Mechanism of Action of Resveratrol in Skin Barrier Repair

The ability of any topical cosmeceutical to permeate the skin barrier is essential to its ability to reach actively metabolic cells and affect their processes. With UV radiation and exposure to exogenous stressors, the antioxidants present in skin can be significantly depleted, leaving the skin vulnerable to oxidative damage. It is therefore imperative that cosmeceuticals be able to penetrate the skin barrier to effectively deliver their antioxidant benefits. An effective topical antioxidant should be able to permeate the stratum corneum and reach the deeper layers of skin including the remainder of the epidermis and dermis. There should not be significant systemic absorption of the antioxidant component.

UVR radiation has been implicated in the development of about 90% of non-melanoma skin cancers, as well as melanoma and precancerous actinic keratoses.Chronic DNA damage, either directly through UV-induced cell death pathways, or indirectly through formation of damaging ROS, leads to the development of non-melanoma skin cancers. UVB radiation also leads to other adverse effects such as erythema, edema, inflammation, hyperplasia, hyperpigmentation, immunosuppression, and, over time, skin aging.26–29 Avoidance of unnecessary sun exposure and use of sunblock is the mainstay in photoprotective measures. More recently, chemoprevention with resveratrol and other antioxidants30 has shown promise in helping to prevent UV-induced skin cancers.

The photoprotective function of resveratrol may be secondary to its anti-apoptotic effects. Bastianetto et al.33 investigated the specific resveratrol binding sites within human epidermis. Human HaCaT cells were incubated with sodium nitroprusside (SNP), a nitric oxide (NO) free radical donor, which resulted in cell death. Resveratrol (1–30 μM) significantly reduced SNP-induced toxicity beginning at a concentration of 10 μM. Utilizing autoradiography, a significant amount of specific [3H]-resveratrol binding sites within the HaCaT cell epidermis as compared to the dermis, with a majority of sites found within the granular layer. Additionally, resveratrol inhibited mitochondrial apoptotic events triggered by SNP (via inhibition of caspase-3) and reduced the number of apoptotic cells.

Resveratrol is able to ameliorate the damages caused by short-term UVB exposure to skin through several mechanisms. In a mouse study by Afaq et  al.,34 a single topical application of resveratrol (25 μM/0.2 mL acetone) to SKH-1 hairless mice was found to significantly inhibit UVB (180 mJ/cm2 )- mediated increase in skin thickness and skin edema. Topical application of resveratrol also significantly inhibited UVB-mediation induction of the tumor-promoting enzymes cyclooxygenase and ornithine decarboxylase. Additionally, topical resveratrol inhibited UVB-mediated lipid peroxidation and generation of hydrogen peroxide (H2O2), markers of oxidative stress.

In a similar study by Aziz et al.,31 the use of topical resveratrol was shown to upregulate specific proteins that can assist in chemoprevention of UVB-induced skin cancers. SKH-1 hairless mice were irradiated with 180 mJ/cm2 twice weekly for 28 weeks. The mice received either pretreatment (30 minutes before UVB exposure) or post-treatment (five minutes after UVB exposure) topical resveratrol at either 25 or 50 μM/0.2 mL acetone. Topical resveratrol was found to significantly inhibit and delay the onset of tumor development when applied before or after UVB exposure. This suggested that resveratrol did not work via a sunscreen mechanism. Survivin, a critical regulator of survival and death in cells (upregulation is associated with several cancers), was found to be significantly elevated with UVB exposure, as well as its mRNA. Treatment with resveratrol to the mice downregulated both Survivin protein and its mRNA. This suggested that resveratrol enhanced chemoprotective effects against UVB-induced skin carcinogenesis and may be mediated through mechanisms such as downregulation of Survivin.

Resveratrol is also able to block nuclear factor kappa B (NF-kappaB), which is known to play a significant role in the development of skin cancer. In a study by Adhami et al.,30 normal human epidermal keratinocytes (NHEK) were pre-treated with various concentrations of resveratrol (0–25 μM) for 24 h and then exposed to UVB radiation (40 mJ/cm2 ). Pre-incubation with resveratrol blocked UVB-mediated activation of NF-kappaB in a dose-dependent and time-dependent (5 μM resveratrol for and 48 hours) manner. Additionally, treatment of NHEK with resveratrol inhibited UVB-mediated (1) phosphorylation and degradation of IϰBα, and (2) activation of IKKα, both of which play a critical role in photocarcinogenesis. All of these mechanisms support the use of resveratrol against the adverse effects of UV-induced photocarcinogenesis.

Photoaging and Hyperpigmentation

Photoaging is caused in part by cumulative sun exposure, which produces excess ROS and resultant oxidative damage to the skin. Oxidative processes such as end-glycation can cross-link sugars and proteins. These proteins aggregate between collagen bundles in the aging dermis, causing the characteristic sallow appearance of photoaged skin.15–17,35 Additionally, loss of bone structure and subcutaneous fat, or the “foundation,” further contributes to an aged appearance.

