Abstract
Resveratrol, a natural phytoalexin found mainly in grapes, possesses a variety of beneficial activities including anticancer, antimicrobial and antiviral. However, there is no information about its effects on kinetoplastid parasites such as Leishmania. Leishmania is a human pathogen responsible for a spectrum of diseases known as leishmaniases and a significant health problem in many parts of the world. In this study, we investigated effects of resveratrol and its hydroxylated analogues on Leishmania major, a causative agent of zoonotic cutaneous leishmaniasis in the Old World. Resveratrol showed antileishmanial activity against promastigotes in vitro and, more importantly, was effective against intracellular amastigotes, a parasite life stage infectious in humans, as detected in in vitro macrophage assay. The hydroxylated stilbenes tested in this study also showed antileishmanial activity against promastigotes, the most promising being 3,4,4′,5′-tetrahydroxy-trans-stilbene. This compound showed excellent antileishmanial activity against extracellular promastigotes in vitro but not intracellular amastigotes. Our results suggest that resveratrol may be useful as a therapeutic agent to treat leishmaniasis and warrant its further assessment in animal models of disease.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Explore related subjects
Discover the latest articles and news from researchers in related subjects, suggested using machine learning.References
Babich H, Reisbaum AG, Zuckerbraun HL (2000) In vitro response of human gingival epithelial S-G cells to resveratrol. Toxicol Lett 114:143–153
Baur JA, Sinclair DA (2006) Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 5:493–506
Chan MM (2002) Antimicrobial effect of resveratrol on dermatophytes and bacterial pathogens of the skin. Biochem Pharmacol 63:99–104
Croft SL, Engel J (2006) Miltefosine—discovery of the antileishmanial activity of phospholipid derivatives. Trans R Soc Trop Med Hyg
Crowell JA, Korytko PJ, Morrissey RL, Booth TD, Levine BS (2004) Resveratrol-associated renal toxicity. Toxicol Sci 82:614–619
Davis AJ, Kedzierski L (2005) Recent advances in antileishmanial drug development. Curr Opin Investig Drugs 6:163–169
del Olmo E, Armas MG, Lopez-Perez JL, Munoz V, Deharo E, San Feliciano A (2001) Leishmanicidal activity of some stilbenoids and related heterocyclic compounds. Bioorg Med Chem Lett 11:2123–2126
Desjeux P (2004) Leishmaniasis: current situation and new perspectives. Comp Immunol Microbiol Infect Dis 27:305–318
Dobrydneva Y, Williams RL, Blackmore PF (1999) trans-Resveratrol inhibits calcium influx in thrombin-stimulated human platelets. Br J Pharmacol 128:149–157
Docherty JJ, Fu MM, Stiffler BS, Limperos RJ, Pokabla CM, DeLucia AL (1999) Resveratrol inhibition of herpes simplex virus replication. Antivir Res 43:145–155
Eibl H, Unger C (1990) Hexadecylphosphocholine: a new and selective antitumor drug. Cancer Treat Rev 17:233–242
Falchetti R, Fuggetta MP, Lanzilli G, Tricarico M, Ravagnan G (2001) Effects of resveratrol on human immune cell function. Life Sci 70:81–96
Feng YH, Zhou WL, Wu QL, Li XY, Zhao WM, Zou JP (2002) Low dose of resveratrol enhanced immune response of mice. Acta Pharmacol Sin 23:893–897
Gao X, Xu YX, Janakiraman N, Chapman RA, Gautam SC (2001) Immunomodulatory activity of resveratrol: suppression of lymphocyte proliferation, development of cell-mediated cytotoxicity, and cytokine production. Biochem Pharmacol 62:1299–1308
Gao X, Deeb D, Media J, Divine G, Jiang H, Chapman RA, Gautam SC (2003) Immunomodulatory activity of resveratrol: discrepant in vitro and in vivo immunological effects. Biochem Pharmacol 66:2427–2435
Handman E (1999) Cell biology of Leishmania. Adv Parasitol 44:1–39
Jha TK, Sundar S, Thakur CP, Bachmann P, Karbwang J, Fischer C, Voss A, Berman J (1999) Miltefosine, an oral agent, for the treatment of Indian visceral leishmaniasis. N Engl J Med 341:1795–1800
