Rasheed Roza Haroon, Aziz Tavga Ahmed
Department of Pharmacology and Toxicology, College of Pharmacy, University of Sulaimani, Sulaimani 46004, Kurdistan Region, Iraq.
J Xenobiot. 2025 Aug 10;15(4):130. doi: 10.3390/jox15040130.
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.
本研究旨在评估两种不同剂量的沙罗格列扎（SAR）在5-氟尿嘧啶（5-FU）诱导的心脏毒性动物模型中的心脏保护作用。将35只大鼠随机分为五组：阴性对照组，给予蒸馏水；5-FU组（腹腔注射150mg/kg）；N-乙酰半胱氨酸组（100mg/kg）；以及SAR组（0.5mg/kg和5mg/kg）。最后三组在第10天接受5-FU并同时进行各自的治疗。在研究开始时和结束时进行旷场试验。在第11天对动物实施安乐死，并采集血样用于检测肌钙蛋白I、肌酸激酶同工酶（CK-MB）、利钠肽、血脂谱、乳酸脱氢酶（LDH）、谷丙转氨酶（ALT）、谷草转氨酶（AST）、C反应蛋白（CRP）、红细胞沉降率（ESR）、肿瘤坏死因子-α（TNF-α）、白细胞介素1β（IL1β）、丙二醛（MDA）和总抗氧化能力（TAOC）。将心脏组织送去进行组织病理学检查。研究表明，5-FU会升高心脏特异性和损伤相关生物标志物、炎症和氧化应激标志物的水平，而使用SAR，尤其是高剂量的SAR，会降低所有与心脏和其他损伤相关的生物标志物，并减轻炎症和氧化应激生物标志物。接受SAR治疗的组表现出运动活动显著增加以及焦虑样行为减少，表现为在一个方格中停留的时间减少和总运动时间增加。此外，组织病理学结果有力地支持了生化结果，通过心脏组织的结构和功能改变（表现为改善充血、炎症、变性、动脉壁变薄和内皮损失）阻止了5-FU造成的有害影响。双重作用的过氧化物酶体增殖物激活受体（PPAR）激动剂SAR通过减轻心脏特异性和非特异性损伤生物标志物以及抗炎和抗氧化活性，并减轻5-FU诱导的焦虑，表现出心脏保护活性，尤其是高剂量时。这些发现使SAR成为有望在临床试验中进行测试的候选药物。有必要用其他心脏毒性药物进行进一步研究以证实这些发现。
