoogduijn et al. (2003) 20 observed that melanin protects melanocytes and keratinocytes from DNA damage caused by hydrogen peroxide, indicating that the pigment has an important antioxidant role in the skin.

Melanin extracted from tea leaves was found to inhibit the oxidation of low-density lipoproteins, which supports the idea of an inhibitory effect of melanin against peroxyl radicals 21. It has also been demonstrated that a reduced form of tea melanin behaves as a free radical chain-breaking antioxidant and competes with β-carotene as a substrate for chain-propagating peroxyl radicals. In addition, reduced tea melanins were found to be more effective as anticarcinogenic agents than non-reduced melanins.

The physicochemical characterization and antioxidant activity of melanin from a strain of Aspergillus bridgeri have been studied by Kumar et al. (2011) 22, who demonstrated that melanin exhibits significant free radical scavenging activity. This work suggests that melanin may have potential applications as a natural antioxidant in the cosmetic and pharmaceutical industries.

Simon et al. 23 have suggested that complex melanins, built of eumelanin and pheomelanin fractions, exhibit an antioxidant effect due to the action of eumelanins, while pheomelanins tend to cause a pro-oxidant effect. According to this, the antioxidant behaviour of melanin should be considered as due to a combination of two opposite effects. But as eumelanin is the predominant fraction in most of the biological organs, what is observed is mostly an antioxidant effect pertaining to eumelanin.

Enhancement and modulation of the immune system by melanin

A number of previous studies have shown that both plant- and synthetic melanin can modulate cytokine production and enhance several immune parameters 24-27.

Recently, it has been demonstrated that animal and fungus melanin (derived from rat and Aspergillus fumigatus, respectively) also modulates cytokine production 28, 29. Sava et al. (2001) 21 extracted melanin-like pigments (MLPs) from black tea and showed that oral administration of MLPs to mice significantly stimulated splenic lymphoid tissue. Later, Hung et al. demonstrated that melanin extracted from different tea species induced cytokine production, with green tea melanin being at least 100 times more active than black tea melanin 30. They have also reported that antibody-secreting cells produced significantly more antibodies in animals treated with tea melanin (32–34%) than did antigen controls. Similarly, Al-Mufarrej et al. (2006) 31 showed that, in albino rats, black seed melanin induced a high and long-lasting antibody response to sheep red blood cells by stimulating the immune system. The immunostimulatory effects of melanin preparations from 30 traditional medical herbs were studied and patented by Pasco et al. (2005) 32. The patent authors reported that the melanins with the highest levels of activity were found in Allium sativum, Tabebuia spp., Serenoa repens and Echinacea spp.

Pugh et al. (2005) 24 demonstrated that ingestion of these melanins by mice caused dendritic cells in Peyer's patches to secrete high levels of IgA and interleukin-1 (IL-1). In these studies, spleen cells from mice that were fed melanins exhibited increased production of interferon gamma (IFG-ɣ) as a result of a shift in the balance of T helper 1 and T helper 2 cells (Th1 and Th2, respectively) in favour of Th1. Avramidis et al. (1998) 33 found that grape melanin modulates the production of IL-1, IL-6 (interleukin-6) and tumour necrosis factor-α (TNF-α) and significantly inhibited adjuvant-induced disease in rats. They suggested a possible role for melanin in inhibiting lymphocyte Th1 (T4 or T8), which led to the suppression of adjuvant-induced disease development. Recently, the important role of Toll-like receptors (TLRs) and their corresponding ligands in modulating cytokine production has been reported 34. TLRs are transmembrane or cytoplasmic receptors that recognize conserved molecular patterns of bacteria, fungi and viruses. They are members of the IL-1 receptor superfamily and share significant homology in their cytoplasmic regions 35, 36.

The most well-defined exogenous ligands for TLRs are lipopolysaccharide (LPS) for TLR4 and TLR2 and peptidoglycans and lipoproteins for TLR2 37, 38. In addition to exogenous ligands, TLR4 and TLR2 can be stimulated by various endogenous ligands such as heat-shock proteins (HSPs) and fibronectin 39-41. Plant melanins represent a new class of polymers that are recognized by the TLR family. Melanin isolated from Echinacea and Nigella sativa seeds were shown to activate monocytes by binding TLR-2 and TLR-4, respectively 42. Ligand binding to TLRs induces dimerization and recruitment of various adaptor molecules, which induce the production of various cytokines and activate downstream signalling pathways such as the myeloid differentiation factor 88 (MyD88) pathways. These cascades primarily include the nuclear factor-kB (NF-kB), MAP-kinase and interferon regulatory factor-3 and interferon regulatory factor-7 (IRF-3 and IRF-7) signalling pathways. In addition, TLR4 activation can induce a MyD88-independent pathway, TRIF, and activate the IRF-3 pathway 43 (fig. 1).

TLR signalling pathways. Transmembrane TLRs (represented here by TLR4) recognize external ligands (exogenous and endogenous), whereas cytoplasmic TLRs (TLR3) recognize intracellular signals. When activated, the majority of TLRs induce activation of NFκ-B (early-phase activation) and cytokine production in a MyD88-dependent manner. However, TLR4, like TLR3, can also signal in a MyD88-independent manner and induce expression of type I interferon (IFN) and IFN-inducible proteins in addition to late-phase NFκ-B activation 43.