Thesis (M.Sc.) - Cairo University - Faculty of Medicine - Department of Pharmacology

Background and Aim : Liver fibrosis is one of the leading causes of morbidity and mortality worldwide with very limited therapeutic options. Nowadays, attention has been directed towards investigating its cellular and molecular mechanisms. Recently, cannabinoid receptor 2 has been identified for its antifibrotic properties. The present study was designed to explore the its antifibrotic and regenerative roles and mechanisms.Methods: Thirty adult male Wistar albino rats were organized into five groups: normal non-operated, sham operated, bile duct ligated rats, bile duct ligated rats co-treated with silymarin and bile duct ligated rats co-treated with CB2 agonist, AM1241 for 3 consecutive weeks. Serum hepatotoxicity markers were determined, and histopathological evaluation was performed. Hepatic fibrosis was assessed by measuring Ü-SMA expression and collagen deposition by Masson{u2019}s trichrome staining and hydroxyproline content. The effects of AM1241 on oxidative stress markers (GSH, lipid peroxides), apoptosis marker (p53), inflammatory markers (TNF-Ü, IL-10) and hepatic progenitor cells markers (cd34 and Ü-FP) were also assessed by immunohistochemistry.Results: Hepatic fibrosis induced by BDL was significantly reduced by AM1241, as indicated by decreased Ü-SMA expression and collagen deposition. AM1241 co-treatment significantly attenuated oxidative stress, apoptosis and inflammation by improvement of IL-10 levels. AM1241 improved liver regeneration by markedly augmenting hepatic progenitor cells. Conclusions: This study points out that either stimulation of CB2 receptors can attenuate hepatic fibrosis and promoting hepatocyte regeneration in bile duct ligated rats. The mechanisms underlying these incidents may open new avenues for oxidative potential, apoptosis and immunomodulation of cholestasis- induced liver diseases

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