Cardioprotective Effects of SAR Through Attenuating Cardiac-Specific Markers, Inflammatory Markers, Oxidative Stress, and Anxiety in Rats Challenged with 5-Fluorouracil.

Abstract

This study aimed to evaluate the cardioprotective effects of two different doses of saroglitazar (SAR) in an animal model of cardiotoxicity induced by 5-fluorouracil (5-FU). Thirty-five rats were randomly allocated into five groups: the negative control, which received distilled water; the 5-FU (150 mg/kg as I.P.) group; the N-acetylcysteine (100 mg/kg) group; and the SAR (0.5 and 5 mg/kg) groups. The last three groups received 5-FU on day 10 along with their treatment. An open field test was performed at zero-time and at the end of the study. On day eleven the animals were euthanized and blood samples were used for measuring troponin I, CK-MB, natriuretic peptide, lipid profile, LDH, ALT, AST, CRP, ESR, TNF-α, IL1β, MDA, and total antioxidant capacity (TAOC). Cardiac tissues were sent for histopathological examination. The study revealed that 5-FU elevated the levels of cardiac-specific and injury-related biomarkers, inflammatory and oxidative stress markers, and that the use of SAR, particularly the high dose, decreased all the cardiac- and other injury-related biomarkers as well as attenuating inflammatory and oxidative stress biomarkers. SAR-treated groups exhibited a significant increase in locomotor activity and a decrease in anxiety-like behavior, indicated by a reduction in time spent in one square and an increase in total movement time. Additionally, the histopathological findings greatly supported the biochemical results evidenced by stopping the detrimental effects caused by 5-FU through structural and functional alterations of cardiac tissues manifested as ameliorating congestion, inflammation, degeneration, arterial wall thinning, and endothelial loss. The dual-acting PPAR agonist SAR demonstrated cardiac protection activity, particularly the high dose, by attenuating cardiac-specific and nonspecific injury biomarkers along with anti-inflammatory and antioxidant activities and attenuated anxiety induced by 5-FU. These findings render SAR a promising candidate to be tested in clinical trials. Further studies are warranted with other cardiotoxicants to confirm these findings.