Parasitology Research

, Volume 96, Issue 1, pp 49–56 | Cite as

Curcumin overcomes the inhibitory effect of nitric oxide on Leishmania

  • Marion Man-Ying Chan
  • Naga Suresh Adapala
  • Dunne Fong
Original Paper


Upon Leishmania infection, macrophages are activated to produce nitrogen and oxygen radicals simultaneously. It is well established that the infected host cells rely on nitric oxide (NO) as the major weapon against the intracellular parasite. In India where leishmaniasis is endemic, the spice turmeric is used prolifically in food and for insect bites. Curcumin, the active principle of turmeric, is a scavenger of NO. This report shows that curcumin protects promastigotes and amastigotes of the visceral species, Leishmania donovani, and promastigotes of the cutaneous species, L. major, against the actions of S-nitroso-N-acetyl-D,L-penicillamine (SNAP) and DETANONOate, which release NO, 3-morpholino-sydnonimine hydrochloride (SIN-1), which releases NO and superoxide, and peroxynitrite, which is formed from the reaction of NO with superoxide. Thus, curcumin, as an antioxidant, is capable of blocking the action of both NO and NO congeners on the Leishmania parasite.


Nitric Oxide Curcumin Peroxynitrite Leishmaniasis Cutaneous Leishmaniasis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We thank Mr. Harry Heverling for technical assistance and Dr. Robert Herman for helpful comments on the manuscript. This work was supported with a grant from the National Institutes of Health (AI-45555) to Marion Chan. The study was performed in accordance with United States law.


