In vitro effects of tropisetron and granisetron against Echinococcus granulosus (s.s.) protoscoleces by involvement of calcineurin and calmodulin

Abstract

Background Cystic echinococcosis (CE) is a disease caused by the larval stage of Echinococcus granulosus sensu lato (s.l.). The treatment of CE mainly relies on the use of benzimidazoles, which can commonly cause adverse side effects. Therefore, more efficient treatment options are needed. Drug repurposing is a useful approach for advancing drug development. We have evaluated the in vitro protoscolicidal effects of tropisetron and granisetron in E. granulosus sensu stricto (s.s.) and assessed the expression of the calcineurin (CaN) and calmodulin (CaM) genes, both of which have been linked to cellular signaling activities and thus are potentially promising targets for the development of drugs. Methods Protoscoleces (PSC) of E. granulosus (s.s.) (genotype G1) obtained from sheep hepatic hydatid cysts were exposed to tropisetron and granisetron at concentrations of 50, 150 and 250 µM for various periods of time up to 10 days. Cyclosporine A (CsA) and albendazole sulfoxide were used for comparison. Changes in the morphology of PSC were investigated by light microscopy and scanning electron microscopy. Gene expression was assessed using real-time PCR at the mRNA level for E. granulosus calcineurin subunit A (Eg-CaN-A), calcineurin subunit B (Eg-CaN-B) and calmodulin (Eg-CaM) after a 24-h exposure at 50 and 250 µM, respectively. Results At 150 and 250 µM, tropisetron had the highest protoscolicidal effect, whereas CsA was most effective at 50 µM. Granisetron, however, was less effective than tropisetron at all three concentrations. Examination of morphological alterations revealed that the rate at which PSC were killed increased with increasing rate of PSC evagination, as observed in PSC exposed to tropisetron. Gene expression analysis revealed that tropisetron at 50 μM significantly upregulated Eg-CaN-B and Eg-CaM expression while at 250 μM it significantly downregulated both Eg-CaN-B and Eg-CaM expressions; in comparison, granisetron decreased the expression of all three genes at both concentrations. Conclusions Tropisetron exhibited a higher efficacy than granisetron against E. granulosus (s.s.) PSC, which is probably due to the different mechanisms of action of the two drugs. The concentration-dependent effect of tropisetron on calcineurin gene expression might reflect its dual functions, which should stimulate future research into its mechanism of action and evaluation of its potential therapeutical effect in the treatment of CE. Graphic Abstract

The Possible Protective Effects of Ondansetron and Tropisetron on Optic Nerve Crush Injury in Rats

“…5-HT3R antagonists, including ondansetron, tropisetron, and granisetron, are primarily used to avert nausea and vomiting after chemotherapy and radiation. Experimental studies showed diverse positive effects of these agents, e.g., anti-depressant effects of ondansetron and tropisetron in rodents [32], diminution of colitis-associated cancer by tropisetron in mice [33], anti-inflammatory and anti-oxidant properties of tropisetron in early diabetic nephropathy of rats [34], suppression of vincristine-induced neuropathy by tropisetron in rats [35], and parasiticidal effects of tropisetron and granisetron against Echinococcus granulosus in-vitro [36]. Ondansetron and tropisetron are 5-HT3R antagonists with various distributions in CNS.…”

Medical management of cystic echinococcosis

“…Both tropisetron and granisetron have dose-dependent protoscolecidal activity, much more so in the case of tropisetron, possibly because of its additional mode of action. Furthermore, tropisetron was more effective than albendazole sulfoxide at the concentrations tested [14 ▪▪ ]. A clinical trial of tropisetron pre and post PAIR or operative surgery should be considered.…”