Ferulic Acid

What is Ferulic acid?

Ferulic acid (FA) ([E]-3-[4-hydroxy-3-methoxy-phenyl] prop-2-enoic acid) is a phenolic antioxidant found in a lot of plants where it mainly functions as an antioxidant in their leaves. It also works as a germination inhibitor, bird repellent and increases the plant’s resistance to pests. It occurs mainly in the bran of corn, rice, wheat, barley, oat and a bunch of other fruits and vegetables (Sri Balasubashini et al., 2003). It exists mainly as a monomer covalently conjugated with saccharides, glycoproteins, polyamines, lignin, and hydroxy fatty acids (Bourne & Rice-Evans, 1998).

Most of the FA produced in plants is in the trans- form, but some cis- and iso- forms also exist. FA can also exist as a lipid moiety in the form of Steryl Ferulates. A good example of this is the group of compounds called Oryzanol, composed of a variety of FA esters: alpha-, beta-, and (the most potent/common) gamma-oryzanol. Gamma-oryzanol, like FA, has synergistic antioxidant ability when combined with tocopherol. It is also capable of inhibiting lipid peroxidation and formation of dienes during peroxidation of linoleic acid by UV radiation. (Graf, 1992)

This plant molecule results from the metabolism of phenylalanine and tyrosine (Srinivasan et al., 2007). It contains a phenolic nucleus and an extended side chain conjugation that enables it to form a resonance stabilized radical able to terminate radical side chain reactions. Because of this ability, FA is widely used in the food and cosmetics industry for antioxidant, anti-inflammatory, antibacterial, and metal chelation properties (Ou & Kwok, 2004).

What is it used for?

• UV protection: FA has been shown to have significant protective effects when applied to human dermal fibroblasts before 30 minutes of UVB exposure. It was determined that FA helps reduce and revert DNA damage and restored mitochondrial membrane potential (Ambothi & Nagarajan, 2014).
• Anti-inflammatory: FA is shown to inhibit neutrophil accumulation and prevent UV-induced cytokine release.
• Atopic dermatitis: Atopic dermatitis (AD) is an inflammatory skin disorder that is influenced by several genetic and environmental factors. One study conducted on mice found that the topical application of FA on mice with AD-like lesions helped reduce the overall symptoms associated with AD. It also decreased several inflammatory biomarkers in the blood (Zhou et al., 2020)
• Anti-aging: Due to FA’s antioxidant properties, it is able to support intracellular antioxidant defense systems. As a result, it exhibits protective functions for skin structures including keratinocytes, fibroblasts, collagen and elastin (Zduńska et al., 2018).
• Blemishes: FA also has the ability to inhibit tyrosinase (a key enzyme in the melanogenesis process). Due to this ability, it has been used in anti-blemish products (Zduńska et al., 2018).
• Skin-brightening: The inhibition of tyrosinase, and the photoprotective role of FA play an important part in its skin-lightening ability. Specifically, it absorbs UV radiation between 290 and 320 nm (Staniforth et al., 2012). FA can also be combined with other skin-brightening ingredients to increase the lightening effect.

How much do you need?

The recommended concentration of FA in skincare products is from 0.5% to 1% (Zduńska et al., 2018). It is preferred to have ferulic acid in a mixture with other antioxidants rather than in a single formulation. 

Which ingredients to avoid with FA?

Some ingredients that can impact the stability of FA include glyceryl stearate, Rapithix A-60, and Optiphen (Bezerra et al., 2017).

Which ingredients or methods to combine with FA?

Does it have any side effects?

The typical concentrations of FA in cosmeceutical products usually range from 0.5% to 1% which is safe. However, FA is also used as a chemical peel, typically at a concentration of 12%. One study compared the efficacy and safety of FA (at 12%), glycolic acid (at 20%) and lactic acid (at 15%) and measured the incidence of two side effects including erythema and itching. Side effects were highest with glycolic acid, followed by lactic acid and least side-effects were reported with ferulic acid (Dayal et al., 2020).

Biochemical Mechanism

How does it perform as an antioxidant?

Ferulic acid’s main antioxidant potential is due to its free-radical scavenging ability. Its structure is composed of three motifs that are responsible for this scavenging action. It is composed of a phenolic nucleus, a methoxy group and an extensive conjugated side chain.

