Mast cell stabilizer modulates Sirt1/Nrf2/TNF pathway and inhibits oxidative stress, inflammation, and apoptosis in rat model of cyclophosphamide hepatotoxicity

Abstract

Objectives: Cyclophosphamide (CYC) is the most common cytotoxic alkylating agent which considered as chemotherapy but its clinical usefulness is challenged with different forms of organ damage including hepatotoxicity. Hepatic mast cells (MC) have an important role in the pathophysiology of liver toxicity. We aimed to evaluate the possible protective effect of mast cell stabilizer, ketotifen in CYC induced-hepatotoxicity.Materials and methods: Twenty-four adult male albino Wistar rats were divided into four groups: control group, ketotifen group (received ketotifen 10 mg/kg/day, p.o.) for 14 days, CYC group (received CYC 200 mg/kg i.p.) as a single dose at the ninth day and ketotifen plus CYC group (received ketotifen and CYC). We measured serum enzyme biomarkers [alanine transaminase (ALT) and aspartate transaminase (AST)], total antioxidant capacity (TAC), interluken-1β (IL-1β), tissue malondialdehyde (MDA), nitric oxide (NOx), reduced glutathione (GSH), P-glycoprotein (P-gp), Sirtuin type 1 (Sirt1) and Nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Furthermore; histological changes, tumor necrosis factor (TNF) and caspase-3 immuno-expressions were evaluated.Results: CYC group showed hepatotoxic effect in the form of a significant increase in ALT, AST, MDA, NOx, IL-1β levels; TNF and caspase-3 immuno-expression. Moreover; it showed toxic histological changes of marked liver injury meanwhile, there is a significant decrease in TAC, GSH, P-gp, Sirt1, and Nrf2 levels. Ketotifen showed a significant improvement in all parameters.Conclusion: Mast cell stabilizer, ketotifen possesses potent ameliorative effects against the hepatotoxic effect of CYC by reducing oxidative stress, inflammatory process, and apoptosis through regulation of Sirt1/Nrf2/TNF pathway.