SynopsisSkin-lightening products are commercially available for cosmetic purposes to obtain lighter skin complexion. Clinically, they are also used for treatment of hyperpigmentary disorders such as melasma, café au lait spot and solar lentigo. All of these target naturally melanin production, and many of the commonly used agents are known as competitive inhibitors of tyrosinase, one of the key enzymes in melanogenesis. In this review, we present an overview of commonly used skin-whitening ingredients that are commercialized, but we also hypothesize on other mechanisms that could be important targets to control skin pigmentation such as for example regulation of the adrenergic and glutaminergic signalling and also control of tetrahydrobiopterins in the human skin. Ré suméLes produits éclaircissants sont disponibles dans le commerce pour des buts cosmétiques afin d'obtenir un tient plus clair. Ils sont égale-ment utilisés en clinique, pour le traitement de troubles hyper pigmentaires comme le melasma, les taches café au lait et le lentigo solaire. Tous ces produits ont pour cible la production naturelle de mélanine et beaucoup de ceux généralement utilisés sont reconnus comme des inhibiteurs compétitifs de la tyrosinase, une des enzymes clés de la mélanogénèse. Dans cette revue, nous présentons une vue d'ensemble des ingrédients généralement utilisés et commercialisés comme blanchissant cutanés mais nous formulons aussi l'hypothèse que d'autres mécanismes pourraient être des cibles importantes pour contrôler la pigmentation de la peau comme par exemple la régula-tion du signal adrénergique et glutaminergique ou le contrôle des tetrahydrobiopterines dans la peau humaine.

Earlier it has been shown that human proliferating/undifferentiated basal keratinocytes hold the full capacity for autocrine catecholamine synthesis/degradation and express beta2-adrenoceptors (beta2-AR). In this report, we show that human melanocytes also express all of the mRNA and enzymes for autocrine synthesis of norepinephrine but fail to produce epinephrine. So far, it was established that human melanocytes express alpha1-AR which are induced by norepinephrine yielding the inosine triphosphate diacylglycerol signal. The presence of catecholamine synthesis and the beta2-AR signal escaped definition at that time. Using RT-PCR, immunofluorescence and radioligand binding with the beta2-AR antagonist (-)-[3H]CGP 12177, we show here that human melanocytes express functional beta2-AR (4230 receptors per cell) with a Bmax at 129.3 and a KD of 3.19 nM but lack beta1-AR expression. beta2-AR stimulation with epinephrine 10(-6) M and salbutamol 10(-6)-10(-5) M yielded a strong cyclic adenosine monophospate (cAMP) response in association with upregulated melanin production. Taken together these results indicate that the biosynthesis and release of epinephrine (10(-6) M) by surrounding keratinocytes can provide the cAMP response leading to melanogenesis in melanocytes via the beta2-AR signal. Moreover, the discovery of this catecholaminergic cAMP response in melanocytes adds a new source for this important second messenger in melanogenesis.

Human skin microbiota might play an important role in maintaining skin health and potentially prevent premature skin ageing. The use of probiotics in therapeutic skin applications is an attractive idea, as it could offer an alternative option for certain inflammatory skin disorders and dry or sensitive skin. Here, we investigated for the first time, a comparative study of live and the lysate products of probiotic strain Lactobacillus reuteri DSM 17938 in skin topical applications using ex vivo skin models focusing on anti‐inflammatory and skin barrier function and in vitro assays for antimicrobial activity. Our results in ultraviolet B radiation (UVB‐R)‐induced inflammation model demonstrated that both live bacteria and the lysate of L. reuteri DSM 17938 reduced proinflammatory IL‐6 and IL‐8, illustrated in both reconstructed human epidermis (RHE) and native skin models. Live L reuteri DSM 17938 significantly increased aquaporin 3 (AQP3) gene expression, while the lysate enhanced laminin A/B levels in a healthy (unstimulated) state of RHE, suggesting a positive impact on skin barrier. In addition, live L. reuteri DSM 17938 had antimicrobial action against pathogenic skin bacteria (Staphylococcus aureus, Streptococcus pyogenes M1, Cutibacterium acnes AS12, Pseudomonas aeruginosa), whereas the lysate did not have such an effect. Therefore, it is hypothesized that L. reuteri DSM 17938 could be beneficial for general skin health, to avoid the UVB‐R‐mediated inflammatory cascade and/or prevent photoageing, improve barrier function or in the management of unhealthy skin prone to inflammatory conditions due to its antimicrobial, anti‐inflammatory and skin barrier enhancing functions.

Glutamate is the major excitatory neurotransmitter in the central nervous system but has also important functions in the epidermis. It is involved in keratinocyte barrier function and in re-epithelialization processes after wounding. Recently, glutamate signalling has been suggested to be implicated in the development of melanoma. The present study examined the expression and functionality of metabotropic and ionotropic glutamate receptors on normal human melanocytes. We found that cultured melanocytes expressed the ionotropic glutamate receptors GluR2 and 4 [alpha-amino-3-hydroxy-5-methyl-4-isoxsazolepropionic acid (AMPA) receptors] and N-methyl-d-aspartate (NMDA) receptors 2A and 2C and possibly the metabotropic glutamate receptor 1. Melanocytes were also found to express specific glutamate transporters and decarboxylases, but appeared neither to produce nor to release l-glutamate. Stimulation with 10 or 100 microM AMPA or NMDA elevated intracellular calcium concentrations in melanocytes, and thus demonstrated the functionality of the glutamate receptors. Millimolar concentrations of l-glutamate did not induce melanocyte toxicity and had no stimulating effect on melanin production. However, blockage of AMPA and NMDA receptors with CFM-2, memantine or MK801 caused a rapid and reversible change in melanocyte morphology, which was associated with disorganisation of actin and tubulin microfilaments. After 24 h of treatment with the AMPA receptor inhibitor CFM-2, there was a sharp reduction in the expression of the crucial melanocyte differentiation and proliferation factor MiTF. The results of this study demonstrate a role for glutamate in melanocyte regulation that may have implications in melanocyte associated disorders.