Research has begun to explore natural compounds that address the oxidative stress, autoimmunity, and altered melanogenesis that drive vitiligo pathogenesis.
The complex relationship between vitiligo and psychiatric disorders such as anxiety and depression demands further research into how natural compounds including antioxidants may help patients with these comorbid conditions, according to a review in Antioxidants.
It remains unclear whether vitiligo triggers mental-health challenges or vice versa, said authors led by Mario Vaccaro, MD, PhD, of the department of clinical and experimental medicine, dermatology, at the University of Messina in Messina, Italy. However, vitiligo and mental-health disorders can exacerbate each other. They also require prolonged therapy that often produces poor results and side effects such as skin atrophy (topical steroids), nausea and abdominal discomfort (oral Janus kinase/JAK inhibitors), and cardiac toxicity (monoamine oxidase inhibitors and tricyclic antidepressants).
In contrast, authors said, natural compounds may provide safe supplementary treatments that might improve patients’ compliance and quality of life while reducing the duration of pharmaceutical and light-based treatment.1 Key causes of vitiligo are believed to include genetic variants in the human leukocyte antigen (HLA) cluster, the gene that encodes tyrosinase (TYR), and the melanocyte proliferating gene 1 (MYG1). Micro-RNAs and cytokine imbalances also appear involved, as does depletion of antioxidant enzymes such as superoxide dismutase and glutathione peroxidase.
Psychiatric disorders shown to impact patients with vitiligo include anxiety, depression and, less commonly, obsessive-compulsive disorder, bipolar disorder, and schizophrenia.2 Although no specific correlation between vitiligo and psychiatric disorders has been found, authors said, common genetic and molecular backgrounds may explain their combined appearance.
Research has begun to explore natural compounds that address the oxidative stress, autoimmunity, and altered melanogenesis that drive vitiligo pathogenesis. Agents such as the following also may impact key causes of depression.
Glycyrrhizin and glycerrhetinic acid—Combined with UVB radiation in a small clinical trial, oral glycyrrhizin led to repigmentation in 87.5% of patients, with no new lesions appearing.3 Additionally, glycyrrhizin has demonstrated antidepressant effects related to its anti-inflammatory properties in clinical research, with greater symptomatic improvement in patients with higher baseline levels of inflammatory markers.4 Glycyrrhizin’s anti-inflammatory effects stem from its ability to inhibit the high-mobility group box-1 gene (HMGB1), which stimulates production of pro-inflammatory cytokines. Moreover, glycyrrhizin protects human melanocytes from oxidative stress by inducing the nuclear translocation of nuclear factor erythroid 2-like factor 2 (Nrf2),5 and glycyrrhizin may normalize serotonin fluctuations.
Epigallocatechin-3-gallate (EGCG)—Because EGCG does not appear to promote melanogenesis directly, its usefulness in vitiligo likely will stem from its antioxidant and anti-inflammatory properties.6 An EGCG-based ointment (Veregen, sinecatechins 15%; PharmaDerm), is licensed for treating external genital warts; a small clinical trial of topical EGCG 3% cream showed repigmentation on par with that of pimecrolimus treatment.7 Additionally, topical EGCG administration in mice with monobenzone-induced vitiligo reduced serum levels of TNF-α, interferon gamma (IFN-y), and interleukin (IL)-6, as well as perilesional CD8+ T cells.8 Consistent with these findings, EGCG has shown promise as a neuromodulator, reducing depression-related behaviors and enhancing serotonin levels in mice.9
Quercetin—This polyphenolic flavonoid offers anti-inflammatory, antioxidant, antineoplastic, and neuroprotective properties.10 Like other flavonoids, quercetin stimulates melanogenesis by activating microphthalmia-associated transcription factor (MITF), which governs expression of key melanogenic enzymes such as tyrosinase, dopachrome tautomerase (DTC, also known as tyrosine-related protein 2/TYRP2), and tyrosine-related protein 1 (TYRP1).11 When given parenterally to mice, quercetin regulated serotonergic and cholinergic neurotransmission, calming anxious and depressed symptoms and improving memory.12
Kaempferol— Although the mechanisms are poorly understood, kaempferol promotes melanogenesis, melanosome maturation, and melanin transport from perinuclear to dendritic tips in melanocytes (in vitro), possibly via phosphorylation of phosphatidylinositol 3‑kinase (p38)/phosphoribulokinase (PRK)/mitogen-activated protein kinase (MAPK) and downregulating PI3K/protein kinase B (Akt) signaling.13 Kaempferol has cancer-fighting and neuroprotective properties as well. Its antidepressant capability stems from antioxidant and anti-inflammatory effects derived by modulating pathways such as Akt and ß-catenin and reducing TNF-α and IL-1ß levels.14 In an animal model, kaempferol demonstrated anxiolytic activity comparable to that of diazepam.15
Baicalein—Possessing both anti-inflammatory and antioxidant properties, this flavonoid may upregulate Nrf2 signaling, protecting cells including melanocytes from oxidative stress.16 Additionally, baicalein may provide antidepressant effects by increasing extracellular signal-related kinase (ERK) phosphorylation and brain-derived neurotrophic factor (BDNF) levels.17
Curcumin—This antioxidant may activate the Nrf2 signaling pathway, regulating antioxidant and detoxification genes.18 Curcumin also inhibits several pro-inflammatory molecules such as IFN-y.19 Curcumin’s poor bioavailability has spurred development of new formulations, one of which suppressed melanogenesis in vitro by activating the ERK pathway.20 Evidence for curcumin’s use in vitiligo remains mixed, authors said, although it appears effective for depressive and anxious symptoms.
