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

Abstract

Tumor necrosis factor-alpha (TNF-α) 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-α 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.), γ-glutamyl transpeptidase (γ-GTP) and alanine aminotransferase (ALT) enzyme activities, bilirubins, and TNF-α 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-α levels, while thalidomide not only failed to inhibit TNF-α, 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. Drug Dev.

Kinetics of cytokine expression in cirrhotic rats

“…21 Furthermore, hepatic necrosis could be prevented by TNF-a inhibition. 1,22 In human studies, hepatic TNF-a mRNA expression was increased in cirrhotic patients. 18 Regarding the circulating TNF-a, an elevated plasma concentration of TNF-a reported in patients with chronic liver disease which was significantly higher in cirrhotics than in noncirrhotics.…”

Inhibition of hepatic tumour necrosis factor‐α attenuates the anandamide‐induced vasoconstrictive response in cirrhotic rat livers

“…Similarly, a significant decrease in PVP was observed in noncirrhotic portal hypertensive rats through chronic administration of thalidomide (20). In comparison with previous studies (20–23), this study was characterized by direct measurements of splanchnic and hepatic haemodynamics in thalidomide‐treated cirrhotic rats. Additionally, previous studies suggested that daily treatment of thalidomide or vehicle should start 2 days before BDL or sham operation in order to achieve effective drug levels in the plasma on the day of surgery, which may immediately induce an acute endotoxaemia and the release of TNF‐α (9, 10, 20).…”

“…The dose (200 mg/kg/day) of thalidomide (Sigma Chemical Co., St Louis, MO, USA) used in this study was chosen according to previous studies in cirrhotic animals (20)(21)(22)(23). In our preliminary studies, three groups of BDL rats (n = 5) were included.…”

“…In alcoholmediated toxicity, thalidomide prevents KCs sensitization and reduces acute liver injury. Thalidomide has also been reported to improve the ongoing hepatic fibrogenesis in rat models induced through carbon tetrachloride, bile duct ligation and thaioacetamide (16,(21)(22)(23).…”

Thalidomide salvages lethal hepatic necroinflammation and accelerates recovery from cirrhosis in rats

“…Recently, Fernandez-Martinez et al reported that thalidomide analog enabled to prevent collagen accumulation on bile duct obstruction-induced cirrhosis in the rats by inhibiting TNFa [18]. In addition, Muriel et al reported that thalidomide enables to ameliorate carbon tetrachloride induced cirrhosis in the rats, however, the therapeutic mechanism remains unexplored [19]. Furthermore, in their study, thalidomide was given quite early before the establishment of cirrhosis, this condition obviously is not fit for clinical implication.…”