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Antileishmanial Activity of the Terpene Nerolidol

2005; American Society for Microbiology; Volume: 49; Issue: 5 Linguagem: Inglês

10.1128/aac.49.5.1679-1687.2005

1098-6596

Denise C. Arruda, Fabio Luiz D’Alexandri, Alejandro M. Katzin, Sílvia Reni Bortolin Uliana,

Bioactive Compounds and Antitumor Agents

ABSTRACT The activity of nerolidol, a sesquiterpene used as a food-flavoring agent and currently under testing as a skin penetration enhancer for the transdermal delivery of therapeutic drugs, was evaluated against Leishmania species. Nerolidol inhibited the growth of Leishmania amazonensis , L. braziliensis , and L. chagasi promastigotes and L. amazonensis amastigotes with in vitro 50% inhibitory concentrations of 85, 74, 75, and 67 μM, respectively. The treatment of L. amazonensis -infected macrophages with 100 μM nerolidol resulted in 95% reduction in infection rates. Inhibition of isoprenoid biosynthesis, as shown by reduced incorporation of [2- 14 C]mevalonic acid (MVA) or [1- 14 C]acetic acid precursors into dolichol, ergosterol, and ubiquinone, was observed in nerolidol-treated promastigotes. This drug effect can be attributed to the blockage of an early step in the mevalonate pathway, since incorporation of the precursor [1( n )- 3 H]farnesyl pyrophosphate in polyisoprenoids is not inhibited by nerolidol. L. amazonensis -infected BALB/c mice were treated with intraperitoneal doses of 100 mg/kg/day for 12 days or topically with 5 or 10% ointments for 4 weeks. Significant reduction of lesion sizes in nerolidol treated mice was observed for both treatment routes. However, long-term follow up indicated that the disease was not cured in this highly susceptible animal model. Nonetheless, the in vitro activity of nerolidol against these parasites may prove a useful tool for the development of new drugs for the treatment of leishmaniasis. In addition, biosynthesis of dolichols with 11 and 12 isoprene units was identified in Leishmania , as described for other trypanosomatids and Apicomplexa.