Hepatoprotective effect of engeletin against risperidone-induced liver injury in rats involvement of TGF-β1/Smad and NF-κB pathways.

Risperidone (RIS) is a potent atypical antipsychotic drug that has gained widespread attention owing to its toxic effects on the body organs such as liver. The current research experiment was executed to elucidate the alleviative efficacy of engeletin (ENG) against risperidone (RIS) induced hepatic dysfunction. Thirty-six Sprague Dawley rats were divided into four groups including control, RIS (2 mg/kg), RIS (2 mg/kg) + ENG (10 mg/kg), and ENG (10 mg/kg) alone administered group for 10 weeks orally. RIS intoxication induced hepatic fibrosis as well as inflammation via upregulating the gene expression of transforming growth factor beta receptor 2 (TGFBR2), transforming growth factor beta receptor 1 (TGFBR1), nuclear factor- kappa B (NF-κB), transforming growth factor beta-1 (TGF-β1), collagen type I alpha 1 (COL1A1), tumor necrosis factor-alpha (TNF-α), SMAD3, cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), SMAD4 & interleukin-1beta (IL-1β). The administration of RIS promoted the levels of ROS and MDA while diminishing the activities of HO-1, GPx, SOD, GSR, CAT and GST. RIS intakes abruptly uplifted levels of gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), & alkaline phosphatase (ALP) while lowering the concentrations of albumin & total proteins in hepatic tissues. RIS exposure promoted the levels of Caspase-3, Bax & Caspase-9 while demolishing levels of Bcl-2. RIS intoxication dysregulated the normal architecture of hepatic tissues. Nonetheless, ENG therapy ameliorated hepatic dysregulations owing to its antioxidative, anti-inflammatory, anti-fibrotic as well as anti-apoptotic properties. In addition, advanced molecular docking analysis demonstrated strong binding affinity of engeletin with the key regulatory proteins SMAD3 (-9.3 kcal/mol) and NF-κB p65 (-9.1 kcal/mol), providing strong evidence that ENG can directly interact with the central regulators of the TGF-β1/Smad and NF-κB signaling pathways. In conclusion, ENG significantly ameliorated RIS-induced hepatotoxicity, highlighting its potential as hepatoprotective adjuvant therapy.