The Effect of Ursolic Acid on Leishmania (Leishmania) amazonensis Is Related to Programed Cell Death and Presents Therapeutic Potential in Experimental Cutaneous Leishmaniasis

Author(s):Show less -

Yamamoto, Eduardo S. ^[1] ; Campos, Bruno L. S. ^[1] ; Jesus, Jessica A. ^[1] ; Laurenti, Marcia D. ^[1] ; Ribeiro, Susan P. ^{[2, 3]} ; Kallas, Esper G. ^[2] ; Rafael-Fernandes, Mariana ^[4] ; Santos-Gomes, Gabriela ^[4] ; Silva, Marcelo S. ^[4] ; Sessa, Deborah P. ^[5] ; Lago, Joao H. G. ^[5] ; Levy, Debora ^[6] ; Passero, Luiz F. D. ^[1]

Affiliation

^[1] Univ Sao Paulo, Lab Pathol Infect Dis LIM50, Dept Pathol, Sch Med, BR-01246903 Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Lab Clin Immunol & Allergy LIM60, Sch Med, BR-01246903 Sao Paulo, SP - Brazil

^[3] Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 - USA

^[4] Univ Nova Lisboa, Global Hlth & Trop Med, IHMT, P-1349008 Lisbon - Portugal

^[5] Univ Fed Sao Paulo, Inst Environm Chem & Pharmaceut Sci, BR-09920000 Diadema, SP - Brazil

^[6] Univ Sao Paulo, Lab Genet & Mol Hematol LIM31, Sch Med, BR-01246903 Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: PLoS One; v. 10, n. 12 DEC 16 2015.
• Web of Science Citations: 18

Abstract

Among neglected tropical diseases, leishmaniasis is one of the most important ones, affecting more than 12 million people worldwide. The available treatments are not well tolerated, and present diverse side effects, justifying the search for new therapeutic compounds. In the present study, the activity of ursolic acid (UA) and oleanolic acid (OA) were assayed in experimental cutaneous leishmaniasis (in vitro and in vivo). Promastigote forms of L. amazonensis were incubated with OA and UA for 24h, and effective concentration 50% (EC50) was estimated. Ultraestructural alterations in Leishmania amazonensis promastigotes after UA treatment were evaluated by transmission electron microscopy, and the possible mode of action was assayed through Annexin V and propidium iodide staining, caspase 3/7 activity, DNA fragmentation and transmembrane mitochondrial potential. The UA potential was evaluated in intracellular amastigotes, and its therapeutic potential was evaluated in L. amazonensis infected BALB/c mice. UA eliminated L. amazonensis promastigotes with an EC50 of 6.4 mu g/mL, comparable with miltefosine, while OA presented only a marginal effect on promastigote forms at 100 mu g/mL. The possible mechanism by which promastigotes were eliminated by UA was programmed cell death, independent of caspase 3/7, but it was highly dependent on mitochondria activity. UA was not toxic for peritoneal macrophages from BALB/c mice, and it was able to eliminate intracellular amastigotes, associated with nitric oxide (NO) production. OA did not eliminate amastigotes nor trigger NO. L. amazonensis infected BALB/c mice submitted to UA treatment presented lesser lesion size and parasitism compared to control. This study showed, for the first time, that UA eliminate promastigote forms through a mechanism associated with programed cell death, and importantly, was effective in vivo. Therefore, UA can be considered an interesting candidate for future tests as a prototype drug for the treatment of cutaneous leishmaniasis. (AU)

• FAPESP's process: 12/03903-9 - Analysis of the effects of the purified oleanolic and ursolic acids from Baccharis uncinella in infected BALB/c mice with Leishmania (Leishmania) amazonensis
• Grantee: Eduardo Seiji Yamamoto
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 13/16297-2 - Analysis of anti-Leishmania and anti-Tripanosoma potencials of oleanolic and ursolic acids
• Grantee: Luiz Felipe Domingues Passero
• Support Opportunities: Regular Research Grants