Ahmed Yasmin M, El-Shoura Ehab A M, Kozman Magy R, Abdel-Wahab Basel A, Abdel-Sattar Asmaa Ramadan
Pharmacology and Toxicology Department, Faculty of Pharmacy, Nile Valley (NVU) University, Fayoum, Egypt.
Clinical Pharmacy Department, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt.
Immunopharmacol Immunotoxicol. 2025 Feb;47(1):68-84. doi: 10.1080/08923973.2024.2435323. Epub 2024 Dec 9.
Arsenic-trioxide (ATO) is an effective therapy for acute promyelocytic leukemia. Unfortunately, its utility is hindered by the risk of myocardial injury. Both bisoprolol (BIS) and trimetazidine (TMZ) have various pharmacological features, including anti-oxidant, anti-inflammatory, and anti-apoptotic properties.
The cardioprotective effects of BIS and TMZ were studied, and their mechanistic role in ameliorating ATO-induced myocardial injury.
Forty male Wistar rats were randomly allotted into five groups as follows: normal control group (received normal saline, orally), ATO group (7.5 mg/kg, orally), BIS (8 mg/kg, orally), TMZ (60 mg/kg, orally), and finally combination group (BIS+TMZ+ATO). Following 21 days, samples of serum and cardiac tissues were obtained to perform biochemical, molecular, and histopathological investigations.
The present study showed that ATO caused myocardial injury evidenced by changes in serum biomarkers (Aspatate aminotransferase, alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase, creatine kinase-MB, and cardiac troponin-1), electrolyte imbalance, and lipid profiles alongside histopathologic changes. In addition, ATO administration significantly elevated malondialdehyde, nicotinamide adenine dinucleotide phosphate hydrogen oxidase, myloperoxidase, total nitrite, inducible nitric oxide synthase, tumor necrosis factor-alpha, interleukin-1β, interleukin-6, 8-Hydroxy-2'-deoxyguanosine, nuclear factor NF-kappa-B p65 subunit, glycogen synthase kinase-3 beta, and caspase-3 expression contemporaneously with down-regulation of reduced glutathione, glutathione peroxidase, superoxide dismutase, catalase, heme oxygenase 1, nuclear factor erythroid 2-related factor 2, phosphatidylinositol-3 kinase, p-PI3K, and Bcl-2 expression. Interestingly, pretreatment with BIS and TMZ significantly reversed the detrimental effects of ATO-induced myocardial injury at both cellular and molecular levels. Otherwise, combining the two drugs displayed more enhancement than each drug alone.
The present research depicted that BIS and TMZ have the potential to protect the heart and provide therapeutic benefits by preventing acute heart injury induced by ATO. This is achieved by reversing the redox-sensitive pathway, reducing inflammation, and inhibiting apoptosis.
三氧化二砷（ATO）是治疗急性早幼粒细胞白血病的有效药物。不幸的是，其应用受到心肌损伤风险的阻碍。比索洛尔（BIS）和曲美他嗪（TMZ）均具有多种药理特性，包括抗氧化、抗炎和抗凋亡特性。
研究BIS和TMZ的心脏保护作用及其在减轻ATO诱导的心肌损伤中的机制作用。
将40只雄性Wistar大鼠随机分为五组：正常对照组（口服生理盐水）、ATO组（7.5mg/kg，口服）、BIS组（8mg/kg，口服）、TMZ组（60mg/kg，口服），最后是联合组（BIS+TMZ+ATO）。21天后，采集血清和心脏组织样本进行生化、分子和组织病理学研究。
本研究表明，ATO导致心肌损伤，表现为血清生物标志物（天冬氨酸转氨酶、丙氨酸转氨酶、碱性磷酸酶、乳酸脱氢酶、肌酸激酶同工酶MB和心肌肌钙蛋白I）变化、电解质失衡和血脂异常以及组织病理学改变。此外，给予ATO显著升高丙二醛、烟酰胺腺嘌呤二核苷酸磷酸氢氧化酶、髓过氧化物酶、总亚硝酸盐、诱导型一氧化氮合酶、肿瘤坏死因子-α、白细胞介素-1β、白细胞介素-6、8-羟基-2'-脱氧鸟苷、核因子NF-κB p65亚基、糖原合酶激酶-3β和半胱天冬酶-3的表达，同时下调还原型谷胱甘肽、谷胱甘肽过氧化物酶、超氧化物歧化酶、过氧化氢酶、血红素加氧酶1、核因子红细胞2相关因子2、磷脂酰肌醇-3激酶、p-PI3K和Bcl-2的表达。有趣的是，BIS和TMZ预处理在细胞和分子水平上均显著逆转了ATO诱导的心肌损伤的有害影响。否则，两种药物联合使用比单独使用每种药物表现出更强的效果。
本研究表明，BIS和TMZ有保护心脏的潜力，并通过预防ATO诱导的急性心脏损伤提供治疗益处。这是通过逆转氧化还原敏感途径、减轻炎症和抑制凋亡来实现的。
