Cell Stress and Chaperones

, Volume 17, Issue 2, pp 267–274 | Cite as

Prevention and treatment of alopecia areata with quercetin in the C3H/HeJ mouse model

  • Tongyu Cao Wikramanayake
  • Alexandra C. Villasante
  • Lucia M. Mauro
  • Carmen I. Perez
  • Lawrence A. Schachner
  • Joaquin J. JimenezEmail author
Original Paper


Alopecia areata (AA) is an autoimmune non-scarring hair loss disorder. AA can be acute, recurrent, or chronic. Current therapeutic options for AA are limited, and there is no effective prevention for recurrent AA. We have previously shown a correlation between the expression of HSP70 (HSPA1A/B), a heat shock protein involved in the inflammatory response, and the onset of AA in the C3H/HeJ mouse model. In this study, we tested the effects of quercetin, a bioflavonoid with anti-inflammatory properties, on AA development and HSP70 expression in the C3H/HeJ model. Mice with spontaneous AA were treated with subcutaneous quercetin or sham injections. Hair regrowth was observed in lesional areas in all the quercetin-treated mice, but in none of the sham-treated mice. In addition, non-alopecic C3H/HeJ mice were heat-treated to induce alopecia, along with quercetin or sham injections. Whereas 24% of the heat-treated mice with sham injections developed alopecia, none of the mice receiving quercetin injections did. As expected, the level of HSP70 expression in quercetin-treated areas was comparable to control. Furthermore, we showed that systemic delivery of quercetin by intraperitoneal injections prevented/reduced spontaneous onset of AA. Our results demonstrated that quercetin provided effective treatment for AA as well as prevention of onset of AA in the C3H/HeJ model, and warrant further clinical studies to determine whether quercetin may provide both treatment for preexisting AA and prevention of recurrent AA. The ready availability of quercetin as a dietary supplement may lead to increased patient compliance and positive outcomes for AA.


Alopecia areata C3H/HeJ HSP70 Heat shock Quercetin 



Alopecia areata


Antigen-presenting cell


Alopecia totalis


Alopecia universalis


Hair follicle


Heat shock protein


Heat shock protein 70

IL-1, IL-2, IL-6, IL-10

Interleukins 1, 2, 6, 10




Insulin-like growth factor 1


Immune privilege


Melanocyte-stimulating hormone


Major histocompatibility complex


Natural killer


Nuclear factor kappa B


Psoralen and ultraviolet A


Transforming growth factor beta 1


Tumor necrosis factor alpha


T helper 1


T helper 2



We gratefully acknowledge the Locks of Love Foundation (J.J.J.) for their support in this investigation. T.C.W. is supported by a Career Development Award from NIH/NIAMS (AR-050487).

Conflict of interest

The authors state no conflict of interest.


