Abstract
Purpose: To evaluate the safety, pharmacological effect and mechanism of action of an antifibrotic compound, safironil (SAF)/praziquantel (PZQ) combination on reversal of liver fibrogenesis in chronic murine Schistosomiasis mansoni.
Methods: The antifibrotic effect of 0.5, 1 and 2 mg/ml of SAF was evaluated in vitro myofibroblast cell culture, using RNAse protection assay for collagen I mRNA expression and quantitative immunoblot for smooth muscle a-actin protein extract. Ninety Swiss albino mice were infected with 50 Schistosoma mansoni cercariae. SAF was provided in drinking water at a concentration of 1.5 mg/ml while praziquantel (PZQ) was given by gavage in a dose of 500 mg/kg. Mice, divided into five groups: infected non-treated; infected and PZQ-treated; infected PZQ- and SAF-treated; infected and SAF-treated; and control. After sacrificing the animals, the liver of each mouse was taken, weighed and used for histopathological examination, hydroxyproline assay and collagen determination.
Results: SAF prevented myofibroblast activation at the pre-transcriptional level in a dose-dependent manner as monitored by collagen I mRNA levels (expression reduced by 40, 70 and 90 % at doses of 0.5, 1 and 2 mg/ml, respectively) or by smooth muscle a-actin (expression reduced by 70, 85 and 95 %, respectively). SAF decreased the production of collagen I by 60 % and laminin by 55 % but increased collagen III by 50 % relative to control. SAF had no effect on liver granuloma size and did not alter total hydroxyproline but altered the pattern of fibrosis by increasing collagen III and decreasing collagen I deposition. The most significant reduction in liver fibrosis was noticed in mice treated with SAF combined with PZQ. No toxic pharmacological effect was noticed during SAF treatment.
Conclusion: When SAF was combined with PZQ, augmented reduction of liver fibrogenesis was achieved. The mechanism is probably through inhibition of new liver injury induced by parasite egg deposition and interruption of collagen type I synthesis with attenuation of pre-existent collagen..