Rutin outperforms gallic acid in mitigating carbon tetrachloride-induced nephrotoxicity: Integrated in silico (docking, MD simulations, DFT) and in vivo mechanistic validation
Abstract
Background: Carbon tetrachloride (CCl₄) induces nephrotoxicity via oxidative stress and inflammation.
Aim: This novel comparative study evaluated the nephroprotective efficacy of rutin and gallic acid (GA) against CCl₄-induced kidney damage by elucidating their antioxidant and anti-inflammatory mechanisms.
Method: In silico, Quantum Mechanics/Molecular Mechanics methods screened rutin and GA's activity against Tumor Necrosis Factor (TNF) by inhibiting TNF-Alpha Convertase Enzyme (TACE) and Interleukin-6 (IL-6) via its receptor IL-6Rα, alongside assessing radical-neutralizing capacity. In vivo, twenty-four male Sprague-Dawley rats were divided into four groups (n = 6): normal control, CCl₄ (1 mL/kg, i.p., twice weekly), CCl₄ + rutin (40 mg/kg/day, oral), and CCl₄ + GA (40 mg/kg/day, oral) for four weeks. Renal function, oxidative stress, inflammation markers, histopathology, and immunohistochemistry were analyzed.
Results: In silico, rutin exhibited radical-neutralizing abilities and potential to inhibit TACE and IL-6Rα. GA showed divergence in molecular dynamics simulations for these targets and lower radical neutralization affinity, based on activation energy and reaction enthalpy. In vivo, CCl₄ induced nephrotoxicity, increasing kidney biomarkers, oxidative stress, and inflammatory markers. Both compounds significantly mitigated damage, reducing creatinine, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, urea, uric acid, lipid peroxidation,…
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