  1. Alkhalifah A, Alsantali A, Wang E, McElwee KJ, Shapiro J (2010a) Alopecia areata update: part I. Clinical picture, histopathology, and pathogenesis. J Am Acad Dermatol 62:177–188PubMedCrossRefGoogle Scholar
  2. Alkhalifah A, Alsantali A, Wang E, McElwee KJ, Shapiro J (2010b) Alopecia areata update: part II. Treatment. J Am Acad Dermatol 62:191–202PubMedCrossRefGoogle Scholar
  3. Al-Mutairi N (2007) 308-nm excimer laser for the treatment of alopecia areata. Dermatol Surg 33:1483–1487PubMedGoogle Scholar
  4. Al-Mutairi N (2009) 308-nm excimer laser for the treatment of alopecia areata in children. Pediatr Dermatol 26:547–550PubMedCrossRefGoogle Scholar
  5. Arck PC, Gilhar A, Bienenstock J, Paus R (2008) The alchemy of immune privilege explored from a neuroimmunological perspective. Curr Opin Pharmacol 8:480–489PubMedCrossRefGoogle Scholar
  6. Asea A, Kraeft SK, Kurt-Jones EA, Stevenson MA, Chen LB, Finberg RW, Koo DC, Calderwood SK (2000) HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med 6:435–442PubMedCrossRefGoogle Scholar
  7. Bhaskar S, Shalini V, Helen A (2011) Quercetin regulates oxidized LDL induced inflammatory changes in human PBMCs by modulating the TLR-NF-κB signaling pathway. Immunobiology 216:367–373PubMedCrossRefGoogle Scholar
  8. Bigelman AK, Chapman DP, Freese EC, Trilk JL, Curetin KJ (2011) Effects of 6 weeks of quercetin supplementation on energy, fatigue, and sleep in ROTC cadets. Mil Med 176:565–572PubMedGoogle Scholar
  9. Boots AW, Haenen GR, Bast A (2008) Health effects of quercetin: from antioxidant to nutraceutical. Eur J Pharmacol 585:325–337PubMedCrossRefGoogle Scholar
  10. Cetin ED, Savk E, Uslu M, Eskin M, Karul A (2009) Investigation of the inflammatory mechanisms in alopecia areata. Am J Dermatopathol 31:53–60PubMedCrossRefGoogle Scholar
  11. de Jong PR, Schadenberg AW, Jansen NJ, Prakken BJ (2009) Hsp70 and cardiac surgery: molecular chaperone and inflammatory regulator with compartmentalized effects. Cell Stress Chaperones 14:117–131PubMedCrossRefGoogle Scholar
  12. De Maio A (2011) Extracellular heat shock proteins, cellular export vesicles, and the stress observation system: a form of communication during injury, infection, and cell damage. Cell Stress Chaperones 16:235–249PubMedCrossRefGoogle Scholar
  13. Dudda-Subramanya R, Alexis AF, Siu K, Sinha AA (2007) Alopecia areata: genetic complexity underlies clinical heterogeneity. Eur J Dermatol 17:367–374PubMedGoogle Scholar
  14. Egert S, Wolffram S, Schulze B, Langguth P, Hubbermann EM, Schwarz K, Adolphi B, Bosy-Westphal A, Rimbach G, Muller MJ (2011) Enriched cereal bars are more effective in increasing plasma quercetin compared with quercetin from powder-filled hard capsules. Br J Nutr. doi: 10.1017/s0007114511003242
  15. Erdman JW Jr, Balentine D, Arab L, Beecher G, Dwyer JT, Folts J, Harnly J, Hollman P, Keen CL, Mazza G, Messina M, Scalbert A, Vita J, Williamson G, Burrowes J (2007) Flavonoids and heart health: proceedings of the ILSI North America Flavonoids Workshop. J Nutr 137:718S–737SPubMedGoogle Scholar
  16. Garg S, Messenger AG (2009) Alopecia areata: evidence-based treatments. Semin Cutan Med Surg 28:15–18PubMedCrossRefGoogle Scholar
  17. Garrido C, Brunet M, Didelot C, Zermati Y, Schmitt E, Kroemer G (2006) Heat shock proteins 27 and 70: anti-apoptotic proteins with tumorigenic properties. Cell Cycle 5:2592–2601PubMedCrossRefGoogle Scholar
