Attenuation of Methotrexate‑induced Hepatorenal Damage by Terminalia bellerica Fruit Extract in Experimental Rats

Background: Methotrexate (MTX) is used for numerous malignancies and autoimmune disorders. With such widespread use, MTX‑induced hepatorenal toxicity is an issue of concern that still needs to be addressed. Objective: The aim of the present study is to evaluate the role of Terminalia bellerica extract (TBE) in MTX‑induced hepatorenal toxicity in Wistar albino rats. Materials and Methods: Rats were randomly divided into six groups (n = 6) – received MTX 20 mg/kg intraperitoneally on the 4th day along with pretreatment with different doses of TBE (100 mg/kg, 200 mg/kg, and 400 mg/kg, p.o) given from 1^st to 15^th day. MTX‑induced hepatorenal toxicity was evaluated by biochemical hepatic and renal parameters along with histopathology and immunohistochemistry. Results: Hepatorenal toxicity induced by MTX was attributed to increased oxidative stress, biochemical liver, and kidney parameters and upregulation of caspase‑3 and nuclear factor kappa B (NFkB). MTX‑treated group observed twofold to threefold rise in aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), and creatinine values–138.49 IU/L, 125.81 IU/L, 63.09 mg/dl, and 1.895 mg/dl, respectively. Groups pretreated with TBE (400 mg/kg) observed a significant decrease (P < 0.001) in oxidative stress and biochemical parameters – AST (63.94 IU/L), ALT (55.98 IU/L), BUN (37.02 mg/dl), and creatinine (1.065 mg/dl). Pretreatment with TBE 400 mg/kg, histopathology of both liver and kidney tissues showed improved architectural damage and immunohistochemistry showed downregulation of increased antigens‑caspase‑3 and NFkB. Conclusion: T. bellerica fruit extract (400 mg/kg) showed significant hepatorenal protection by reducing oxidative stress, elevating serum enzymes, and downregulating the tissue expressions of caspase‑3 and NFkB.