Resveratrol against Echinococcus sp.: Discrepancies between In Vitro and In Vivo Responses

Abstract

In an attempt to find new anti-echinococcal drugs, resveratrol (Rsv) effectiveness against the larval stages of Echinococcus granulosus and E. multilocularis was evaluated. The in vitro effect of Rsv on parasites was assessed via optical and electron microscopy, RT-qPCR and immunohistochemistry. In vivo efficacy was evaluated in murine models of cystic (CE) and alveolar echinococcosis (AE). The impact of infection and drug treatment on the mouse bone marrow hematopoietic stem cell (HSC) population and its differentiation into dendritic cells (BMDCs) was investigated via flow cytometry and RT-qPCR. In vitro treatment with Rsv reduced E. granulosus metacestode and protoscolex viability in a concentration-dependent manner, caused ultrastructural damage, increased autophagy gene transcription, and raised Eg-Atg8 expression while suppressing Eg-TOR. However, the intraperitoneal administration of Rsv was not only ineffective, but also promoted parasite development in mice with CE and AE. In the early infection model of AE treated with Rsv, an expansion of HSCs was observed followed by their differentiation towards BMCDs. The latter showed an anti-inflammatory phenotype and reduced LPS-stimulated activation compared to control BMDCs. We suggest that Rsv ineffectiveness could have been caused by the low intracystic concentration achieved in vivo and the drug’s hormetic effect, with opposite anti-parasitic and immunomodulatory responses in different doses.

Enemies or Allies? Hormetic and Apparent Non-Dose-Dependent Effects of Natural Bioactive Antioxidants in the Treatment of Inflammation

“…In the literature, there are other studies in which the activity of resveratrol does not depend on the dose, but those are not classified as hormetic responses [118][119][120]. However, as was the case with the examples of this type using curcumin, these studies were performed with a reduced number of subjects, so they must be taken with some caution.…”

“…It is also possible that these responses hide other unforeseen effects, such as reactions that are related to a cumulative dose or saturation of the absorption of the compound by the individual. Another issue to consider is, as already indicated, that some of these studies have been conducted with a limited number of subjects, which can reduce the statistical validity of the results [100,101,[118][119][120].…”