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Parasitology Research

, Volume 113, Issue 1, pp 333–339 | Cite as

Treatment with triterpenic fraction purified from Baccharis uncinella leaves inhibits Leishmania (Leishmania) amazonensis spreading and improves Th1 immune response in infected mice

  • Eduardo Seiji Yamamoto
  • Bruno Luiz S. Campos
  • Márcia Dalastra Laurenti
  • João H.G. Lago
  • Simone dos Santos Grecco
  • Carlos E. P. Corbett
  • Luiz Felipe D. Passero
Original Paper

Abstract

The current medications used to treat leishmaniasis have many side effects for patients; in addition, some cases of the disease are refractory to treatment. Therefore, the search for new leishmanicidal compounds is indispensable. Recently, it was demonstrated that oleanolic- and ursolic-containing fraction from Baccharis uncinella leaves eliminated the promastigote and amastigote forms of Leishmania (Leishmania) amazonensis and L. (Viannia) braziliensis without causing toxic effects for J774 macrophages. Thus, the aim of the present work was to characterize the therapeutic effect of the triterpenic fraction in L. (L.) amazonensis-infected BALB/c mice. Oleanolic- and ursolic acid-containing fraction was extracted from B. uncinella leaves using organic solvents and chromatographic procedures. L. (L.) amazonensis-infected BALB/c mice were treated intraperitoneally with triterpenic fraction during five consecutive days with 1.0 and 5.0 mg/kg of triterpenic fraction, or with 10.0 mg/kg of amphotericin B drug. Groups of mice treated with the triterpenic fraction, presented with decreased lesion size and low parasitism of the skin—both of which were associated with high amounts of interleukin-12 and interferon gamma. The curative effect of this fraction was similar to amphotericin B-treated mice; however, the final dose, required to eliminate amastigotes, was lesser than amphotericin B. Moreover, triterpenic fraction did not cause microscopic alterations in liver, spleen, heart, lung, and kidney of experimental groups. This work suggests that this fraction possesses compounds that are characterized by leishmanicidal and immunomodulatory activities. From this perspective, the triterpenic fraction can be explored as a new therapeutic agent for use against American Tegumentar Leishmaniasis.

Keywords

Infected Mouse Leishmaniasis Ursolic Acid Parasite Load 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.

Notes

Acknowledgments

This work was supported by grant number 2012/03903-9 from the São Paulo Research Foundation and HCFMUSP-LIM50.

