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

CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPSchistosomiasis 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 limited135119CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPCONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP404134/2012-22014/02282-76, 2016/18023-5, 2016/22488-3The 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

Anthelmintic Activity In Vivo of Epiisopiloturine against Juvenile and Adult Worms of Schistosoma mansoni

Schistosomiasis is a serious disease currently estimated to affect more that 207 million people worldwide. Due to the intensive use of praziquantel, there is increasing concern about the development of drug-resistant strains. Therefore, it is necessary to search for and investigate new potential schistosomicidal compounds. This work reports the in vivo effect of the alkaloid epiisopiloturine (EPI) against adults and juvenile worms of Schistosoma mansoni. EPI was first purified its thermal behavior and theoretical solubility parameters charaterised. In the experiment, mice were treated with EPI over the 21 days post-infection with the doses of 40 and 200 mg/kg, and 45 days post-infection with single doses of 40, 100 and 300 mg/kg. The treatment with EPI at 40 mg/kg was more effective in adult worms when compared with doses of 100 and 300 mg/kg. The treatment with 40 mg/kg in adult worms reduced parasite burden significantly, lead to reduction in hepatosplenomegaly, reduced the egg burden in faeces, and decreased granuloma diameter. Scanning electron microscopy revealed morphological changes to the parasite tegument after treatment, including the loss of important features. Additionally, the in vivo treatment against juvenile with 40 mg/kg showed a reduction of the total worm burden of 50.2%. Histopathological studies were performed on liver, spleen, lung, kidney and brain and EPI was shown to have a DL50 of 8000 mg/kg. Therefore EPI shows potential to be used in schistosomiasis treatment. This is the first time that schistosomicidal in vivo activity of EPI has been reported

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

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

The Skin Secretion of the Amphibian Phyllomedusa nordestina: A Source of Antimicrobial and Antiprotozoal Peptides

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Hematological parameters of Swiss mice treated with EPIIS by oral route.

<p>Hematological parameters of Swiss mice treated with EPIIS by oral route.</p

Biochemical parameters in sera obtained from Swiss mice treated with EPIIS by oral route.

<p>Biochemical parameters in sera obtained from Swiss mice treated with EPIIS by oral route.</p

<i>In silico</i> analysis of toxicological properties of EPIIS predicted using the pkCSM methodology.

<p><i>In silico</i> analysis of toxicological properties of EPIIS predicted using the pkCSM methodology.</p

<i>In vitro</i> cytotoxicity assay with EPIIS.

<p>Adhesion indices of NIH-3T3 and HaCaT cells treated with EPIIS. The concentrations of EPIIS were 32 or 512 μg/mL and the adhered cell rates were measured every 30 min for 137 h.</p

Physicochemical parameters through <i>in silico</i> analysis of EPIIS using pkCSM methodology.

<p>Physicochemical parameters through <i>in silico</i> analysis of EPIIS using pkCSM methodology.</p

Effect on egg development and on Stoll egg count of a single dose 100 mg/kg of EPIIS administered to mice harboring a 60-day-old adult <i>S</i>. <i>mansoni</i> infection.

<p><b>(A)</b> EPIIS effect on egg development stages (oogram) <b>(B)</b> Effect on Stoll egg count. Points represent data from individual mice that were infected and treated with EPIIS, or infected and untreated (control). The horizontal bars represent median values. **<i>P</i> < 0.01 and ***<i>P</i> < 0.001 compared with untreated groups.</p