RESUMEN
Four sesquiterpene lactones, mikanolide, deoxymikanolide, dihydromikanolide and scandenolide, were isolated by a bioassay-guided fractionation of Mikania variifolia and Mikania micrantha dichloromethane extracts. Mikanolide and deoxymikanolide were the major compounds in both extracts (2.2% and 0.4% for Mikania variifolia and 21.0% and 6.4% for Mikania micrantha respectively, calculated on extract dry weight). Mikanolide, deoxymikanolide and dihydromikanolide were active against Trypanosoma cruzi epimastigotes (50% inhibitory concentrations of 0.7, 0.08 and 2.5 µg/mL, for each compound respectively). These sesquiterpene lactones were also active against the bloodstream trypomastigotes (50% inhibitory concentrations for each compound were 2.1, 1.5 and 0.3 µg/mL, respectively) and against amastigotes (50% inhibitory concentrations for each compound were 4.5, 6.3 and 8.5 µg/mL, respectively). By contrast, scandenolide was not active on Trypanosoma cruzi. Besides, mikanolide and deoxymikanolide were also active on Leishmania braziliensis promastigotes (50% inhibitory concentrations of 5.1 and 11.5 µg/mL, respectively). The four sesquiterpene lactones were tested for their cytotoxicity on THP 1 cells. Deoxymikanolide presented the highest selectivity index for trypomastigotes (SI = 54) and amastigotes (SI = 12.5). In an in vivo model of Trypanosoma cruzi infection, deoxymikanolide was able to decrease the parasitemia and the weight loss associated to the acute phase of the parasite infection. More importantly, while 100% of control mice died by day 22 after receiving a lethal T. cruzi infection, 70% of deoxymikanolide-treated mice survived. We also observed that this compound increased TNF-α and IL-12 production by macrophages, which could contribute to control T. cruzi infection.
Asunto(s)
Lactonas/farmacología , Leishmania braziliensis/efectos de los fármacos , Mikania/química , Extractos Vegetales/farmacología , Sesquiterpenos/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/parasitología , Descubrimiento de Drogas , Interleucina-12/biosíntesis , Interleucina-12/inmunología , Lactonas/administración & dosificación , Lactonas/química , Lactonas/aislamiento & purificación , Lactonas/uso terapéutico , Estadios del Ciclo de Vida/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , Extractos Vegetales/química , Sesquiterpenos/química , Sesquiterpenos/aislamiento & purificación , Sesquiterpenos de Germacrano/administración & dosificación , Sesquiterpenos de Germacrano/aislamiento & purificación , Sesquiterpenos de Germacrano/farmacología , Sesquiterpenos de Germacrano/uso terapéutico , Trypanosoma cruzi/aislamiento & purificación , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
The aim of this study was to investigate the antiprotozoal and antiviral activities of four Argentinean Mikania species. The organic and aqueous extracts of Mikania micrantha, M. parodii, M. periplocifolia, and M. cordifolia were tested on Trypanosoma cruzi epimastigotes, Leishmania braziliensis promastigotes, and dengue virus type 2. The organic extract of M. micrantha was the most active against T. cruzi and L. braziliensis exhibiting a growth inhibition of 77.6 ± 4.5% and 84.9 ± 6.1%, respectively, at a concentration of 10 µg/ml. The bioguided fractionation of M. micrantha organic extract led to the identification of two active fractions. The chromatographic profile and infrared analysis of these fractions revealed the presence of sesquiterpene lactones. None of the tested extracts were active against dengue virus type 2.