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Background  Echinococcosis, which is caused by the larvae of cestodes of the genus  Echinococcus , is a parasitic zoonosis that poses a serious threat to the health of humans and animals globally. Albendazole is the drug of choice for the treatment of echinococcosis, but it is difficult to meet clinical goals with this chemotherapy due to its low cure rate and associated side effects after its long-term use. Hence, novel anti-parasitic targets and effective treatment alternatives are urgently needed. A previous study showed that verapamil (Vepm) can suppress the growth of  Echinococcus granulosus  larvae; however, the mechanism of this effect remains unclear. The aim of the present study was to gain insight into the anti-echinococcal effect of Vepm on  Echinococcus  with a particular focus on the regulatory effect of Vepm on calcium/calmodulin-dependent protein kinase II (Ca 2+ /CaM-CaMKII) in infected mice.    Methods  The anti-echinococcal effects of Vepm on  Echinococcus granulosus  protoscoleces (PSC)  in vitro  and  Echinococcus multilocularis  metacestodes in infected mice were assessed. The morphological alterations in  Echinococcus  spp. induced by Vepm were observed by scanning electron microscopy (SEM), and the changes in calcium content in both the parasite and mouse serum and liver were measured by SEM-energy dispersive spectrometry, inductively coupled plasma mass spectrometry and alizarin red staining. Additionally, the changes in the protein and mRNA levels of CaM and CaMKII in infected mice, and in the mRNA levels of  CaMKII  in  E. granulosus  PSC, were evaluated after treatment with Vepm by immunohistochemistry and/or real-time quantitative polymerase chain reaction.    Results   In vitro ,  E. granulosus  PSC could be killed by Vepm at a concentration of 0.5 μg/ml or higher within 8 days. Under these conditions, the ultrastructure of PSC was damaged, and this damage was accompanied by obvious calcium loss and downregulation of  CaMKII  mRNA expression.  In vivo , the weight and the calcium content of  E. multilocularis  metacestodes from mice were reduced after treatment with 40 mg/kg Vepm, and an elevation of the calcium content in the sera and livers of infected mice was observed. In addition, downregulation of CaM and CaMKII protein and mRNA expression in the livers of mice infected with  E. multilocularis  metacestodes was found after treatment with Vepm.    Conclusions  Vepm exerted a parasiticidal effect against  Echinococcus  both  in vitro  and  in vivo  through downregulating the expression of Ca 2+ /CaM-CaMKII, which was over-activated by parasitic infection. The results suggest that Ca 2+ /CaM-CaMKII may be a novel drug target, and that Vepm is a potential anti-echinococcal drug for the future control of echinococcosis.

parasites and vectors

Anti-echinococcal effect of verapamil involving the regulation of the calcium/calmodulin-dependent protein kinase II response in vitro and in a murine infection model