When a free radical comes in contact with FA, it readily takes a hydrogen atom leaving FA to form a phenoxy radical. However, unlike other radicals and pro-oxidants, FA forms a stable ferulate radical as it is able to delocalize the energy through resonance stabilization as seen below. The unpaired electron may be present not only on the oxygen but also across the entire molecule even up to the conjugated side chain. This resonance stabilization allows the ferulate radical to be stable and not attack your skin cells. In addition to that, the presence of a methoxy side-group, the antioxidant potential of FA is increased due to additional resonance stabilization and formation of O-quinone. (Graf, 1992)

What’s interesting is that Ferulic acid is a member of a group of antioxidants called hydroxycinnamic acids. If you refer to Figure 2 above, you’ll see that ferulic acid is derived from the hydroxylation of cinnamic acid. The addition of a hydroxyl group to the structure of cinnamic acid increases its antioxidant potential. In fact the more hydroxyl radical added to cinnamic acid, the higher its antioxidant potential as shown in this following figure (Gupta 1979).

How does it work as an anti-inflammatory?

Ferulic acid has shown to have some anti-inflammatory properties. Although not as potent as dexamethasone in one comparison, it is still able to reduce inflammation as evidenced by a decrease in cytokine formation in LPS or TNF-induced cells. Cytokines are inflammatory messengers that propagate the inflammatory signal to other cells. FA was shown to reduce the amount of MIP-2 (a type of cytokine) which plays a role in neutrophil accumulation. What this means is that FA helps reduce inflammation by decreasing the number of neutrophils flooding the site of injury.

Does it Penetrate?

Several properties play a role in whether an ingredient is able to successfully penetrate the skin. One key characteristic that helps with absorption is lipophilicity. Lipophilic compounds have an easier time passing through the skin because skin cells are also lipophilic in nature. This similarity plays an important role in the skin permeation process (Franz, 1975). Being a lipophilic molecule, FA has been shown to penetrate the stratum corneum at pH values of 3 and 7.2 (Saija et al., 2000), indicating that pH does not play a significant factor in the penetration of FA. However, another study determined that the permeation of FA in gel formulations is affected by pH with deeper permeation with a pH of 7.4 compared to 6 (Monti et al., 2011).

