Hepatoprotective effect of Ginkgo biloba extract against methotrexate-induced hepatotoxicity via targeting STAT3/miRNA-21 axis

Abstract

The usage of the chemotherapeutic agent methotrexate (MTX) was associated with hepatotoxicity that minimized its clinical use. The Ginkgo biloba extract (GBE) was used before to alleviate the MTX-induced liver injury through its antioxidant activity. This work was carried out to elucidate other molecular hepatoprotective mechanisms of GBE via examining the IL-6/STAT3 pathway in addition to the miRNA-21 expression in hepatic tissue. Sprague Dawley rats were allocated into four groups: normal control (NC); Ginkgo biloba extract control (GBEC); methotrexate (MTX); and Ginkgo biloba extract and methotrexate (GBE + MTX) group. GBE was administered orally 60 mg/kg/day for 10 days while MTX was intraperitoneally injected with 20 mg/kg on day 5. After the experiment, the serum was separated for liver enzyme determination while liver tissues were collected for biochemical and histopathological examinations. MTX induced marked elevation in the liver enzymes, hepatic IL-6, and HGF mRNA expressions, phospho-STAT3/STAT3 ratio, and miRNA-21 hepatic expression when compared with the NC group. Liver injury was observed histopathologically after MTX. The GBE administration reversed these biochemical alterations and improved liver histopathology. The hepatoprotective mechanism of GBE against MTX-induced hepatotoxicity via the modulation of the IL-6/STAT3 signaling pathway and the downregulation of the miRNA-21 hepatic expression was reported for the first time.

Keywords:

• Methotrexate;
• Ginkgo biloba extract;
• IL-6;
• STAT3;
• miRNA-21

Acknowledgements

The authors appreciated Dr. Walaa Awadin for the histopathological work.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This research was funded by the Deanship of Scientific Research at Princess Nourah bint Abdulrahman University through the Fast-track Research Funding Program.