Ellagic Acid

Berries and pomegranates are a plentiful source of ellagic acid, a powerful antioxidant that may also help lighten the skin, improve its elasticity and prevent wrinkles from forming.

Effects


Grade Level of Evidence
A Multiple double-blind, controlled clinical trials.
B 1 double-blind, controlled clinical trial.
C At least 1 controlled or comparative clinical trial.
D Uncontrolled, observational, animal or in-vitro studies only.
Grade Effect Size of Effect Comments

D

Antioxidant

Strong

Protects the skin against oxidative stress and damage by inhibiting the production of reactive oxygen species.

D

Skin lightening

Moderate

Suppresses melanin formation in vitro and in animals, but is not particularly effective in protecting the skin from UV-induced pigmentation when taken orally by humans.

D

Increased skin elasticity

Moderate

Stimulates the production of new tropoelastin and its effective assembly into new elastic fibers in skin fibroblasts.

D

Wrinkle treatment

Moderate

Diminishes wrinkle formation following UV irradiation of mice skin, presumably by blocking the production of collagen-degrading enzymes, as well as by facilitating the assembly of elastic fibers.

D

Photoprotection

Mild

Increases the viability of skin cells and inhibits the degradation of collagen observed following UV-B irradiation.

D

Healing

Mild

Increased the tensile strength of an incision wound and accelerated the contraction of an excision wound and a burn wound in rats.

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Scientific Research


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Table of contents:

1. Sources

Ellagic acid is a natural polyphenol produced by plants from the hydrolysis of tannins.[1] It is found in a wide variety of fruits and nuts,[2] including pomegranates,[2][3] strawberries,[4][5] muscadine grapes,[6][7], cranberries,[8], blueberries,[5], blackberries,[5][9] raspberries,[10][11], pecans,[12] walnuts,[13] and honey.[14][15][16] Among fruits consumed in Brazil, jabuticaba, grumixama and cambuci have the highest total contents of ellagic acid.[17]

It has also been found in oak leaves,[18] chestnut tree leaves[19] and bark[20] and in Phellinus linteus,[21] a type of mushroom used in traditional medicine in Asia.[22]

Ellagic acid can also be produced the action of fungi such as Aspergillus oryzae[23][24][25] and Aspergillus niger[26] or microbial enzymes[27][28] on ellagitannins from acorn fringe,[23][24][27] acorn cups[25] or pomegranate residue.[26]

2. Bioavailability

On its own, ellagic acid has poor solubility and low permeability, making formulation design difficult. Fortunately, Span 60 and Tween 60 niosomes appear to be good carriers to the dermal delivery of ellagic acid. While ellagic acid in solution cannot penetrate to the viable epidermis and dermis, ellagic acid from ellagic acid-loaded niosomes is capable of penetrating the skin up to a depth of 120µm, where the dermis resides.[29]

3. Effects on the skin

3.1 Lightening effect

Ellagic acid lightens the skin by inhibiting tyrosinase, an enzyme involved in the synthesis of melanin. Based on the results of in vitro experiments, it is thought to react specifically with the copper located at the active site of the enzyme.[30]

When applied to the skin of brownish guinea pigs exposed to UV light at the same time for 2 weeks, ellagic acid suppressed skin pigmentation, with applied sites showing features similar to that of non-irradiated skin.[30] Guinea pigs fed with pomegranate extract containing 90% ellagic acid also showed an inhibition of UV-induced skin pigmentation, indicating that ellagic acid may be an effective whitening agent when taken orally as well.[31] There was an attempt to replicate this result in humans in a double-blind, placebo-controlled trial. 39 women were irradiated on the upper right arm before starting their intake of 200 mg/day, 100 mg/day or 0 mg/day of ellagic acid over a 4-week period. There were no statistically significant differences in the rates of change of values for luminance, melanin or erythema between-groups however, suggesting that oral administration of ellagic acid in humans is less effective in protecting the skin against UV-induced pigmentation and sunburn.[32]

In 2013, 2 studies on topical products containing ellagic acid were published. The first contained 0.5% ellagic acid + 0.1% salicyclic acid, and its efficacy was compared with that of a generic product containing 4% hydroquinone. 54 subjects used either formulation twice daily for 12 weeks, and the product with ellagic acid was found to provide comparable skin depigmentation benefit as 4% hydroquinone.[33] The second study evaluated SkinCeuticals Advanced Pigment Corrector, a product containing hydroxyphenoxy propionic acid, ellagic acid, yeast extract and salicyclic acid in its formulation, versus 4% hydroquinone cream + 0.025% tretinoin. 82 men and women were randomly assigned to use the SkinCeuticals product twice daily or the generic creams nightly. The products demonstrated parity with respect to skin tone evenness, spot intensity and size, hyperpigmentation, smoothness, clarity, imperfections, radiance, firmness and overall appearance.[1] However, the 2 study products both contained active ingredients that have proven skin whitening effects (salicyclic acid and hydroxyphenoxy propionic acid), so these results cannot be solely attributed to the action of ellagic acid alone. Moreover, both studies appear to be sponsored by L'Oreal, a cosmetics company and owner of the SkinCeuticals brand.

Apart from its brightening effect on the skin, ellagic acid may also be able to improve skin elasticity and protect against wrinkle formation.

Fully differentiated adult dermal fibroblasts lose the ability to synthesize elastin, and therefore cannot replace damaged elastic fibers. This is problematic as elastic fibers are entirely responsible for skin elasticity, and it explains why aged skin is less elastic. Histological analysis of wrinkled skin also show the disappearance and altered organization of elastic fibers due to premature degradation and impaired remodeling.[34] Ellagic acid is known to decrease the expression of prometalloproteinase (MMP)-2 and pro-MMP-9, the precursors of 2 elastolytic enzymes.[35] Pretreatment of dermal fibroblasts with ellagic acid also led to an increase in elastic fiber content, apparently by enhancing elastogenesis and protecting against the proteolytic degradation of tropoelastin and elastin, thereby facilitating their assembly into elastic fibers.[34]

Further, an experiment on mice showed that topical application of ellagic acid attenuated the formation of wrinkles and the epidermal thickening of skin exposed to long-term UVB irradiation. It dose-dependently reversed the augmented collagen destruction brought about by UV radiation by blocking the secretion of matrix metalloproteinases in dermal fibroblasts. It also enhanced the viability of UV-irradiated keratinocytes.[36]

3.3 Antioxidant effect

Ellagic acid is a potent antioxidant. In an assay of antioxidant activity, it inhibited 71.2% lipid peroxidation of a linoleic acid emulsion, superior to butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), α-tocopherol (vitamin E) and ascorbic acid (vitamin C), which displayed 69.8%, 66.8%, 64.5% and 59.7% inhibition respectively at the same concentration.[37] It is also a good scavenger of free radicals and reactive oxygen species (ROS) such as superoxide anion and hydrogen peroxide.[38][37]

At physiological pH, the ellagic acid anion is proposed as the key species responsible for its protective effects against oxidative stress. It is predicted to be continuously regenerated after scavenging two free radicals per cycle, which may explain its unusually high antioxidant activity even at low concentrations. The anionic species of ellagic acid is also capable of chelating copper, enabling it to reduce the production of free radicals.[39]

The results of an in vitro study suggest that ellagic acid may protect the skin against oxidative stress and skin damage. Pretreatment of human keratinocytes with ellagic acid markedly increased their viability, suppressed the generation of ROS and malondialdehyde, prevented DNA damage and inhibited apoptosis induced by UVA radiation.[40]

3.4 Anti-inflammatory effect

Topical application of ellagic acid holds promise for use in the treatment of inflammatory skin disorders.[41] In one study, topical treatment with ellagic acid significantly inhibited the production of the pro-inflammatory cytokines IL-1β and IL-6 in the skin tissues of hairless mice, retarded the migration of inflammatory macrophages in UVB-inflamed mouse skin, and dose-dependently inhibited the UVB-elevated expression of ICAM-1, the surface adhesion molecule which plays an important role in the generation of the epidermal inflammatory infiltrate.[36]

Topical application of both a standardized pomegranate rind extract or ellagic acid also reduced ear edema, the inflammatory response elicited by phenol or croton oil, in mice and inhibited MPO activity, a quantitative index of neutrophil infiltration, to an extent that was similar to that of the synthetic corticosteriod triamcinolone and more significant than that of the NSAID diclofenac.[41][42] Both also suppressed carrageenan-induced rat paw edema and joint swelling in CFA-induced polyarthritis, tests frequently used to evaluate agents for acute and chronic inflammation, as well as decreased inflammatory pain, as measured by the mechanical hyperalgesia and formalin tests.[42][43]

3.5 Wound healing

In an investigation of 3 rat dermal wound models, both 0.325% and 0.65% ellagic acid increased the tensile strength of the incision wound by more than 30%, but only 0.65% ellagic acid accelerated the contraction of the excision wound and the burn wound.[44]

4. Side Effects

There are no published studies on the safety of topically applied ellagic acid that we are aware of. Ellagic acid as a food additive has been tested in a toxicity study on rats however, which showed no observed effects in male rats at a dose of 3011 mg/kg of body weight per day and no observed adverse effects in female rats at a dose of 3254 mg/kg of body weight per day.[45]

Scientific References


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