References

1. Ambothi, K., & Nagarajan, R. P. (2014). Ferulic acid prevents ultraviolet-B radiation induced oxidative DNA damage in human dermal fibroblasts. International Journal of Nutrition, Pharmacology, Neurological Diseases, 4(4), 203. https://doi.org/10.4103/2231-0738.139400
2. Bezerra, G. S. N., Pereira, M. A. V., Ostrosky, E. A., Barbosa, E. G., de Moura, M. de F. V., Ferrari, M., Aragão, C. F. S., & Gomes, A. P. B. (2017). Compatibility study between ferulic acid and excipients used in cosmetic formulations by TG/DTG, DSC and FTIR. Journal of Thermal Analysis and Calorimetry, 127(2), 1683–1691. https://doi.org/10.1007/s10973-016-5654-9
3. Bourne, L. C., & Rice-Evans, C. (1998). Bioavailability of Ferulic Acid. Biochemical and Biophysical Research Communications, 253(2), 222–227. https://doi.org/10.1006/bbrc.1998.9681
4. Dayal, S., Sangal, B., & Sahu, P. (2020). Ferulic acid 12% peel: An innovative peel for constitutional type of periorbital melanosis—Comparing clinical efficacy and safety with 20% glycolic peel and 15% lactic peel. Journal of Cosmetic Dermatology, 19(9), 2342–2348. https://doi.org/10.1111/jocd.13292
5. Franz, T. J. (1975). Percutaneous Absorption. On the Relevance of in Vitro Data. Journal of Investigative Dermatology, 64(3), 190–195. https://doi.org/10.1111/1523-1747.ep12533356
6. Graf, E. (1992). Antioxidant potential of ferulic acid. Free Radical Biology And Medicine, 13(4), 435-448. doi: 10.1016/0891-5849(92)90184-i
7. Gupta, S.; Sukhija, P. S.; Bhatia, I. S. Role of phenolics and phospholipids as antioxidants for Ghee. Milchwissenschaft 34:205-206; 1979.
8. Guo, T., Sun, Y., Sui, Y., & Li, F. (2003). Determination of ferulic acid and adenosine in Angelicae Radix by micellar electrokinetic chromatography. Analytical and Bioanalytical Chemistry, 375(6), 840–843. https://doi.org/10.1007/s00216-003-1794-4
9. Kamila, M. Z.-P., & Helena, R. (2020). The effectiveness of ferulic acid and microneedling in reducing signs of photoaging: A split-face comparative study. Dermatologic Therapy, 33(6), e14000. https://doi.org/10.1111/dth.14000
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11. Milani, M., Hashtroody, B., Piacentini, M., & Celleno, L. (2019). Skin protective effects of an antipollution, antioxidant serum containing Deschampsia antartica extract, ferulic acid and vitamin C: A controlled single-blind, prospective trial in women living in urbanized, high air pollution area. Clinical, Cosmetic and Investigational Dermatology, 12, 393–399. https://doi.org/10.2147/CCID.S204905
12. Monti, D., Tampucci, S., Chetoni, P., Burgalassi, S., Saino, V., Centini, M., Staltari, L., & Anselmi, C. (2011). Permeation and Distribution of Ferulic Acid and Its α-Cyclodextrin Complex from Different Formulations in Hairless Rat Skin. AAPS PharmSciTech, 12(2), 514–520. https://doi.org/10.1208/s12249-011-9609-y
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14. Oresajo, C.; Stephens, T.; Hino, P.D.; Law, R.M.; Yatskayer, M.; Foltis, P.; Pillai, S.; Pinnell, S.R. Protective effects of a topical antioxidant mixture containing vitamin C, ferulic acid, and phloretin against ultraviolet-induced photodamage in human skin. J. Cosmet. Dermatol, v.7, n.4, p.290-297, 2008.
15. Ou, S., & Kwok, K.-C. (2004). Ferulic acid: Pharmaceutical functions, preparation and applications in foods. Journal of the Science of Food and Agriculture, 84(11), 1261–1269. https://doi.org/10.1002/jsfa.1873
16. Saija, A., Tomaino, A., Trombetta, D., De Pasquale, A., Uccella, N., Barbuzzi, T., Paolino, D., & Bonina, F. (2000). In vitro and in vivo evaluation of caffeic and ferulic acids as topical photoprotective agents. International Journal of Pharmaceutics, 199(1), 39–47. https://doi.org/10.1016/s0378-5173(00)00358-6
17. Sri Balasubashini, M., Rukkumani, R., & Menon, V. P. (2003). Protective effects of ferulic acid on hyperlipidemic diabetic rats. Acta Diabetologica, 40(3), 118–122. https://doi.org/10.1007/s00592-003-0099-6
18. Srinivasan, M., Sudheer, A. R., & Menon, V. P. (2007). Ferulic Acid: Therapeutic Potential Through Its Antioxidant Property. Journal of Clinical Biochemistry and Nutrition, 40(2), 92–100. https://doi.org/10.3164/jcbn.40.92
19. Staniforth, V., Huang, W.-C., Aravindaram, K., & Yang, N.-S. (2012). Ferulic acid, a phenolic phytochemical, inhibits UVB-induced matrix metalloproteinases in mouse skin via posttranslational mechanisms. The Journal of Nutritional Biochemistry, 23(5), 443–451. https://doi.org/10.1016/j.jnutbio.2011.01.009
20. Trombino, S., Serini, S., Di Nicuolo, F., Celleno, L., Andò, S., Picci, N., Calviello, G., & Palozza, P. (2004). Antioxidant Effect of Ferulic Acid in Isolated Membranes and Intact Cells: Synergistic Interactions with α-Tocopherol, β-Carotene, and Ascorbic Acid. Journal of Agricultural and Food Chemistry, 52(8), 2411–2420. https://doi.org/10.1021/jf0303924
21. Wang, Q.-J., Gao, X., Gong, H., Lin, X.-R., Saint-Leger, D., & Senee, J. (2011). Chemical stability and degradation mechanisms of ferulic acid (F.A) within various cosmetic formulations. Journal of Cosmetic Science, 62(5), 483–503.
22. Zduńska, K., Dana, A., Kolodziejczak, A., & Rotsztejn, H. (2018). Antioxidant Properties of Ferulic Acid and Its Possible Application. Skin Pharmacology and Physiology, 31(6), 332–336. https://doi.org/10.1159/000491755
23. Zhou, Z., Shi, T., Hou, J., & Li, M. (2020). Ferulic acid alleviates atopic dermatitis-like symptoms in mice via its potent anti-inflammatory effect. Immunopharmacology and Immunotoxicology, 42(2), 156–164. https://doi.org/10.1080/08923973.2020.1733012