Juan ME, Vinardell MP, Planas JM (2002) The daily oral administration of high doses of trans-resveratrol to rats for 28 days is not harmful. J Nutr 132:257–260
Jung HJ, Hwang IA, Sung WS, Kang H, Kang BS, Seu YB, Lee DG (2005) Fungicidal effect of resveratrol on human infectious fungi. Arch Pharm Res 28:557–560
Kedzierski L, Montgomery J, Bullen D, Curtis J, Gardiner E, Jimenez-Ruiz A, Handman E (2004) A leucine-rich repeat motif of Leishmania parasite surface antigen 2 binds to macrophages through the complement receptor 3. J Immunol 172:4902–4906
Kelleher M, Moody SF, Mirabile P, Osborn AH, Bacic A, Handman E (1995) Lipophosphoglycan blocks attachment of Leishmania major amastigotes to macrophages. Infect Immun 63:43–50
Kiderlen AF, Kayser O, Ferreira D, Kolodziej H (2001) Tannins and related compounds: killing of amastigotes of Leishmania donovani and release of nitric oxide and tumour necrosis factor alpha in macrophages in vitro. Z Naturforsch [C] 56:444–454
Kolodziej H, Kiderlen AF (2005) Antileishmanial activity and immune modulatory effects of tannins and related compounds on Leishmania parasitised RAW 264.7 cells. Phytochemistry 66:2056–2071
Leiro J, Arranz JA, Parama A, Alvarez MF, Sanmartin ML (2004a) In vitro effects of the polyphenols resveratrol, mangiferin and (−)-epigallocatechin-3-gallate on the scuticociliate fish pathogen Philasterides dicentrarchi. Dis Aquat Org 59:171–174
Leiro J, Cano E, Ubeira FM, Orallo F, Sanmartin ML (2004b) In vitro effects of resveratrol on the viability and infectivity of the microsporidian Encephalitozoon cuniculi. Antimicrob Agents Chemother 48:2497–2501
Mickuviene I, Kirveliene V, Juodka B (2004) Experimental survey of non-clonogenic viability assays for adherent cells in vitro. Toxicol In Vitro 18:639–648
Mikus J, Steverding D (2000) A simple colorimetric method to screen drug cytotoxicity against Leishmania using the dye Alamar Blue. Parasitol Int 48:265–269
Murias M, Handler N, Erker T, Pleban K, Ecker G, Saiko P, Szekeres T, Jager W (2004) Resveratrol analogues as selective cyclooxygenase-2 inhibitors: synthesis and structure-activity relationship. Bioorg Med Chem 12:5571–5578
Murias M, Jager W, Handler N, Erker T, Horvath Z, Szekeres T, Nohl H, Gille L (2005) Antioxidant, prooxidant and cytotoxic activity of hydroxylated resveratrol analogues: structure-activity relationship. Biochem Pharmacol 69:903–912
Murray HW, Berman JD, Davies CR, Saravia NG (2005) Advances in leishmaniasis. Lancet 366:1561–1577
Redondo P, Jimenez E, Perez A, Garcia-Foncillas J (2000) N-acetylcysteine downregulates vascular endothelial growth factor production by human keratinocytes in vitro. Arch Dermatol Res 292:621–628
Sacks D, Noben-Trauth N (2002) The immunology of susceptibility and resistance to Leishmania major in mice. Nat Rev Immunol 2:845–858
Siemann EH, Creasy LL (1992) Concentration of the phytoalexin resveratrol in wine. Am J Enol Vitic 43:49–52
Son IH, Chung IM, Lee SJ, Moon HI (2007) Antiplasmodial activity of novel stilbene derivatives isolated from Parthenocissus tricuspidata from South Korea. Parasitol Res 101:237–241
Tapiero H, Tew KD, Ba GN, Mathe G (2002) Polyphenols: do they play a role in the prevention of human pathologies? Biomed Pharmacother 56:200–207
Acknowledgements
The authors would like to thank Drs Emanuela Handman and Katherine Kedzierska for critical review of the manuscript. This work was supported by the National Health and Medical Research Council grant (to LK) and NHMRC/ARC Network for Parasitology.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Kedzierski, L., Curtis, J.M., Kaminska, M. et al. In vitro antileishmanial activity of resveratrol and its hydroxylated analogues against Leishmania major promastigotes and amastigotes. Parasitol Res 102, 91–97 (2007). https://doi.org/10.1007/s00436-007-0729-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00436-007-0729-y