The breakdown of collagen is another causative factor in aging skin. ROS can also upregulate photoaging transcription factors such as activator protein 1 (AP-1) and NF-kappaB, as discussed earlier. AP-1 is an essential transcription factor in the production of metalloproteinases (MMPs), which are enzymes that break down collagen. The loss of collagen and accumulation of end-glycation products cause the skin to become thin and wrinkled. Several in vitro studies have shown that resveratrol can downregulate both AP-1 and NF-kappaB, which would in turn help to prevent the premature breakdown of collagen associated with aging skin.

Additionally, post-menopausal women lose around 1% of their collagen every year.38 This is thought to be secondary to the loss of estrogen, as replacement therapy helps to prevent collagen loss. The chemical structure of resveratrol is similar to diethylstilbestrol, a synthetic estrogen. Gehm et al. showed that resveratrol at concentrations comparable to those required for biological effects of estrogen (approximately 3–10 μM), resveratrol was able to inhibit the binding of labeled estradiol to estrogen receptors. 

Resveratrol also activated the transcription of estrogen-responsive reporter genes. Therefore, resveratrol can function as a phytoestrogen and estrogen beta-receptor agonist. Further studies should be performed to investigate the use of resveratrol as a topical anti-aging cosmeceutical with similar collagen-boosting effects of estrogen, which can decrease the associated risk factors of oral estrogen use.

Facial hyperpigmentation can also contribute to an aged appearance and can be distressing. There are several types of irregular hyperpigmentation. Post-inflammatory hyperpigmentation can result after an inflammatory dermatosis or irritation, in which increased melanin production or transfer of melanin to keratinocytes is induced by skin injury. Melasma presents as symmetric hyperpigmented patches and is common among females of young- to middle-aged and Fitzpatrick skin types IV–VI. Causative factors include increased amounts of melanin in response to sun exposure, oral contraceptives, and pregnancy. Studies have shown that stilbenes such as resveratrol are potent tyrosinase inhibitors. Newton et al. investigated the mechanisms by which resveratrol could prevent hyperpigmentation. Cultured human melanocytes were treated with resveratrol 20 μg/mL for 24 h, which significantly decreased in situ tyrosinase activity without adversely affecting cell viability or numbers. This decrease in tyrosinase activity was time-dependent, requiring 18–24 h of exposure for a maximum of 80% tyrosinase inhibition. Additionally, resveratrol caused a significant reduction of tyrosinase protein levels that correlated with the decrease in tyrosinase activity.

Scarring

Wound healing is a complex process. Scar formation is a response to local tissue injury; inflammation, cell migration and proliferation, and synthesis of the extracellular matrix (ECM) components such as collagen are the processes by which scars are formed. Hypertrophic and keloid scars are an abnormal form of wound healing characterized by excessive fibroblast proliferation and collagen production after injury. Keloids extend upwards and beyond the original site of the scar onto normal adjacent skin, while hypertrophic scars are within the margins of the original site of injury. Hypertrophic scars present as erythematous, itchy, raised lesions on the site of the skin injury. These can cause a negative psychosocial impact in affected patients. First- and second-line treatments include intralesional corticosteroids, excision, skin grafting, and pressure therapy, among others.

Wound Healing

Wound healing is a dynamic, complex, restorative process in response to skin injury. There are three phases involved in wound healing: inflammation, proliferation, and maturation and remodeling. The immediate inflammatory phase is characterized by activation of the local innate immune system, which leads to an influx of neutrophils and macrophages. This phase is significant for the release of cytokines and growth factors, such as IL-1, IL-6, vascular endothelial growth factor (VEGF), TNF, and TGF-β. VEGF is a mediator for the development of endothelial cells and helps to regulate angiogenesis. Both VEGF and nitric oxide (NO) stimulate wound healing by causing inflammation, angiogenesis, endothelial and epithelial cell proliferation, extracellular matrix formation, and remodeling.

Acne

As mentioned earlier, resveratrol is a natural phytoalexin exhibiting natural antimicrobial and antiinflammatory properties. Acne vulgaris is one of the most common skin disorders seen by dermatologists, affecting patients from infancy into adulthood. There are many different causes of acne, most commonly beginning with hormonal changes in puberty, which leads to stimulation of sebaceous glands within an obstructed pilosebaceous unit; this creates a favorable environment for bacteria to play a pathogenic role in inflammatory acne. The causative bacterium, Propionibacterium acnes, induces inflammation in the comedo by inducing the release of neutrophils and pro-inflammatory cytokines, which causes the characteristic inflamed lesions of acne. First-line treatments for acne include oral and topical antibiotics, which are often combined with comedolytic treatments such as topical retinoids and salicylic acid.

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