Alogliptin exhibits multifaceted effects in thioacetamide-insulted rats: A novel approach to combating hepatic inflammation and fibrogenesis

Abstract

Hepatic fibrosis arising from chronic liver injury is characterized by dysregulated healing, including hepatic stellate cell activation and excessive deposition of extracellular matrix proteins. Administration of the hepatotoxin thioacetamide (TAA) induces liver injury coupled to fibrogenesis in rodents, mimicking aspects of human disease. Alogliptin is a highly selective inhibitor of dipeptidyl peptidase-4 with purported antifibrotic actions. We investigated the protective effects of alogliptin against TAA-mediated hepatic fibrosis in rats. Adult male Sprague-Dawley rats received intraperitoneal injections of TAA (150 mg/kg) twice weekly for 6 weeks to induce liver fibrosis. A subset of rats also received daily oral alogliptin (20 mg/kg). At 6 weeks, liver injury and fibrosis were assessed by histology, hydroxyproline content, serum liver enzymes, inflammatory cytokines, oxidative stress markers, and genes related to inflammation, apoptosis, and fibrosis. TAA elicited necroinflammation, oxidative stress, upregulation of pro-fibrogenic mediators, increased hydroxyproline content, and excessive collagen deposition, indicating hepatic fibrosis. The administration of Alogliptin led to notable enhancements in liver histology, an extension in survival time, a decrease in hydroxyproline levels and the expression of fibrogenic genes, a reduction in inflammatory cytokines and oxidative stress, and mitigation of hepatocellular apoptosis in rats subjected to TAA treatment. Alogliptin displayed potent antifibrotic, antioxidant, and hepatoprotective properties in this model of toxic liver damage, likely by impeding NFκB while enhanced Nrf2 DNA binding activity which together modulate oxidative stress, inflammation, myofibroblast activation, and apoptosis. These results highlight the potential therapeutic value of alogliptin offering hope for improved treatment of hepatic fibrosis.