Ginkgo biloba Extract Protects against Methotrexate-Induced Hepatotoxicity: A Computational and Pharmacological Approach
Lina T. Al Kury, Fazli Dayyan, Fawad Ali Shah, Z. Malik, Atif Ali Khan Khalil, Abdullah Alattar, Reem Alshaman, Amjad Ali, Zahid Khan
Abstract
(Gb) in methotrexate (MTX)-induced liver toxicity model. These effects were analyzed using different in vivo experimental approaches and by bioinformatics analysis. Male SD rats were grouped as follows: saline; MTX; Gb (pretreated for seven days with 60, 120, and 180 mg/kg daily dose before MTX treatment); silymarin (followed by MTX treatment); Gb 180 mg/kg daily only; and silymarin only. Histopathological results revealed that MTX induced marked hepatic injury, associated with a substantial surge in various hepatic enzymes such as alanine transaminase (ALT), aspartate transaminase (AST), and serum alkaline phosphatase (ALP). Furthermore, MTX caused the triggering of oxidative distress associated with a depressed antioxidant system. All these injury markers contributed to a significant release of apoptotic (caspase-3 and c-Jun N-terminal kinases (JNK)) and tumor necrosis factor (TNF-α)-like inflammatory mediators. Treatment with Gb counteracts MTX-mediated apoptosis and inflammation dose-dependently along with modulating the innate antioxidative mechanisms such as glutathione (GSH) and glutathione S-transferase (GST). These results were further supplemented by in silico study to analyze drug-receptor interactions (for several Gb constituents and target proteins) stabilized by a low energy value and with a good number of hydrogen bonds. These findings demonstrated that Gb could ameliorate MTX-induced elevated liver reactive oxygen species (ROS) and inflammation, possibly by JNK and TNF-α modulation