From medicinal plant extracts to defined chemical compounds targeting the histamine H4 receptor: Curcuma longa in the treatment of inflammation



The aim was to evaluate the activity of seven medicinal, anti-inflammatory plants at the hH4R with focus on defined chemical compounds from Curcuma longa.


Activities were analyzed with membrane preparations from Sf9 cells, transiently expressing the hH4R, Gαi2 and Gβ1γ2 subunits.


From the methanolic extract of C. longa curcumin (1), demethoxycurcumin (2) and bis(4-hydroxy-cinnamoyl)methane (3) were isolated, purified with HPLC (elution-time 10.20, 9.66, 9.20 min, respectively) and together with six additional extracts, were characterized via radioligand binding studies at the hH4R.


Compounds from C. longa were the most potent ligands at the hH4R. They exhibited estimated K i values of 4.26–6.26 µM (1.57–2.31 µg/mL) (1); 6.66––8.97 µM (2.26–3.04 µg/mL) (2) and 10.24–14.57 µM (3.16–4.49 µg/mL) (3) (95% CI). The estimated K i value of the crude extract of curcuma was 0.50–0.81 µg/mL. Fractionated curcumin and the crude extract surpassed the effect of pure curcumin with a K i value of 5.54 µM or 2.04 µg/mL [95% CI (4.47–6.86 µM), (1.65–2.53 µg/mL)].


Within this study, defined compounds of C. longa were recognized as potential ligands and reasonable lead structures at the hH4R. The mode of anti-inflammatory action of curcumin was further elucidated and the role of extracts in traditional phytomedicine was strengthened.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3


  1. 1.

    Dunford PJ, O’Donnell N, Riley JP, Williams KN, Karlsson L, Thurmond RL. The histamine H4 receptor mediates allergic airway inflammation by regulating the activation of CD4+ T cells. J Immunol. 2006;176:7062–70.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Zaid H, Raiyn J, Osman M, Falah M, Srouji S, Rayan A. In silico modeling techniques for predicting the tertiary structure of human H4 receptor. Front Biosci. 2015;21:597–619.

    Google Scholar 

  3. 3.

    Cragg GM, Newman DJ. Medicinals for the millennia. The historical record. Ann N Y Acad Sci. 2001;8:2–25.

    Google Scholar 

  4. 4.

    Lee K-H. Discovery and development of natural product-derived chemotherapeutic agents based on a medicinal chemistry approach. J Nat Prod. 2010;73:500–16.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Lahlou M. The success of natural products in drug discovery. Pharmacol Pharm. 2013;4:17–31.

    Article  Google Scholar 

  6. 6.

    Harvey A. The role of natural products in drug discovery and development in the new millennium. IDrugs. 2010;13:70–2.

    PubMed  Google Scholar 

  7. 7.

    Aggarwal BB, Harikumar KB. Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. Int J Biochem Cell Biol. 2009;41:40–59.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Mousavi SZ, Bathaie SZ. Historical uses of saffron: identifying potential new avenues for modern research. AJP. 2011;1:57–66.

    Google Scholar 

  9. 9.

    Bhat SP, Rizvi W, Kumar A. Effect of Cuminum cyminum L. seed extracts on pain and inflammation. J Neurosci Res. 2014;14:186–92.

    Google Scholar 

  10. 10.

    Ocana-Fuentes A, Arranz-Gutierrez E, Senorans FJ, Reglero G. Supercritical fluid extraction of oregano (Origanum vulgare) essentials oils: anti-inflammatory properties based on cytokine response on THP-1 macrophages. Food Chem Toxicol. 2010;48:1568–75.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Ali-Shtayeh MS, Jamous RM, Salameh NMY, Jamous RM, Hamadeh AMA. Complementary and alternative medicine use among cancer patients in Palestine with special reference to safety-related concerns. J Ethnopharmacol. 2016;187:104–22.

    Article  PubMed  Google Scholar 

  12. 12.

    Ammon HPT, Wahl MA. Pharmacology of Curcuma longa. Planta Med. 1991;57:1–7.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Mahdizadeh S, Ghadiri MK, Gorji A. Avicenna’s canon of medicine: a review of analgesics and anti-inflammatory substances. AJP. 2015;5:182–202.

