Pentoxifylline mitigates CCl4-induced liver damage in rats: integrated biochemical, hematological, histopathological, and correlation heatmap analysis

Abstract

Abstract Pentoxifylline (PTX), a methylxanthine-derived phosphodiesterase inhibitor, has demonstrated anti-inflammatory and hepatoprotective potential. This study evaluated the effects of PTX on carbon tetrachloride (CCl4)-induced liver injury in rats, with clear differentiation between treatment conditions. Sixty Wistar rats were allocated into four groups: control, CCl4-only, PTX-only, and CCl4 followed by PTX (post-treatment model). CCl4 (1 mL/kg, i.p.) induced hepatic injury, while PTX was administered orally (50 mg/kg/day) for seven consecutive days either alone or after CCl4 exposure. CCl4 administration resulted in significant hepatotoxicity, evidenced by elevated serum ALT, AST, and LDH levels (p < 0.001), along with marked reductions in hepatic antioxidant markers (GSH, GPX, and CAT; p < 0.001), and alterations in organ weights and hematological parameters. PTX administered after CCl4 significantly ameliorated liver injury, as demonstrated by reductions in ALT (66.3 U/L, p < 0.001) and AST (184.7 U/L, p < 0.001), and restoration of antioxidant defenses, including GSH (6.70 µmol/g, p < 0.001). In contrast, PTX administered alone did not enhance antioxidant status and was associated with reductions in GSH, GPX, and CAT compared to control (p < 0.05), indicating that its protective effects are context-dependent. Correlation heatmap analysis revealed strong associations between liver enzymes and oxidative stress markers, supporting the mechanistic link between hepatocellular damage and redox imbalance. Hematological alterations induced by CCl4, including monocytosis and neutropenia, were partially normalized following PTX post-treatment. Histopathological findings corroborated the biochemical results, showing improved hepatocyte architecture and reduced inflammatory infiltration in PTX-treated rats. These findings suggest that PTX exerts significant hepatoprotective effects when administered after toxic insult, likely through modulation of oxidative stress and inflammation. Further studies are warranted to optimize dosing strategies and clarify its therapeutic window.