References

  1. Aït-Oudhia K, Gazanion E, Vergnes B, Oury B, Sereno D (2009) Leishmania antimony resistance: what we know what we can learn from the field. Parasitol Res 109:1225–1232CrossRefGoogle Scholar
  2. Bohlmann F, Knauf W, King RM, Robinson H (1979) Ein neues diterpen und weitere inhaltsstoffe aus Baccharis-arten. Phytochemistry 18:1011–1014CrossRefGoogle Scholar
  3. Brenzan MA, Nakamura CV, Prado Dias Filho B, Ueda-Nakamura T, Young MC, Aparício Garcia Cortez D (2007) Antileishmanial activity of crude extract and coumarin from Calophyllum brasiliense leaves against Leishmania amazonensis. Parasitol Res 101:715–722PubMedCrossRefGoogle Scholar
  4. Campos MB, De Castro Gomes CM, de Souza AA, Lainson R, Corbett CE, Silveira FT (2008) In vitro infectivity of species of Leishmania (Viannia) responsible for American cutaneous leishmaniasis. Parasitol Res 103:771–776PubMedCrossRefGoogle Scholar
  5. Carvalho AK, Silveira FT, Passero LF, Gomes CM, Corbett CE, Laurenti MD (2012) Leishmania (V.) braziliensis and L. (L.) amazonensis promote differential expression of dendritic cells and cellular immune response in murine model. Parasite Immunol 34:395–403PubMedCrossRefGoogle Scholar
  6. Ferreira DS, Esperandim VR, Toldo MP, Saraiva J, Cunha WR, de Albuquerque S (2010) Trypanocidal activity and acute toxicity assessment of triterpene acids. Parasitol Res 106:985–989CrossRefGoogle Scholar
  7. Frézard F, Demicheli C, Ribeiro RR (2009) Pentavalent antimonials: new perspectives for old drugs. Molecules 14:2317–2336PubMedCrossRefGoogle Scholar
  8. Grecco SS, Reimão JQ, Tempone AG, Sartorelli P, Cunha RL, Romoff P, Ferreira MJ, Fávero OA, Lago JH (2012) In vitro antileishmanial and antitrypanosomal activities of flavanones from Baccharis retusa DC. (Asteraceae). Exp Parasitol 130:141–145CrossRefGoogle Scholar
  9. Jarvis BB, Mokhtari-Rejali N, Schenkel EP, Barros CS, Matzenbacher NI (1991) Trichothecene mycotoxins from Brazilian Baccharis species. Phytochemistry 30:789–797CrossRefGoogle Scholar
  10. Kaur S, Kaur T, Garg N, Mukherjee S, Raina P, Athokpam V (2008) Effect of dose and route of inoculation on the generation of CD4+ Th1/Th2 type of immune response in murine visceral leishmaniasis. Parasitol Res 103:1413–1419PubMedCrossRefGoogle Scholar
  11. Kontogianni VG, Exarchou V, Troganis A, Gerothanassis IP (2009) Rapid and novel discrimination and quantification of oleanolic and ursolic acids in complex plant extracts using two-dimensional nuclear magnetic resonance spectroscopy-Comparison with HPLC methods. Anal Chim Acta 635:188–195PubMedCrossRefGoogle Scholar
  12. Labbe C, Rovirosa J, Faini F, Mahu M, San-Martin A, Castillo M (1986) Secondary metabolites from Chilean Baccharis species. J Nat Prod 49:517–518CrossRefGoogle Scholar
  13. Liu J (1995) Pharmacology of oleanolic acid and ursolic acid. J Ethnopharmacol 49:57–68PubMedCrossRefGoogle Scholar
  14. Liu J (2005) Oleanolic acid and ursolic acid: research perspectives. J Ethnopharmacol 100:92–94PubMedCrossRefGoogle Scholar
  15. Lúcio KA, Rocha Gda G, Monção-Ribeiro LC, Fernandes J, Takiya CM, Gattass CR (2011) Oleanolic acid initiates apoptosis in non-small cell lung cancer cell lines and reduces metastasis of a B16F10 melanoma model in vivo. PLoS One 6:e28596PubMedCentralPubMedCrossRefGoogle Scholar
  16. Masihi KN (2003) Concepts of immunostimulation to increase antiparasitic drug action. Parasitol Res 90(Suppl 2):S97–S104PubMedCrossRefGoogle Scholar
  17. Mishra J, Saxena A, Singh S (2007) Chemotherapy of leishmaniasis: past, present and future. Curr Med Chem 14:1153–1169PubMedCrossRefGoogle Scholar
  18. Muelas-Serrano S, Nogal JJ, Martínez-Díaz RA, Escario JA, Martínez-Fernández AR, Gómez-Barrio A (2000) In vitro screening of american plant extracts on Trypanosoma cruzi and Trichomonas vaginalis. J Ethnopharmacol 71:101–107PubMedCrossRefGoogle Scholar
  19. Musayeib NM, Mothana RA, Gamal AA, Al-Massarani SM, Maes L (2013) In vitro antiprotozoal activity of triterpenoid constituents of Kleinia odora growing in Saudi Arabia. Molecules 18:9207–9218PubMedCrossRefGoogle Scholar
  20. Nakaya M, Hamano S, Kawasumi M, Yoshida H, Yoshimura A, Kobayashi T (2011) Aberrant IL-4 production by SOCS3-over-expressing T cells during infection with Leishmania major exacerbates disease manifestations. Int Immunol 23:195–202PubMedCrossRefGoogle Scholar
  21. Ota H, Takashima Y, Matsumoto Y, Hayashi Y, Matsumoto Y (2008) Pretreatment of macrophages with the combination of IFN-gamma and IL-12 induces resistance to Leishmania major at the early phase of infection. J Vet Med Sci 70:589–593PubMedCrossRefGoogle Scholar
  22. Passero LF, Costa Bordon ML, De Carvalho AK, Martins LM, Corbett CE, Laurenti MD (2010) Exacerbation of Leishmania (Viannia) shawi infection in BALB/c mice after immunization with soluble antigen from amastigote forms. APMIS 118:973–981PubMedCrossRefGoogle Scholar