  18. Gilhar A (2010) Collapse of the immune privilege in alopecia areata: coincidental or substantial? J Investig Dermatol 130:2535–2537PubMedCrossRefGoogle Scholar
  19. Gilhar A, Kalish RS (2006) Alopecia areata: a tissue specific autoimmune disease of the hair follicle. Autoimmun Rev 5:64–69PubMedCrossRefGoogle Scholar
  20. Gilhar A, Paus R, Kalish RS (2007) Lymphocytes, neuropeptides, and genes involved in alopecia areata. J Clin Invest 117:2019–2027PubMedCrossRefGoogle Scholar
  21. Gregoriou S, Papafragkaki D, Kontochristopoulos G, Rallis E, Kalogeromitros D, Rigopoulos D (2010) Cytokines and other mediators in alopecia areata. Mediators Inflamm 2010:928030Google Scholar
  22. Hajheydari Z, Jamshidi M, Akbari J, Mohammadpour R (2007) Combination of topical garlic gel and betamethasone valerate cream in the treatment of localized alopecia areata: a double-blind randomized controlled study. Indian J Dermatol Venereol Leprol 73:29–32PubMedCrossRefGoogle Scholar
  23. Harwood M, Danielewska-Nikiel B, Borzelleca JF, Flamm GW, Williams GM, Lines TC (2007) A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties. Food Chem Toxicol 45:2179–2205PubMedCrossRefGoogle Scholar
  24. Hirsh MI, Junger WG (2008) Roles of heat shock proteins and gamma delta T cells in inflammation. Am J Respir Cell Mol Biol 39:509–513PubMedCrossRefGoogle Scholar
  25. Huang RY, Yu YL, Cheng WC, OuYang CN, Fu E, Chu CL (2010) Immunosuppressive effect of quercetin on dendritic cell activation and function. J Immunol 184:6815–6821PubMedCrossRefGoogle Scholar
  26. Jimenez JJ, Roberts SM, Mejia J, Mauro LM, Munson JW, Elgart GW, Connelly EA, Chen Q, Zou J, Goldenberg C, Voellmy R (2008) Prevention of chemotherapy-induced alopecia in rodent models. Cell Stress Chaperones 13:31–38PubMedCrossRefGoogle Scholar
  27. Kos L, Conlon J (2009) An update on alopecia areata. Curr Opin Pediatr 21(4):475–480PubMedCrossRefGoogle Scholar
  28. Lee KH, Park E, Lee HJ, Kim MO, Cha YJ, Kim JM, Lee H, Shin MJ (2011) Effects of daily quercetin-rich supplementation on cardiometabolic risks in male smokers. Nutr Res Pract 5:28–33PubMedCrossRefGoogle Scholar
  29. Marzouki SM, Almagro L, Sabater-Jara AB, Ros Barcelo A, Pedreno MA (2010) Kinetic characterization of a basic peroxidase from garlic (Allium sativum L.) cloves. J Food Sci 75:C740–C746PubMedCrossRefGoogle Scholar
  30. McDonagh AJ, Tazi-Ahnini R (2002) Epidemiology and genetics of alopecia areata. Clin Exp Dermatol 27:405–409PubMedCrossRefGoogle Scholar
  31. McElwee KJ, Hoffmann R, Freyschmidt-Paul R, Wenzel E, Kissling S, Sundberg JP, Zoller M (2002) Resistance to alopecia areata in C3H/HeJ mice is associated with increased expression of regulatory cytokines and a failure to recruit CD4+ and CD8+ cells. J Invest Dermatol 119:1426–1433PubMedCrossRefGoogle Scholar
  32. McElwee KJ, Freyschmidt-Paul P, Sundberg JP, Hoffman R (2003) The pathogenesis of alopecia areata in rodent models. J Investig Dermatol Symp Proc 8:6–11PubMedCrossRefGoogle Scholar
  33. Molvarec A, Tamasi L, Gyorgy L, Madach K, Prohaszka Z, Rigo J Jr (2010) Circulating heat shock protein 70 (HSPA1A) in normal and pathological pregnancies. Cell Stress and Chaperones 15:237–247PubMedCrossRefGoogle Scholar
