Role of IL-6/STAT3 pathway in mediating the protective effect of agomelatine against methotrexate-induced lung/intestinal tissues damage in rats

Methotrexate (MTX), an anticancer drug, has been linked to multiple organ toxicity. The drug-induced acute toxic symptoms can negatively affect the patient's commitment to the course of treatment.This study aimed to investigate the mitigating action of agomelatine (Ago) against MTX-induced lung and intestinal toxicity. Forty eight male Wister rats were randomized into six experimental groups: Group 1: Control; Groups 2 and 3: received Ago L&H (20/40 mg/kg, respectively by gavage); Group 4: received MTX 10 mg/kg/day, i.p. on days 7-9; Group 5: received Ago L (20 mg/kg) + MTX; Group 6: received Ago H (40 mg/kg) +MTX. The duration of the study was 10 days. Lung/intestine oxidative markers were measured. Lung/intestinal tissues IL-6, STAT3, and HO-1 levels were evaluated by ELISA. Besides, lung/intestinal tissues were examined for Histological changes, collagen fibers detection using Massonꞌs trichome stain, and immunohistochemical study using HSP70 antibody.MDA, NOx, IL-6, and STAT3 levels were significantly higher in the MTX group's lungs and intestines, indicating lung and intestinal toxicity. There were substantial decreases in GSH, SOD tissue levels, and HSP 70 immunoexpression, as well as histological changes suggesting significant lung and intestinal injury. All of the above parameters improved significantly by using Ago.By reducing oxidative stress, inflammatory processes, and modulating the IL-6/STAT3 pathway, Ago has potent ameliorative effects against MTX-induced lung/intestinal toxicities.