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

Abstract

Background

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.

Materials and methods

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.

Results

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.

Conclusion

By reducing oxidative stress, inflammatory processes, and modulating the IL-6/STAT3 pathway, Ago has potent ameliorative effects against MTX-induced lung/intestinal toxicities.

Keywords:

• Methotrexate
• agomelatine
• interleukin 6
• heat shock protein 70
• STAT3

Author contributions

M.Y.K. and A.M.A.: conceptualization and supervision. A.M.A. and W.Y.A.: investigation, methodology, and project administration. S.M.A.: methodology and writing the histopathological analysis. N.N.W., M.Y.K., W.Y.A., and A.M.A.: data curation, writing—review, and editing.

Disclosure statement

The authors declare that they have no conflicts of interest.

Data availability statement

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Additional information

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.