Efficacy and tolerability of a double-conjugated retinoid cream vs 1.0% retinol cream or 0.025% tretinoin cream in subjects with mild to severe photoaging

Aging of skin is an intricate biological process consisting of two types. While intrinsic or chronological aging is an inevitable process, photoaging involves the premature aging of skin occurring due to cumulative exposure to ultraviolet radiation. Chronological and photoaging both have clinically differentiable manifestations. Various natural and synthetic retinoids have been explored for the treatment of aging and many of them have shown histological and clinical improvement, but most of the studies have been carried out in patients presenting with photoaged skin. Amongst the retinoids, tretinoin possibly is the most potent and certainly the most widely investigated retinoid for photoaging therapy. Although retinoids show promise in the treatment of skin aging, irritant reactions such as burning, scaling or dermatitis associated with retinoid therapy limit their acceptance by patients. This problem is more prominent with tretinoin and tazarotene whereas other retinoids mainly represented by retinaldehyde and retinol are considerably less irritating. In order to minimize these side effects, various novel drug delivery systems have been developed. In particular, nanoparticles have shown a good potential in improving the stability, tolerability and efficacy of retinoids like tretinoin and retinol. However, more elaborate clinical studies are required to confirm their advantage in the delivery of topical retinoids.

Daily topical application of 0.05% tretinoin in a cream base was compared with its vehicle with regard to moderation of photoaging changes of the face and forearms. In comparison with the control tissue, tretinoin-treated tissue examined by light and electron microscopy showed the following effects: replacement of the atrophic epidermis by hyperplasia, elimination of dysplasia and atypia, eradication of microscopic actinic keratoses, uniform dispersion of melanin granules, new collagen formation in the papillary dermis, new vessel formation (angiogenesis), and exfoliation of retained horn in the follicles. Physiologic studies demonstrated: increased blood flow and dermal clearance, increased transepidermal water loss, and greater permeability and reactivity. It was concluded that topical tretinoin is capable of at least partly reversing the structural damages of excessive sunlight exposure and may be useful in decelerating the photoaging process.

α-Hydroxyl acids (AHAs) from natural sources act as proton donors and topical compounds that penetrate skin and are well known in the cosmetic industry for their use in chemical peels and improvement of the skin. However, little is known about how AHAs cause exfoliation to expose fresh skin cells. Here we report that the transient receptor potential vanilloid 3 (TRPV3) channel in keratinocytes is potently activated by intracellular acidification induced by glycolic acid. Patch clamp recordings and cell death assay of both human keratinocyte HaCaT cells and TRPV3-expressing HEK-293 cells confirmed that intracellular acidification led to direct activation of TRPV3 and promoted cell death. Site-directed mutagenesis revealed that an N-terminal histidine residue, His-426, known to be involved in 2-aminoethyl diphenylborinate-mediated TRPV3 activation, is critical for sensing intracellular proton levels. Taken together, our findings suggest that intracellular protons can strongly activate TRPV3, and TRPV3-mediated proton sensing and cell death in keratinocytes may serve as a molecular basis for the cosmetic use of AHAs and their therapeutic potential in acidic pH-related skin disorders.