Influence of various structural patterns in a series of novel bi- and tricyclic N-heterocycles on the activity against Leishmania major and Leishmania panamensis has been studied and compounds that are active in the low micromolar region have been identified. Both quinolines and tetrahydrooxazinoindoles (TOI) proved to have significant antileishmanial activities, while substituted indoles were inactive. We have also showed that a chloroquine analogue induces Leishmania killing by modulating macrophage activation.
Leishmania panamensis
is a relevant causative agent of tegumentary leishmaniasis in several Latin American countries. Available antileishmanial drugs have several limitations including relatively high toxicity, difficult administration, high production costs and the emergence of resistance in circulating strains. Therefore, the identification of new molecules as potential therapeutics for leishmaniasis is of great relevance. Here, we developed a murine model of
L. panamensis
infection and evaluated the effect of a new compound
in vivo
. After treatment of animals with the compound, we observed a significant reduction of inflammation and parasite load at the inoculation site, in a dose-dependent manner. We observed a reduction in IL-10 production by popliteal lymph nodes cells of infected mice. These results pave the way for future evaluation of this compound as a potential antileishmanial drug or as a suitable scaffold for lead optimization strategies.
Leishmania parasites can trigger different host immune responses that result in varying levels of disease severity. The C57BL/6 and BALB/c mouse strains are among the host models commonly used for characterizing the immunopathogenesis of Leishmania species and the possible antileishmanial effect of novel drug candidates. C57BL/6 mice tend to be resistant to Leishmania infections, whereas BALB/c mice display a susceptible phenotype. Studying species-specific interactions between Leishmania parasites and different host systems is a key step to characterize and validate these models for in vivo studies. Here, we use RNA-Seq and differential expression analysis to characterize the transcriptomic profiles of C57BL/6 and BALB/c peritoneal-derived macrophages in response to Leishmania panamensis infection. We observed differences between BALB/c and C57BL/6 macrophages regarding pathways associated with lysosomal degradation, arginine metabolism and the regulation of cell cycle. We also observed differences in the expression of chemokine and cytokine genes associated with regulation of immune responses. In conclusion, infection with L. panamensis induced an inflammatory gene expression pattern in C57BL/6 macrophages that is more consistently associated with a classic macrophage M1 activation, whereas in BALB/c macrophages a gene expression pattern consistent with an intermediate inflammatory response was observed.
En los animales de laboratorio, se conoce que los procedimientos de rutina como la manipulación, la sujeción, las inyecciones o la toma de muestras de sangre provocan una respuesta aguda de estrés. El objetivo de este ensayo fue determinar si la condición de enriquecimiento del alojamiento de las ratas Sprague Dawley producidas en el Bioterio de INDICASAT-AIP, puede favorecer una conducta ansiolítica luego de un procedimiento aversivo como la toma de muestra de sangre. Al destete, los animales se segregaron en 2 grupos que incluyeron: grupo con y sin enriquecimiento. El enriquecimiento ambiental consistió en 2 tubos de policloruro de vinilo por caja. Ocho semanas después, los animales se sometieron a las pruebas de conducta de campo abierto y laberinto en cruz elevado antes y después de un procedimiento de toma de muestra sanguínea vía retroorbital previa sedación con isofluorano. En los parámetros valorados en campo abierto: tiempo de movilidad e inmovilidad, no se observó un efecto significativo entre los grupos con enriquecimiento y sin enriquecimiento. En relación a los parámetros del laberinto en cruz elevado, se encontró que los animales alojados en el ambiente con enriquecimiento pasaron en promedio una mayor cantidad de tiempo (35±21s), en brazos abiertos, que el grupo sin enriquecimiento (7±6s). Estos datos permitieron comprobar que el enriquecimiento ayudó a disminuir la ansiedad en las ratas del ensayo, luego de ser sometidas a un procedimiento aversivo como la toma de muestra sanguínea.
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