Cannabidiol (CBD)—CBD may minimize oxidative stress by preventing free-radical formation and activating Nrf2.21 However, authors said, evidence supporting use of CBD in vitiligo is lacking, and CBD’s impact on melanogenesis remains unclear. Animal and human studies have shown promising results in depression, anxiety, and schizophrenia.22
Dermatologists should address psychological issues that impact patients with vitiligo, authors said, and additional research into antioxidants can help dermatologists to do so.
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10. Shen P, Lin W, Deng X, et al. Potential implications of quercetin in autoimmune diseases. Front Immunol. 2021;12:689044. Published 2021 Jun 23. doi:10.3389/fimmu.2021.689044
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12. Samad N, Saleem A, Yasmin F, Shehzad MA. Quercetin protects against stress-induced anxiety- and depression-like behavior and improves memory in male mice. Physiol Res. 2018;67(5):795-808. doi:10.33549/physiolres.933776
13. Tang H, Yang L, Wu L, et al. Kaempferol, the melanogenic component of Sanguisorba officinalis, enhances dendricity and melanosome maturation/transport in melanocytes. J Pharmacol Sci. 2021;147(4):348-357. doi:10.1016/j.jphs.2021.08.009
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15. Ahmad H, Rauf K, Zada W, et al. Kaempferol facilitated extinction learning in contextual fear conditioned rats via inhibition of fatty-acid amide hydrolase. Molecules. 2020;25(20):4683. Published 2020 Oct 14. doi:10.3390/molecules25204683
16. Ma J, Li S, Zhu L, et al. Baicalein protects human vitiligo melanocytes from oxidative stress through activation of NF-E2-related factor2 (Nrf2) signaling pathway. Free Radic Biol Med. 2018;129:492-503. doi:10.1016/j.freeradbiomed.2018.10.421
17. Xiong Z, Jiang B, Wu PF, et al. Antidepressant effects of a plant-derived flavonoid baicalein involving extracellular signal-regulated kinases cascade. Biol Pharm Bull. 2011;34(2):253-259. doi:10.1248/bpb.34.253
18. Ashrafizadeh M, Ahmadi Z, Mohammadinejad R, Farkhondeh T, Samarghandian S. Curcumin activates the Nrf2 pathway and induces cellular protection against oxidative injury. Curr Mol Med. 2020;20(2):116-133. doi:10.2174/1566524019666191016150757
19. Skyvalidas DΝ, Mavropoulos A, Tsiogkas S, et al. Curcumin mediates attenuation of pro-inflammatory interferon γ and interleukin 17 cytokine responses in psoriatic disease, strengthening its role as a dietary immunosuppressant. Nutr Res. 2020;75:95-108. doi:10.1016/j.nutres.2020.01.005
20. Lv J, Yang Y, Jia B, Li S, Zhang X, Gao R. The inhibitory effect of curcumin derivative J147 on melanogenesis and melanosome transport by facilitating ERK-mediated MITF degradation. Front Pharmacol. 2021;12:783730. Published 2021 Nov 23. doi:10.3389/fphar.2021.783730
21. Atalay S, Jarocka-Karpowicz I, Skrzydlewska E. Antioxidative and anti-inflammatory properties of cannabidiol. Antioxidants (Basel). 2019;9(1):21. Published 2019 Dec 25. doi:10.3390/antiox9010021
22. García-Gutiérrez MS, Navarrete F, Gasparyan A, Austrich-Olivares A, Sala F, Manzanares J. Cannabidiol: A potential new alternative for the treatment of anxiety, depression, and psychotic disorders. Biomolecules. 2020;10(11):1575. Published 2020 Nov 19. doi:10.3390/biom10111575
Study authors reported no conflicts of interest. The study received no external funding.