Niclosamide modulates cyclosporin A-induced hepatotoxicity in a mouse model: PPAR-γ and Wnt/β-catenin crosstalk.

Objectives: The aim of this study was to evaluate whether: 1) Wnt/β-catenin signaling is involved in cyclosporin A (CsA)-induced hepatotoxicity, and 2) knockdown of this pathway by niclosamide (NCL) attenuate CsA-induced hepatotoxicity.

Methods: The experiment was accomplished in 21 days. Adult male mice were randomly distributed into five groups: control group, CsA (25 mg/kg/day) group, CsA + NCL (2.5 mg/kg/day) group, CsA + NCL (5 mg/kg/day) group, and NCL (5 mg/kg/day) group.

Results: NCL showed marked hepatoprotection by significantly decreasing liver enzymes activities and ameliorating the histopathological alterations induced by CsA. Besides, NCL alleviated oxidative stress and inflammation. NCL-treated groups (2.5 and 5 mg/kg) displayed rise in the expression of hepatic peroxisome proliferator-activated receptor-γ (PPAR-γ) by 2.1- and 2.5-fold, respectively. Notably, NCL (2.5 and 5 mg/kg) significantly inhibited Wnt/β-catenin signaling, evidenced by a marked decrease in the hepatic expression of Wnt3a by 54 % and 50 %, frizzled-7 receptor by 50 % and 50 %, β-catenin by 22 % and 49 %, and c-myc by 50 % and 50 %, respectively.

Conclusions: NCL can be regarded as a potential agent to mitigate CsA-induced hepatotoxicity.