Praziquantel ameliorates CCl₄‐induced liver fibrosis in mice by inhibiting TGF‐β/Smad signalling via up‐regulating Smad7 in hepatic stellate cells

Abstract

Background and Purpose: Praziquantel is a schistosomicide, which has been used for more than 30 years due to its efficiency, safety, and mild side effects. Previous studies showed that prolonged treatment with praziquantel suppressed the development of liver fibrosis in mice with schistosomiasis. In this study, we investigated the potential mechanisms underlying the antifibrotic effects of praziquantel. Experimental Approach: To avoid the effect of schistosomicidal activity of praziquantel against liver fibrosis induced by Schistosoma japonicum infection, we established a mouse model of carbon tetrachloride (CCl 4 )-induced liver fibrosis for in vivo studies and used TGF-β1-stimulated human hepatic stellate cell line (LX-2) in addition to other fibroblast-like cell line (MES13) and fibroblast cell line (NIH3T3) in vitro. Western blotting, immunohistochemistry, quantitative real-time PCR, siRNA, and immunofluorescence staining were utilized to assess the expression of key molecules in liver fibrosis and the TGF-β/Smad pathway. Key Results: Praziquantel significantly attenuated CCl 4 -induced liver fibrosis by inhibiting the activation of hepatic stellate cells (HSCs) and expression of collagen matrix via enhancement of Smad7 expression, which were confirmed in LX-2, MES13, and NIH3T3 cells in vitro. In contrast, knockdown of Smad7 in LX-2 cells prevented praziquantel-mediated inhibition of LX-2 cell activation and TGF-β1-mediated collagen type I α1 induction, revealing the critical role of Smad7 in the antifibrotic effect of praziquantel during liver fibrosis. Conclusions and Implications: PZQ exhibited a strong efficacy against liver fibrosis by inhibiting activation of HSCs via Smad7 up-regulation, suggesting potential broad utility in treatment of diseases characterized by liver fibrosis.

Investigating the antifibrotic effect of the antiparasitic drug Praziquantel in in vitro and in vivo preclinical models

“…This data suggests that PZQ has very limited but apparent antifibrotic activities in the model. This is in agreement with recent reports of PZQ ability to oppose fibrosis onset in a murine model of acute fibrosis 33 .…”

“…investigated the effect of PZQ treatment (using either R or S enantiomers) on multi-donor hepatocytes seeded and co-cultivated with Kupffer cells, liver endothelial cells and hepatic stellate cells until aggregation into 3D microtissue for 48h 37,38 . Microtissues kept in culture were treated with TGF-β for 7 days and PZQ enantiomers were added during these 7 days of treatment (at day 2 and day 5) at various concentrations (10,33 or 100 µM, as shown in Fig. 2A).…”

“…collagen deposition 14,15,19,21,25,33,34 , has now suggested a potential ability of the drug to also directly treat/reverse established tissue fibrosis.…”

The Differential and Dynamic Progression of Hepatic Inflammation and Immune Responses During Liver Fibrosis Induced by Schistosoma japonicum or Carbon Tetrachloride in Mice

“…In several studies, both S. japonicum infection and CCl 4 intraperitoneal injection models were used. Similar results were obtained in the two models ( 11 – 13 ). The difference between the two models was also reported, such as the expression of protein Septin4 ( 14 ).…”

TGF-β in Hepatic Stellate Cell Activation and Liver Fibrogenesis—Updated 2019

“…In a recent mechanistic study, the authors showed that PZQ inhibits CCl 4 -induced liver fibrosis by upregulating SMAD7 in HSC. The link between PZQ, SMAD7 expression, and HSC activation was further confirmed in LX-2 and other fibroblast cell lines [268].…”