A comparative study to assess two doses of a novel aldose reductase inhibitor (ARI)/Antioxidant drug candidate Cemtirestat, the current ARI drug Epalrestat, and the antioxidant Stobadine on Fructose- and Streptozotocin-Induced hepatic and pancreatic stress responses in rats

Abstract

PurposeThis study aimed to investigate the effects of cemtirestat, a promising drug candidate with both aldose reductase (AR) inhibitor (ARI) and antioxidant (AO) properties, on hepatic and pancreatic stress responses in rats, by comparing it with the ARI drug epalrestat and the antioxidant compound stobadine.MethodsTwo metabolic disorder models characterized by glycolipotoxicity were induced in rats by administering fructose alone (CF) or together with streptozotocin (DF). The rats were subsequently treated once daily for 14 weeks with either cemtirestat at two different doses (2.5, 7.5 mg/kg), the ARI drug epalrestat (25, 50 mg/kg), or antioxidant compound stobadine (25, 50 mg/kg).ResultsLiver enzymes (ALP, AST, ALT, and GGT) and oxidative stress markers (malondialdehyde, carbonyl, glutathione S-transferase, catalase) were elevated in both CF and DF compared to control rats (C). Cemtirestat, especially at the low dose, significantly prevented the noted abnormalities (except for ALT) and the increase in cholesterol in DF and the increase in triglycerides in CF. While epalrestat only partially prevented the decrease in the GSH to GSSG ratio, but cemtirestat and stobadine almost completely restored the ratio in both CF and DF models. However, histochemical and immunohistochemical analyses revealed that unlike epalrestat and stobadine, cemtirestat did not improve liver histopathology (PAS, Masson trichrome, TUNEL, PCNA and caspase-3 staining) and pancreatic histopathology (TUNEL, PCNA and caspase-3 staining), nor did it alleviate damage to insulin-, glucagon-, and somatostatin-secreting cells in the islets.ConclusionThe findings may offer valuable insights that could facilitate the development of novel ARI/AO compounds and CMTI derivatives.