Paradoxical pharmacology effect of resveratrol against Echinococcosis

Abstract

Resveratrol (Rsv) is a phytoalexin with antibacterial, anticancer and antiparasite properties. We analyzed for the first time the pharmacological effects of resveratrol (Rsv) on Echinococcus granulosus sensu lato complex and E. multilocularis. In vitro treatment with 50 and 100 μM Rsv reduced the viability of E. granulosus metacestodes and protoscoleces by at least 75% after 4 and 13 days, respectively. Rsv treatment caused deleterious ultrastructural effects in metacestodes, increased the transcription of autophagy genes, and raised Eg-Atg8 expression while suppresed Eg-TOR, leading to autophagy and parasite death. However, the intraperitoneal administration of Rsv (100 mg kg−1 day−1) was not only ineffective, but also promoted parasite development in mice with cystic and alveolar echinococcosis. We also showed in early alveolar echinococcosis treated with Rsv a hematopoietic stem cell expansion followed by their differentiation towards dendritic cells (BMCDs), with CD80, CD86 and MHCII induction. BMDCs from early stage of AE infection produce high gene expression levels of IL-6 and TGF-β, which could to determine T cell activation and polarization to Th17 subset, characteristic of the immune response during early infection phase. Contrarily, BMDCs from Rsv-treated AE mice inhibited-transcription of IL-6 (p<0.01), TNFα (p<0.05), TGFβ (p<0.05) and IL-10 (p<0.05), as well as it provoked a reduction of LPS-stimulated BMDC activation in comparison with control BMDCs, provoking an anti-inflammatory response in BMDCs from Rsv-treated mice. We suggest that Rsv ineffectiveness could be caused by the low intracystic concentration (≈ 30 ± 2 μM) achieved in vivo and the drug´s hormetic effect, which accounts for the opposite anti-parasitic and immodulatory responses at different doses. Therefore, our assays do not allow us to propose to the RSV as a drug for the treatment of CE neither AE, due to it was perhaps not delivered and accumulated in the parasite in optimal amounts.