  34. Multhoff G, Hightower LE (2011) Distinguishing integral and receptor-bound heat shock protein 70 (Hsp70) on the cell surface by Hsp70-specific antibodies. Cell Stress Chaperones 16:251–255PubMedCrossRefGoogle Scholar
  35. Nam NH (2006) Naturally occurring NF-kB inhibitors. Mini-Reviews in Medicinal Chemistry 6:945–951PubMedCrossRefGoogle Scholar
  36. Nickel T, Hanssen H, Sisic Z, Pfeiler S, Summo C, Schmauss D, Hoster E, Weis M (2011) Immunoregulatory effects of the flavonol quercetin in vitro and in vivo. Eur J Nutr 50:163–172PubMedCrossRefGoogle Scholar
  37. Ohtsuki A, Hasegawa T, Ikeda S (2010) Treatment of alopecia areata with 308-nm excimer lamp. J Dermatol 37:1032–1035PubMedCrossRefGoogle Scholar
  38. Paus R, Ito N, Takigawa M, Ito T (2003) The hair follicle and immune privilege. J Investig Dermatol Symp Proc 8:188–194PubMedCrossRefGoogle Scholar
  39. Pockley AG, Muthana M, Calderwood SK (2008) The dual immunoregulatory roles of stress proteins. Trends Biochem Sci 33:71–79PubMedCrossRefGoogle Scholar
  40. Price VH (1991) Alopecia areata: clinical aspects. J Invest Dermatol 96:68SPubMedCrossRefGoogle Scholar
  41. Roberts RJ, Agius C, Saliba C, Bossier P, Sung YY (2010) Heat shock proteins (chaperones) in fish and shellfish and their potential role in relation to fish health: a review. J Fish Dis 33:789–801PubMedCrossRefGoogle Scholar
  42. Safavi KH, Muller SA, Suman VJ, Moshell AN, Melton LJ 3rd (1995) Incidence of alopecia areata in Olmsted County, Minnesota, 1975 through 1989. Mayo Clin Proc 70:628–633PubMedCrossRefGoogle Scholar
  43. Sharquie KE, Al-Obaidi HK (2002) Onion juice (Allium cepa L.), a new topical treatment for alopecia areata. J Dermatol 29:343–346PubMedGoogle Scholar
  44. Slimestad R, Fossen T, Vagen IM (2007) Onions: a source of unique dietary flavonoids. J Agric Food Chem 55:10067–10080PubMedCrossRefGoogle Scholar
  45. Sun J, Chen P, Lin LZ, Harnly JM (2011) A non-targeted approach to chemical discrimination between green tea dietary supplements and green tea leaves by HPLC/MS. J AOAC Int 94:487–497PubMedGoogle Scholar
  46. van den Biggelaar FJ, Smolders J, Jansen JF (2010) Complementary and alternative medicine in alopecia areata. Am J Clin Dermatol 11:11–20PubMedCrossRefGoogle Scholar
  47. Wang RE, Kao JLF, Hilliard CA, Pandita RK, Roti Roti JL, Hunt CR, Taylor JS (2009) Inhibition of heat shock induction of heat shock protein 70 and enhancement of heat shock protein 27 phosphorylation by quercetin derivatives. J Med Chem 52:1912–1921PubMedCrossRefGoogle Scholar
  48. Wasserman D, Guzman-Sanchez DA, Scott K, McMichael A (2007) Alopecia areata. Int J Dermatol 46:121–131PubMedCrossRefGoogle Scholar
  49. Wikramanayake TC, Alvarez-Connelly E, Simon J, Mauro LM, Guzman J, Elgart G, Schachner LA, Chen J, Plano LR, Jimenez JJ (2010) Heat treatment increases the incidence of alopecia areata in the C3H/HeJ mouse model. Cell Stress and Chaperones 15:985–991PubMedCrossRefGoogle Scholar

Copyright information

© Cell Stress Society International 2011

Authors and Affiliations

  • Tongyu Cao Wikramanayake
    • 1
  • Alexandra C. Villasante
    • 1
  • Lucia M. Mauro
    • 1
  • Carmen I. Perez
    • 1
  • Lawrence A. Schachner
    • 1
  • Joaquin J. Jimenez
    • 1
    Email author
  1. 1.Department of Dermatology and Cutaneous SurgeryUniversity of Miami Miller School of MedicineMiamiUSA

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