  23. Passero LFD, Bonfim-Melo A, Corbett CE, Laurenti MD, Toyama MH, de Toyama DO, Romoff P, Fávero OA, dos Grecco SS, Zalewsky CA, Lago JH (2011) Anti-leishmanial effects of purified compounds from aerial parts of Baccharis uncinella C. DC. (Asteraceae). Parasitol Res 108:529–536PubMedCrossRefGoogle Scholar
  24. Passero LFD, Carvalho AK, Bordon ML, Bonfim-Melo A, Toyama MH, Corbett CE, Laurenti MD (2012) Leishmania (Viannia) shawi purified antigens confer protection against murine cutaneous leishmaniasis. Inflamm Res 61:255–263PubMedCrossRefGoogle Scholar
  25. Passero LFD, Laurenti MD, Santos-Gomes G, Campos BLS, Sartorelli P, Lago (2013) In vivo antileishmanial activity of plant-based secondary metabolites. In: Rai M, Kon K (eds) Fighting multidrug resistance with herbal extracts, essential oils and their components, 1st edn. Academic, New York, pp 95–107Google Scholar
  26. Peixoto JA, Andrade E, Silva ML, Crotti AE, Cassio Sola Veneziani R, Gimenez VM, Januário AH, Groppo M, Magalhães LG, Dos Santos FF, Albuquerque S, da Silva Filho AA, Cunha WR (2011) Antileishmanial activity of the hydroalcoholic extract of Miconia langsdorffii, isolated compounds, and semi-synthetic derivatives. Molecules 16:1825–1833PubMedCrossRefGoogle Scholar
  27. Rath S, Trivelin LA, Imbrunito TR, Tomazela DM, Jesús MN, Marzal PC, Andrade Junior HF, Tempone AG (2003) Antimonials employed in the treatment of leishmaniaisis: the state of the art. Quim Nova 4:550–555CrossRefGoogle Scholar
  28. Rittig MG, Bogdan C (2000) Leishmania-host-cell interaction: complexities and alternative views. Parasitol Today 16:292–297PubMedCrossRefGoogle Scholar
  29. Rocha FJ, Schleicher U, Mattner J, Alber G, Bogdan C (2007) Cytokines, signaling pathways, and effector molecules required for the control of Leishmania (Viannia) braziliensis in mice. Infect Immun 75:3823–3832PubMedCentralPubMedCrossRefGoogle Scholar
  30. Saha AK, Mukherjee T, Bhaduri A (1986) Mechanism of action of amphotericin B on Leishmania donovani promastigotes. Mol Biochem Parasitol 19:195–200PubMedCrossRefGoogle Scholar
  31. Sannigrahi S, Mazumder UK, Pal D, Mishra SL (2012) Terpenoids of methanol extract of Clerodendrum infortunatum exhibit anticancer activity against Ehrlich’s ascites carcinoma (EAC) in mice. Pharm Biol 50:304–309PubMedCrossRefGoogle Scholar
  32. Santos DO, Coutinho CE, Madeira MF, Bottino CG, Vieira RT, Nascimento SB, Bernardino A, Bourguignon SC, Corte-Real S, Pinho RT, Rodrigues CR, Castro HC (2008) Leishmaniasis treatment—a challenge that remains: a review. Parasitol Res 103:1–10PubMedCrossRefGoogle Scholar
  33. Seebacher W, Simic N, Weis R, Saf R, Kunert O (2003) Complete assignments of 1H and 13C NMR resonances of oleanolic acid, 18α‐oleanolic acid, ursolic acid and their 11‐oxo derivatives. Magn Reson Chem 8:636–638CrossRefGoogle Scholar
  34. Silva Filho AA, Resende DO, Fukui MJ, Santos FF, Pauletti PM, Cunha WR, Silva ML, Gregório LE, Bastos JK, Nanayakkara NP (2009) In vitro antileishmanial, antiplasmodial and cytotoxic activities of phenolics and triterpenoids from Baccharis dracunculifolia D. C. (Asteraceae). Fitoterapia 80:478–482PubMedCrossRefGoogle Scholar
  35. Silveira FT, Lainson R, De Castro Gomes CM, Laurenti MD, Corbett CE (2009) Immunopathogenic competences of Leishmania (V.) braziliensis and L. (L.) amazonensis in American cutaneous leishmaniasis. Parasite Immunol 31:423–431PubMedCrossRefGoogle Scholar
  36. Sundar S, Chakravarty J (2013) Leishmaniasis: an update of current pharmacotherapy. Expert Opin Pharmacother 14:53–63PubMedCrossRefGoogle Scholar
  37. Verdi LG, Brighente IMC, Pizzolati MG (2005) Gênero Baccharis (Asteraceae): aspectos químicos, econômicos e biológicos. Quim Nova 28:85–94CrossRefGoogle Scholar
  38. Walker J, Saravia NG (2004) Inhibition of Leishmania donovani promastigote DNA topoisomerase I and human monocyte DNA topoisomerases I and II by antimonial drugs and classical antitopoisomerase agents. J Parasitol 90:1155–1162PubMedCrossRefGoogle Scholar
  39. Zdero C, Bohlmann F, Solomon JC, King RM, Robinson H (1988) Ent-clerodanes and other constituents from Bolivian Baccharis species. Phytochemistry 28:531–542CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Eduardo Seiji Yamamoto
    • 1
  • Bruno Luiz S. Campos
    • 1
  • Márcia Dalastra Laurenti
    • 1
  • João H.G. Lago
    • 2
  • Simone dos Santos Grecco
    • 3
  • Carlos E. P. Corbett
    • 1
  • Luiz Felipe D. Passero
    • 1
  1. 1.Laboratório de Patologia de Moléstias Infeciosas, Departamento de Patologia da Faculdade de Medicinada Universidade de São PauloSão PauloBrazil
  2. 2.Departamento de Ciências Exatas e da TerraUniversidade Federal de São PauloDiademaBrazil
  3. 3.Centro de Ciências Naturais e HumanasUniversidade Federal do ABCSanto AndréBrazil

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