    PubMed  PubMed Central  Google Scholar 

  14. 14.

    Jurenka JS. Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa. Altern Med Rev. 2009;14:141–53.

    PubMed  Google Scholar 

  15. 15.

    Shehzad A, Lee YS. Molecular mechanisms of curcumin action: signal transduction. Biofactors. 2013;39:27–36.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Schneider EH, Seifert R. Sf9 cells: a versatile model system to investigate the pharmacological properties of G protein-coupled receptors. Pharmacol Ther. 2010;128:387–418.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Kottke T, Sander K, Weizel L, Schneider EH, Seifert R, Stark H. Receptor-specific functional efficacies of alkyl imidazoles as dual histamine H3/H4 receptor ligands. Eur J Pharmacol. 2011;654:200–8.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Yung-Chi C, Prusoff WH. Relationship between the inhibition constant (K i ) and the concentration of inhibitor which causes 50 per cent inhibition (IC50) of an enzymatic reaction. Biochem Pharmacol. 1973;22:3099–108.

    Article  Google Scholar 

  19. 19.

    Raz O, Rogowski O, Rosenzweig T, Shapira I, Berliner S, Boaz M. Anti inflammatory effect of high complex carbohydrate diet in obese volunteers: gender related effects. Atherosclerosis. 2015. doi:10.1016/j.atherosclerosis.2015.04.942.

    Google Scholar 

  20. 20.

    Williamson EM. Synergy and other interactions in phytomedicines. Phytomedicine. 2001;8:401–9.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Stark H. Histamine H4 receptor: a novel drug target for immunoregulation and inflammation. London: Versita; 2013.

    Google Scholar 

  22. 22.

    Cheng A-L, Hsu C-H, Lin J-K, Hsu M-M, Ho Y-F, Shen T-S, et al. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res. 2001;21:2895–900.

    CAS  PubMed  Google Scholar 

  23. 23.

    Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PS. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med. 1998;64:353–6.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Sasaki H, Sunagawa Y, Takahashi K, Imaizumi A, Fukuda H, Hashimoto T, et al. Innovative preparation of curcumin for improved oral bioavailability. Biol Pharm Bull. 2011;34:660–5.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Tsai Y-M, Chang-Liao W-L, Chien C-F, Lin L-C, Tsai T-H. Effects of polymer molecular weight on relative oral bioavailability of curcumin. Int J Nanomed. 2012;7:2957–66.

    CAS  Article  Google Scholar 

  26. 26.

    Cho E, Jung S. Supramolecular complexation of carbohydrates for the bioavailability enhancement of poorly soluble drugs. Molecules. 2015;20:19620–46.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Nelson KM, Dahlin JL, Bisson J, Graham J, Pauli GF, Walters MA, et al. The essential medicinal chemistry of curcumin: miniperspective. J Med Chem. 2017;60:1620–37.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Pappalardo M, Shachaf N, Basile L, Milardi D, Zeidan M, Raiyn J, et al. Sequential application of ligand and structure based modeling approaches to index chemicals for their hH4R antagonism. PLoS One. 2014. doi:10.1371/journal.pone.0109340.

    Google Scholar 

  29. 29.

    Wagner H, Ulrich-Merzenich G. Synergy research: approaching a new generation of phytopharmaceuticals. Phytomedicine. 2009;16:97–110.

    CAS  Article  PubMed  Google Scholar 

Download references


This study was supported by the Al-Qasemi Research Foundation, the Ministry of Science, Space and Technology, BM0806, CM1204 and CA15125 COST Actions as well as DFG INST 208/664 and GRK2158. We declare that the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author information



Corresponding author

Correspondence to Holger Stark.

Additional information

Responsible Editor: Bernhard Gibbs.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Frank, A., Abu-Lafi, S., Adawi, A. et al. From medicinal plant extracts to defined chemical compounds targeting the histamine H4 receptor: Curcuma longa in the treatment of inflammation. Inflamm. Res. 66, 923–929 (2017).

Download citation


  • Curcuma longa
  • Natural compounds
  • hH4R
  • Inflammatory diseases
  • Phenylpropanoids