Department of Medical Parasitology and Mycology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
Cell-Based Therapies Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
Parasit Vectors. 2021 Apr 12;14(1):197. doi: 10.1186/s13071-021-04691-9.
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.
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.
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.
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.
包虫病（CE）是由细粒棘球绦虫幼虫引起的疾病。CE 的治疗主要依赖于苯并咪唑类药物，但这些药物通常会引起不良反应。因此，需要寻找更有效的治疗方法。药物再利用是推进药物开发的一种有用方法。我们评估了托烷司琼和格拉司琼对细粒棘球蚴（s.s.）的原头蚴杀虫作用，并评估了钙调磷酸酶（CaN）和钙调蛋白（CaM）基因的表达，这两个基因都与细胞信号转导活动有关，因此可能是开发药物的有前途的靶点。
从绵羊肝包虫囊肿中获得细粒棘球蚴（s.s.）（基因型 G1）的原头蚴（PSC），用托烷司琼和格拉司琼在 50、150 和 250 μM 下暴露不同时间，最长达 10 天。环孢菌素 A（CsA）和阿苯达唑砜用于比较。通过光镜和扫描电子显微镜观察 PSC 形态变化。在 50 和 250 μM 下分别暴露 24 小时后，通过实时 PCR 在 mRNA 水平评估 Eg-CaN-A、Eg-CaN-B 和 Eg-CaM 的基因表达。
在 150 和 250 μM 时，托烷司琼的原头蚴杀虫作用最高，而 CsA 在 50 μM 时最有效。然而，在所有三个浓度下，格拉司琼的效果都不如托烷司琼。形态改变的检查表明，随着 PSC 外翻率的增加，PSC 的死亡率增加，这在暴露于托烷司琼的 PSC 中观察到。基因表达分析表明，托烷司琼在 50 μM 时显著上调 Eg-CaN-B 和 Eg-CaM 的表达，而在 250 μM 时显著下调 Eg-CaN-B 和 Eg-CaM 的表达；相比之下，格拉司琼在两个浓度下均降低了三个基因的表达。
托烷司琼对细粒棘球蚴（s.s.）PSC 的疗效高于格拉司琼，这可能是由于两种药物的作用机制不同。托烷司琼对钙调磷酸酶基因表达的浓度依赖性作用可能反映了其双重功能，这应刺激对其作用机制的进一步研究，并评估其在治疗包虫病中的潜在治疗效果。
