Effects of thalidomide and 3-phthalimido-3-(3,4-dimethoxyphenyl)-propanamide on bile duct obstruction-induced cirrhosis in the rat

Tumor necrosis factor-alpha (TNF-alpha) plays a central role in cellular necrosis, apoptosis, organ failure, tissue damage, inflammation, and fibrosis. These processes, occurring in liver injury, may lead to cirrhosis. Thalidomide and its analogs have shown to be effective TNF-alpha inhibitors. The aim of this work was to synthesize a thalidomide analog, the 3-phthalimido-3-(3,4-dimethoxyphenyl)-propanamide (PDP) and to evaluate its hepatoprotective properties on bile duct obstruction-induced cirrhosis. Synthesis, purification, and spectroscopic characterization of PDP were carried out. Thalidomide (200 mg/kg) or PDP (15 mg/kg) were administered to sham (Sh) or bile duct ligated (BDL) rats. The animals were sacrificed 28 days after treatments. Alkaline phosphatase (Alk. Phosph.), gamma-glutamyl transpeptidase (gamma-GTP) and alanine aminotransferase (ALT) enzyme activities, bilirubins, and TNF-alpha concentrations were evaluated in plasma. Collagen was estimated by the liver hydroxyproline content and histopathology was performed. Both drugs showed partial amelioration of cirrhosis. However, the hepatoprotective effects of thalidomide were poor when compared to those afforded by PDP. While PDP improved the majority of the biochemical markers of liver injury and prevented partial but significantly collagen accumulation, thalidomide showed only modest beneficial effects on bilirubins and ALT. PDP was effective in preventing the increase in plasma TNF-alpha levels, while thalidomide not only failed to inhibit TNF-alpha, but increased it. Differences between thalidomide and PDP effectiveness may be due to their stability and different mechanism of action, as reported by others. Inhibition of proinflamatory cytokines is an interesting pharmacological aim to treat cirrhosis. (C) 2002 Wiley-Liss, Inc.