In vitro and in vivo effects of 3-bromopyruvate against Echinococcus metacestodes

Qi Xin,Tao Jing,Xiaoxia Song,Miaomiao Yuan,Jun Lu,Huanping Li

doi:10.1186/s13567-019-0710-7

Abstract

While searching for novel anti-echinococcosis drugs, we have been focusing on glycolysis which is relied on by Echinococcus for energy production and intermediates for other metabolic processes. The aim of this study was to investigate the potential therapeutic implication of glycolytic inhibitors on Echinococcus. Our results demonstrate that at an initial concentration of 40 μM, all inhibitors of glycolysis used in the current experiment [3-bromopyruvate (3-BrPA), ornidazole, clorsulon (CLS), sodium oxamate and 2,6-dihydroxynaphthalene (NA-P2)] show considerable in vitro effects against Echinococcus granulosus protoscoleces and Echinococcus multilocularis metacestodes. Among them, 3-BrPA exhibited the highest activity which was similar to that of nitazoxanide (NTZ) and more efficacious than albendazole (ABZ). The activity of 3-BrPA was dose dependent and resulted in severe ultrastructural destructions, as visualized by electron microscopy. An additional in vivo study in mice infected with E. multilocularis metacestodes indicates a reduction in parasite weight after the twice-weekly treatment of 25 mg/kg 3-BrPA for 6 weeks, compared to that of the untreated control. In particular, in contrast to ABZ, the administration of 25 mg/kg 3-BrPA did not cause toxicity to the liver and kidney in mice. Similarly, at the effective dose against Echinococcus larvae, 3-BrPA showed no significant toxicity to human hepatocytes. Taken together, the results suggest that interfering with the glycolysis of the parasite may be a novel chemotherapeutical option and 3-BrPA, which exhibited a remarkable activity against Echinococcus, may be a promising potential drug against cystic echinococcosis (CE) and alveolar echinococcosis (AE).

Highlights

Echinococcosis, caused by the larval stage of the parasitic cestode Echinococcus is a serious but neglected helminthic zoonosis
In vitro effectivities of the selected glycolytic inhibitors against E. granulosus protoscoleces We investigated the in vitro effectivities of the selected glycolytic inhibitors on E. granulosus protoscoleces in comparison to that of NTZ, which served as a positive control, using an initial concentration of 40 μM and a treatment course of 7 days
The results demonstrate that, in comparison to the dimethyl sulfoxide (DMSO) control group, in vitro treatment with each of the selected glycolytic inhibitors could result in an increased release of AP activity, which indicates the damage to metacestodes

Summary

Introduction

Echinococcosis, caused by the larval stage of the parasitic cestode Echinococcus is a serious but neglected helminthic zoonosis. Cystic echinococcosis (CE) caused by Echinococcus granulosus is endemic in regions of western and central Europe, eastern Europe, North America and Asia, in China [1], where CE is endemic in at least 23 provinces, with an estimated 380,000 patients and nearly 66 million individuals at risk of infection [2, 3]. Alveolar echinococcosis (AE) caused by Echinococcus multilocularis is endemic in the Northern hemisphere, and the greatest prevalence is found in Central Asia, Russia, north-western China, parts of Europe and Japan [4]. Most of the disease (over 90%) of AE occurs in western China [5] Both diseases are acquired through the accidental ingestion of parasite eggs shed by the definitive hosts (mainly dogs for E. granulosus and foxes and dogs for E. multilocularis). The larval stage of Echinococcus proliferate asexually in humans or other intermediate hosts, leading to space-occupying lesions, organ malfunction and even death [6]

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