  1. Abu-Soud HM, Stuehr DJ (1993) Nitric oxide synthases reveal a role for calmodulin in controlling electron transfer. Proc Natl Acad Sci USA 90:10769–10772Google Scholar
  2. Araujo CAC, Alegrio LV, Gomes DCF, Lima MEF, Gomes-Cardoso L, Leon LL (1999) Studies on the effectiveness of diarylheptanoids derivatives against Leishmania amazonensis. Mem Inst Oswaldo Cruz 94:791–794Google Scholar
  3. Assreuy J, Cunha FQ, Epperlein M, Noronha-Dutra A, O’Donnell CA, Liew FY, Moncada S (1994) Production of nitric oxide and superoxide by activated macrophages and killing of Leishmania major. Eur J Immunol 24:672–676Google Scholar
  4. Chan MM (1995) Inhibition of tumor necrosis factor by curcumin, a phytochemical. Biochem Pharmacol 49:1551–1556Google Scholar
  5. Chan MM, Grogl M, Chen CC, Bienen EJ, Fong D (1993) Herbicides to curb human parasitic infections: in vitro and in vivo effects of trifluralin on the trypanosomatid protozoans. Proc Natl Acad Sci USA 90:5657–5661Google Scholar
  6. Chan MM, Ho CT, Huang HI (1995) Effects of three dietary phytochemicals from tea, rosemary and turmeric on inflammation-induced nitrite production. Cancer Lett 96:23–29Google Scholar
  7. Chan MM, Huang H, Fenton MR, Fong D (1998) In vivo inhibition of nitric oxide synthase gene expression by curcumin, a cancer preventive natural product with anti-inflammatory properties. Biochem Pharmcol 55:1955–1962Google Scholar
  8. Chan MM, Bulinski JC, Chang KP, Fong D (2003) A microplate assay for Leishmania amazonensis promastigotes expressing multimeric green fluorescent protein. Parasitol Res 89:266–271Google Scholar
  9. Chan MM, Huang HI, Mattiacci JA, Fong D (2003b) Modulation of cytokine gene expression by curcumin. In: Shahidi F, Ho CT, Watanabe S, Osawa (eds) Food factors in health promotion and disease prevention. American Chemical Society Press, Washington DC, pp 86–99Google Scholar
  10. Chang KP, Hendricks LD (1985) Laboratory cultivation and maintenance of Leishmania. In: Chang KP, Bray RS (eds) Human parasitic diseases I. Leishmaniasis. Elsevier, Netherlands, pp 213–246Google Scholar
  11. Das KC, Das CK (2002) Curcumin (diferuloylmethane), a singlet oxygen quencher. Biochem Biophys Res Commun 295:62–66Google Scholar
  12. Gantt KR, Goldman TL, McCormick ML, Miller MA, Jeronimo SM, Nascimento ET, Britigan BE, Wilson ME (2001) Oxidative responses of human and murine macrophages during phagocytosis of Leishmania chagasi. J Immunol 167:893–901Google Scholar
  13. Ghosh S, Goswami S, Adhya S (2003) Role of superoxide dismutase in survival of Leishmania within the macrophage. Biochem J 369:447–452Google Scholar
  14. Giorgio S, Linares E, Capurro M, de L, Bianchi AG, Augusto O (1996) Formation of nitrosyl hemoglobin and nitrotyrosine during murine leishmaniasis. Photochem Photobiol 63:750–754Google Scholar
  15. Giorgio S, Linares E, Ischiropoulos H, Von Zuben FJ, Yamada A, Augusto O (1998) In vivo formation of electron paramagnetic resonance-detectable nitric oxide and of nitrotyrosine is not impaired during murine leishmaniasis. Infect Immun 66: 807–814Google Scholar
  16. Green SJ, Crawford RM, Hockmeyer JT, Meltzer MS, Nacy CA (1990) Leishmania major amastigotes initiate the L-arginine-dependent killing mechanism in IFN-γ-stimulated macrophages by induction of tumor necrosis factor-α. J Imuunol 145:4290–4297Google Scholar
  17. Hodgkinson VH, Herman R, Semprevivo L (1980) Leishmania donovani: correlation among assays of amastigote viability. Exp Parasitol 50:397–408Google Scholar
  18. Huang MT, Lysz T, Ferraro T, Conney AH (1991) Inhibitory effects of curcumin on in vivo lipoxygenase and cyclooxygenase activities in mouse epidermis. Cancer Res 51:813–819Google Scholar
  19. Huang MT, Ma W, Lu Y, Chang RL, Fisher C, Manchand PS, Newwark HL, Conney AH (1995) Effects of curcumin, demethoxycurcumin, bisdemethoxycurcumin and tetrahydrocurcumin on 12-o-tetradecanoylphorbol-13-acetate-induced tumor promotion. Carcinogenesis 16:2493–2497Google Scholar
  20. Huang MT, Ma W, Yen P, Xie J-G, Han J, Frenkel K, Grunberger D, Conney AH (1997) Inhibitory effects of topical application of low doses of curcumin on 12-o-tetradecanoyl-phorbol-13-acetate-induced tumor promotion and oxidized DNA bases in mouse epidermis. Carcinogenesis 18:83–88Google Scholar
  21. Ischiropoulos H, Zhu L, Beckman JS (1992) Peroxynitirtie formation from macrophage-derived nitric oxide. Arch Biochem Biophys 298:446–451Google Scholar
  22. Joe B, Vijaykumar M, Lokesh BR (2004) Biological properties of curcumin-cellular and molecular mechanisms of action. Crit Rev Food Sci Nutr 44:97–111Google Scholar
  23. Kelloff GJ, Crowell JA, Hawk ET, Steele VE, Lubet RA, Boone CW, Covey JM, Doody LA, Omenn GS, Greenwald P, Hong WK, Parkinson DR, Bagheri D, Baxter GT, Blunden M, Doeltz MK, Eisenhauer KM, Johnson K, Knapp GG, Longfellow DG, Malone WF, Nayfield SG, Seifried HE, Swall LM, Sigman CC (1996) Strategy and planning for chemopreventive drug development: clinical development plans II. J Cell Biochem Suppl 26:54–71Google Scholar
  24. Koide T, Nose M, Ogihara Y, Yabu Y, Ohta N (2002) Leishmanicidal effect of curcumin in vitro. Biol Pharm Bull 25:131–133Google Scholar
