Role of simvastatin, tetrandrine and candesartan in experimental induced liver fibrosis in rats

ABSTRACT

Liver fibrosis which insidiously and frequently develops to cirrhosis showed implications of manymitogenic and fibrogenic cytokines such as tumor necrosis factor a [TNF alpha] and transforming growth factor beta [TGF- beta] respectively. Moreover, the chemoattractant effect of reactive oxygen metabolites which recruit Kupffercells, hepatic stellate cells [HSCs]and other inflammatory cells makes more cytokine release and production ofextracellular matrix [ECM] proteins and myoflbroblast mitogens.In this study, three drugs were chosen, each of them is supposed to act by a quite differentmechanism in thioacetamide [TAA] experimental model of hepatic fibrosis in rats. Simvastatin, an example ofHMG Co A reductase inhibitor. Tetrandrine, an alkaloid with calcium channel blocking property and Candesartanas a receptor blacker for angiotensin II.This study was carried out on 40 male albino rats,8 rats served as normal controls, while in the other32 rats liver fibrosis was induced by intraperitonial TAA injection. The incidence of fibrosis or its protection wasassessed by intrasplenic pressure measurement, spleen /body weight ratio, liver hydroxyproline [HPO] contents,serum TNF alpha and TGF- beta levels, oxidative stress parameters as reduced glutathione [GSH] and malondialdehyde [MDA] levels were measured. In addition to liver transaminases and tissue inhibitor of matrix metalloproteinase [TIMP-1] activities.In the present study Six weeks administration of TAA resulted in significant rise in portal blood pressureas compared to saline control rats; associated with a significant reduction in hepatic GSH contents and asignificant increase in hepatic HPO and serum MDA concentration in TAA group as compared to all groups.Meanwhile, there were significant increases in serum levels of TNF- alpah, TGF- 01, and TIMP-lactivity in TAA ratsas compared to control group . There were also statistical significant reduction in the cytokine levels and inhibitorof metalloproteinase activities in Simvastatin, Tetrandrine and Candesartan groups as compared to TAA nontreated group.The same was the effect on liver function tests; there were significant higher serum activities of aspartateaminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase [ALB] and y - glutamyl transferase [GGT] in TAA group as compared to saline control group. However, these serum enzymes activities showedsignificant reduction in the drug treated groups Simvastatin, Tetrandrine and Candesartan respectively. The studyfailed in detecting any significant statistical difference between the degree of protection against TAA inducedfibrosis that had been exerted by the three drugs used in the study.It was concluded that both Tetrandrine and Candesartan have marked protective effects in TAAinduced liver fibrosis by more than one mechanism .Simvastatin had a modest effect that may be by its antioxidanteffect. Clinical trials are recommended to support or disprove these results: