Epiisopilosine alkaloid has activity against Schistosoma mansoni in mice without acute toxicity

PLoS One. 2018 May 11;13(5):e0196667. doi: 10.1371/journal.pone.0196667. eCollection 2018.

Abstract

Schistosomiasis is a disease caused by parasites of the genus Schistosoma, currently affecting more than 200 million people. Among the various species of this parasite that infect humans, S. mansoni is the most common. Pharmacological treatment is limited to the use of a single drug, praziquantel (PZQ), despite reports of parasite resistance and low efficacy. It is therefore necessary to investigate new potential schistosomicidal compounds. In this study, we tested the efficacy of epiisopilosine (EPIIS) in a murine model of schistosomiasis. A single dose of EPIIS (100 or 400 mg/kg) administered orally to mice infected with adult S. mansoni resulted in reduced worm burden and egg production. The treatment with the lower dose of EPIIS (100 mg/kg) significantly reduced total worm burden by 60.61% (P < 0.001), as well as decreasing hepatosplenomegaly and egg excretion. Scanning electron microscopy revealed morphological changes in the worm tegument after treatment. Despite good activity of EPIIS in adult S. mansoni, oral treatment with single dose of EPIIS 100 mg/kg had only moderate effects in mice infected with juvenile S. mansoni. In addition, we performed cytotoxicity and toxicological studies with EPIIS and found no in vitro cytotoxicity (in HaCaT, and NIH-3T3 cells) at a concentration of 512 μg/mL. We also performed in silico analysis of toxicological properties and showed that EPIIS had low predicted toxicity. To confirm this, we investigated systemic acute toxicity in vivo by orally administering a 2000 mg/kg dose to Swiss mice. Treated mice showed no significant changes in hematological, biochemical, or histological parameters compared to non-treated animals. Epiisopilosine showed potential as a schistosomicidal drug: it did not cause acute toxicity and it displayed an acceptable safety profile in the animal model.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaloids / pharmacology*
  • Animals
  • Cell Line
  • Disease Models, Animal
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • NIH 3T3 Cells
  • Parasite Egg Count / methods
  • Praziquantel / pharmacology
  • Schistosoma mansoni / drug effects*
  • Schistosomiasis mansoni / drug therapy*
  • Schistosomiasis mansoni / parasitology
  • Schistosomicides / pharmacology

Substances

  • Alkaloids
  • Schistosomicides
  • Praziquantel

Grant support

The authors are grateful to Phytobios Pesquisa Desenvolvimento e Inovação LTDA., company of the Centroflora Group, for its support during the realization of this research. SMA is grateful to Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (MCTI/Cnpq/MS-SCTIE DECIT N. 404134/2012-2). ACM is grateful to Foundation for Research Support of São Paulo State (FAPESP) (Grants 2014/02282-76 and 2016/18023-5). JM is grateful to FAPESP (Grant 2016/22488-3). Phytobios company played a role in the study design, data analysis, decision to publish and preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. The other funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.