  25. Krishnaswamy K, Raghuramulu N (1998) Bioactive phytochemicals with emphasis on dietary practices. Ind J Med Res 108: 167–181Google Scholar
  26. Kunchandy E, Rao MNA (1989) Efect of curcumin on hydroxyl radical generation through Fenton reaction. J Pharm 57:173–176Google Scholar
  27. Kunchandy E, Rao MNA (1990) Oxygen redical scavenging activity of curcumin. Int J Pharm 58:237–240Google Scholar
  28. Lemerse J, Sereno D, Daulouede S, Veyret B, Brajon N, Vincendeau P (1997) Leishmania spp: Nitric oxide-mediated metabolic inhibition of promastigote and axenically grown amastigote forms. Exp Parasitol 86:58–68Google Scholar
  29. Liew FY, Millott S, Parkinson C, Palmer RMJ, Moncada S (1990) Macrophage killing of Leishmania parasite in vivo is mediated by nitric oxide from L-arginine. J Immunol 144:4794–4797Google Scholar
  30. Liew FY, Yun L, Moss D, Parkinson C, Rogers MV, Moncada S (1991) Resistance to Leishmania major infection correlates with the induction of nitric oxide synthase in murine macrophages. Eur J Immunol 21:3009–3014Google Scholar
  31. Linares E, Giorgio S, Mortara RA, Santos CX, Yamada AT, Augusto O (2001) Role of peroxynitrite in macrophage microbicidal mechanisms in vivo revealed by protein nitration and hydroxylation. Free Radic Biol Med 30:1234–1242Google Scholar
  32. Lu YP, Chang RL, Lou YR, Huang MT, Newmark HL, Reuhl KR, Conney AH (1994) Effect of curcumin on 12-O-tetradecanoylphorbol-13-acetate- and ultraviolet B light-induced expression of c-Jun and c-Fos in JB6 cells and in mouse epidermis. Carcinogenesis 15:2363–2370Google Scholar
  33. Mauel J, Ransijin A (1997) Leishmania spp.: mechanisms of toxicity of nitrogen oxidation products. Exp Parasitol 87:98–111Google Scholar
  34. Murray HW and Nathan CF (1999) Macrophage microbicidal mechanisms in vivo: reactive nitrogen versus oxygen intermediates in the killing of intracellular visceral Leishmania donovani. J Exp Med 189:741–746Google Scholar
  35. Nose M, Koide T, Ogihara Y, Yabu Y, Ohta N (1998) Trypanocidal effects of curcumin in vitro. Biol Pharm Bull 21:643–645Google Scholar
  36. Polasa K, Raghuram TC, Krishna TP, Krishnaswamy K (1992) Effect of turmeric on urinary mutagens in smokers. Mutagenesis 7:107–109Google Scholar
  37. Pou S, Pou WS, Bredt DS, Snyder SH, Rosen GM (1992) Generation of superoxide by purified brain nitric oxide synthase. J Biol Chem 267:24137–24176Google Scholar
  38. Rao CV, Kawamori T, Hamid R, Reddy BS (1999) Chemoprevention of colonic crypt foci by an inducible nitric oxide synthase-selective inhibitor. Carcinogenesis 20:641–644Google Scholar
  39. Rasyid A, Lelo A (1999) The effect of curcumin and placebo on human gall-bladder function: an ultrasound study. Aliment Pharmacol Ther 13:245–249Google Scholar
  40. Saleheen D, Ali SA, Ashfaq K, Siddiqui AA, Agha A, Yasinzai MM (2002) Latent activity of curcumin against leishmaniasis in vitro. Biol Pharm Bull 25:386–389Google Scholar
  41. Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PS (1998) Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med 64:353–356Google Scholar
  42. Sreejayan, Rao MN (1997) Nitric oxide scavenging by curcuminoids. J Pharm Pharmacol 49:105–107Google Scholar
  43. Stamler JS (1996) S-nitrosothiols and the bioregulatory actions of nitrogen oxides through reactions with thiol groups. Curr Top Microbiol Immunol 196:19–36Google Scholar
  44. Stamler JS, Singel DJ, Loscalzo L (1992) Biochemistry of nitric oxide and its redox-activated forms. Science 258:1898–1902PubMedGoogle Scholar
  45. Toniolo R, Di Narda F, Susmel S, Martelli M, Martelli L, Bontempelli G (2002) Quenching of superoxide anions by curcumin. A mechanistic study in acetonitrile. Ann Chem 92:281–288Google Scholar
  46. Unnikrishnan MK, Rao MNA (1995) Curcumin inhibits nitrogen dioxide induced oxidation of hemoglobin. Mol Cell Biochem 146:35–37Google Scholar
  47. Venkatesan P, Rao MN (2000) Structure-activity relationships for the inhibition of lipid peroxidation and the scavenging of free radicals by synthetic symmetrical curcumin analogues. J Pharm Pharmacol 52:1123–1128Google Scholar
  48. Vouldoukis I, Riveros-Moreno V, Dugas B, Ouaaz F, Becherel P, Debra P, Moncada S, Mossalayi MD (1995) The killing of Leishmania major by human macrophages is mediated by nitric oxide induced after ligation of the Fc epsilon RII/CD23 surface antigen. Proc Natl Acad Sci USA 92:7804–7808Google Scholar
  49. Vouldoukis I, Becherel PA, Riveros-Moreno V, Arock M, da Silva O, Debre P, Mazier D, Mossalayi MD (1997) Interleukin-10 and interleukin-4 inhibit intracellular killing of Leishmania infantum and Leishmania major by human macrophages by decreasing nitric oxide generation. Eur J Immunol 27:860–865Google Scholar
  50. Xia Y, Roman LJ, Masters BS, Zweier JL (1998) Inducible nitric-oxide synthase generates superoxide from the reductase domain. J Biol Chem 273:22635–22639Google Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Marion Man-Ying Chan
    • 1
  • Naga Suresh Adapala
    • 1
  • Dunne Fong
    • 2
  1. 1.Department of Microbiology and ImmunologyTemple University School of MedicinePhiladelphiaUSA
  2. 2.Department of Cell Biology and Neuroscience, RutgersThe State University of New JerseyPiscatawayUSA

Personalised recommendations