RESUMEN
Visceral leishmaniasis (VL) is a chronic and systemic disease; if untreated, it can cause death in a large number of cases. The therapy is based on the use of antimonials, which have been used for over 50 years. However, cases of resistance have been reported in some countries. In this context, miltefosine (MIL) was introduced to treat antimonial unresponsive cases. Nonetheless, in recent years MIL unresponsive and relapse cases of VL have increasingly been reported. In the current study, the therapeutic potential of compound 5-(4-(3-methanesulfonatepropyl)-1H-1,2,3-triazol-1-yl)dodecyl methanesulfonate (C11), an MIL derivative, was assessed in an experimental VL hamster model. For this purpose, golden hamsters (Mesocricetus auratus) were infected with Leishmania (L.) infantum chagasi and treated daily for 10 days with C11 and MIL administered orally; in addition, Glucantime (GLU), peritoneal route, were administered at 15, 10, 50 mg/kg body weight/day, respectively. Twenty four hours after the end of treatment the animals were euthanatized; and the specimens were collected to evaluate the relative mRNA expression of cytokines IFN-γ, TNF-α, IL-17, TGF-ß, IL-4 and IL-10 in fragments of the spleen and liver; moreover, the parasitism in these organs was evaluated as well as the main histopathological alterations. The C11-treated animals showed greater expression of IL-17 and TNF-α cytokines and reduced expression of IL-10 in the spleen in comparison to the infected untreated group (UTG) (p <0.05). The C11 and GLU groups showed a significant reduction in the IgG levels in comparison to the UTG group (p <0.05). Moreover, the C11-treated animals had fewer parasites in the spleen than the UTG animals (reduction of 95.9%), as well as a greater preservation of white pulp architecture in the spleen than the UTG, GLU and MIL groups (p <0.05). For the liver, the animals from the C11 and MIL groups showed a significant increase in TNF-α relative expression in comparison to the UTG animals, which would explain the increase in the number of granulomas and the reduction in the parasitic load (p <0.05). Combined, these findings indicate that C11 is an interesting compound that should be considered for the development of new drugs against VL, mainly due to its leishmanicidal effect and immunostimulating action.
Asunto(s)
Antiprotozoarios/uso terapéutico , Leishmaniasis Visceral/tratamiento farmacológico , Fosforilcolina/análogos & derivados , Animales , Antiprotozoarios/farmacología , Cricetinae , Citocinas/genética , Leishmania infantum , Leishmaniasis Visceral/inmunología , Masculino , Antimoniato de Meglumina/uso terapéutico , Mesocricetus , Fosforilcolina/uso terapéutico , Bazo/parasitologíaRESUMEN
Despite defenses by polymorphonuclear neutrophils in the host against invading agents, overproduction of oxidant species by phagocytes can lead to damage in the surrounding tissues. Several benzophenones have been shown to possess anti-inflammatory properties. The effect of the natural benzophenone 7-epiclusianone isolated from leaves of Garcinia brasiliensis was investigated by using in vitro antioxidant and ex vivo anti-inflammatory assays, focusing on the neutrophil respiratory burst and on the biochemical pathways involved. The bioactive extract, 7-epiclusianone, showed low in vitro antioxidant activity as evaluated by the 2,2-diphenyl-1-picrylhydrazyl free radical scavenging assay, the reducing power test, or the chelating power assay. However, the benzophenone displayed potent activity in the ex vivo model of the neutrophil respiratory burst, inhibiting the generation of superoxide anions in a dose-dependent manner. When the respiratory burst was triggered by N-formyl-methionyl-leucyl-phenylalanine, a chemotactic peptide, the 50% effective concentration (EC(50)) was 41.18 µg/10(7) cells. When phagocytes were stimulated directly through protein kinase C via phorbol, the EC(50) was 34.3 µg/10(6) cells. The results indicated that 7-epiclusianone was able to down-regulate inflammatory phagocyte superoxide anion release through a mechanism controlled by tyrosine protein phosphorylation and by a direct stimulation of protein kinase C. These findings could lead to new therapeutic approaches for inflammation management and the development of new drugs.