Alpha Tocopherol Outperforms Melatonin and Silymarin Antioxidant Defense Against Cyclophosphamide Induced Cardiorenal Toxicity

Abstract

Introduction: Cyclophosphamide induces cardio-renal oxidative stress by its metabolite, acrolein. Alpha tocopherol, silymarin and melatonin are predetermined antioxidants, but comparative data on their capability to conserve tissue integrity is limited. This study addresses this gap by conducting detailed comparative analysis on multiple sera and tissue markers.

Aims and Objectives: To compare the protective potential of alpha-tocopherol, silymarin and melatonin against cyclophosphamide induced cardio-renal toxicity and elevated interleukin-23 levels, using sera, oxidative stress and histopathologic markers, to suggest most effective antioxidant for optimizing cancer chemotherapy.

Place and Duration of Study: Eight-month laboratory-based randomized control trial, conducted in Army Medical College, Rawalpindi following ethical approval ERC-ID11/2024/435.

Materials & Methods: Homogeneous population of 50 Sprague Dawley rats were selected via stratified random sampling and divided into five groups by lottery method. Experimental groups received alpha-tocopherol, silymarin and melatonin intraperitoneally for five days followed by cyclophosphamide to compare with untreated and cyclophosphamide groups. Analyses included cardiac (CK-MB, LDH), renal (urea, creatinine, electrolytes) and oxidative stress parameters (GSH, MDA), IL-23, and histology. Statistical analysis utilized Graph-pad Prism version 5 with Shapiro-Wilk and Levene’s test for data distribution and variance. Quantitative variables were compared through one- way analysis of variance with Tukey test and qualitative variables via Chi-square test. p?0.05 considered significant.

Results: Cyclophosphamide elevated LDH (3049.33±89.33IU/L), CK-MB (964.16±39.89IU/L), urea (78±5.6 mg/dL), creatinine (1.8±0.1mg/dL), potassium (5.9±0.2mEq/L) and decreased sodium (132±1.9mEq/L) than controls (p?0.001). Tocopherol reduced these values the most, (LDH: 1547.16±21.92IU/L; CK-MB:302.16±36.03IU/L, urea:59±3.2mg/dL, creatinine:1.2±0.1mg/dL, potassium:4.7±0.3mEq/L, sodium:140±2.3mEq/L, p?0.001), and oxidative stress markers (MDA cardiac:1.976±0.005, renal:2.01±0.01 nmol/ml; GSH cardiac:0.941±0.09, renal:1.22±0.16ng/ml, p? 0.001). Tocopherol showed superiority over silymarin and melatonin, in reducing IL-23 and histologic damage (p?0.001).

Conclusion: This study suggests alpha-tocopherol as superior antioxidant than melatonin and silymarin against CP- induced oxidative damage advocating its co-supplementation with cyclophosphamide.