Pharmacotherapeutic potential of artemetin against amiodarone instigated sub-chronic hepatotoxicity via modulating TLR4/HMGB1/RAGE and NF-κB signaling pathways: An in-vivo and in-silico approach.

Amiodarone (AMI) has been widely used in cardiac patients to prevent the onset of life-threating cardiac arrhythmias. However, its excessive use induces various organ damages including the liver. Artemetin (ART) is a flavonoid that exhibits immense medicinal values. This investigation explored the palliative potential of ART against AMI induced sub-chronic hepato-toxicity. Thirty-two rats (Sprague Dawley) were randomly apportioned into control, AMI (40 mgkg-1), AMI (40 mgkg-1) + ART (1.5 mgkg-1) and ART (1.5 mg/kg) alone treated group. Our findings elucidated that AMI administration instigate severe hepatocellular inflammation which is evident by elevated gene expression of interleukin-6 (IL-6), receptor for advanced glycation end products (RAGE), tumor necrosis factor- α (TNF-α), cyclooxygenase-2 (COX-2), monocyte chemoattractant protein-1 (MCP-1), high mobility group box1 (HMGB1), interleukin-1β (IL-1β), nuclear factor-kappa B (NF-κB), toll-like receptor 4 (TLR4). AMI exposure promoted the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) while suppressing the activities of superoxide dismutase (SOD), heme oxygenase-1 (HO-1), glutathione reductase (GSR), glutathione Peroxidase (GPx), catalase (CAT), and glutathione (GSH). Besides, AMI intoxication lowered the levels of albumin and total proteins while increasing the levels of ALT, GGT, AST, and ALP. Moreover, AMI administration exacerbated Caspase-9, Bax and Caspase-3 while diminishing Bcl-2 concentrations. The normal morphology of hepatic tissues was disrupted following the AMI exposure. Nonetheless, ART treatment significantly alleviated hepatic damage via regulating abovementioned biochemical as well as histological impairments. Our results demonstrated that ART can strongly interact with the active sites of these proteins and exhibit potential as hepatoprotective agent.