Anti-inflammatory and Antioxidant Effects of Ketotifen Against Gentamicin-Induced Hepatotoxicity Through NF-κB Pathway Suppression

Abstract

Background: Gentamicin (GEN) is one of the most effective aminoglycoside antibiotics, and its repeated use leads to impaired liver function. The antioxidant, anti-inflammatory, and anti-apoptotic properties of ketotifen (KTF) as a first-generation antihistamine have been proven in various studies. Objectives: The present study aimed to evaluate the hepatoprotective effects of KTF against GEN-induced toxicity in mice, focusing on inflammation, oxidative stress, and NF-κB modulation. Methods: Thirty-seven male NMRI mice were randomly divided into 5 groups (n = 6 - 10), including: Control (normal saline 80 mL/kg, i.p, n = 6), GEN (80 mg/kg, i.p, n = 10), KTF (3 mg/kg, i.p, n = 7), and groups treated with GEN 80 mg/kg + KTF 2 mg/kg (n = 7) and GEN 80 mg/kg + KTF 3 mg/kg (n = 7). On day 8 of the study, mice were anesthetized, and their liver tissue was removed. Oxidative stress and inflammation factors, NF-κB protein expression were evaluated, and histological examinations were conducted. Results: Ketotifen resulted in significant reductions in the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), thiobarbituric acid-reactive substances (TBARS), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 1β (IL-1β), and NF-κB expression, and significant increases in total thiol and the activities of antioxidant enzymes catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD) compared to the GEN group (P < 0.001). Histopathology results confirmed this finding. Conclusions: The results of this study showed that KTF can significantly improve GEN-induced liver injury in mice. The hepatoprotective mechanism of KTF is through inhibiting inflammation, reducing oxidative stress, and modulating the NF-κB signaling pathway. This research can provide a new approach to the treatment of liver injury and help identify new drugs.