Possible antifibrotic effect of GDC-0449 (Vismodegib), a hedgehog-pathway inhibitor, in mice model of Schistosoma-induced liver fibrosis

摘要

Liver fibrosis is a pathological process complicating schistosomiasis. It is an active process of continuous extracellular matrix accumulation. In Egypt, schistosomiasis re-infection is a continuing problem especially in rural areas. In this study we examined the antifibrotic effect of GDC-0449 (Vismodegib), a hedgehog-pathway inhibitor as a new molecular target for Schistosoma-induced liver fibrosis, in addition to exploring its effect as antischistosomal drug. The effect of GDC-0449 alone or combined with Praziquantel was tried experimentally in infected mice with Schistosoma mansoni. Fifty CD-1 Swiss female albino mice were used, forty mice were infected with Schistosoma mansoni cercariae. Animals were grouped into five groups; uninfected control, infected untreated, infected treated with Praziquantel (500 mg/kg/day) for two days, infected treated with GDC-0449 (40 mg/kg/day) for seven days, and infected treated with combined Praziquantel and GDC-0449. Parasitological and chemical parameters, hydroxyproline level and liver granuloma were assessed. Liver fibrosis was reduced significantly evidenced by reduced hydroxyproline levels [P 0.01 for combined (Praziquantel/GDC-0449) treatment groups, P 0.001 for GDC-0449-treated group]. Also, histopathological examination of liver tissues revealed that the mean diameter of granulomas was statistically reduced (P = 0.001) with a reduction rate of 24.4% on treatment with GDC-0449. In GDC-0449/Praziquantel combined treatment group, number and mean diameter of the granulomas were reduced significantly P 0.001, and P = 0.001 respectively. No antischistosomal effect was recorded for GDC-0449 in this study.