Babaei-Kouchaki Sara, Babapour Vahab, Panahi Negar, Badalzadeh Reza
Department of Basic Sciences, Faculty of Veterinary Medicine, Science and Research Branch, Islamic Azad University, Tehran, Iran.
Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Naunyn Schmiedebergs Arch Pharmacol. 2020 Jul;393(7):1187-1195. doi: 10.1007/s00210-020-01818-0. Epub 2020 Jan 21.
Because of limitation of doxorubicin (DOX) clinical application in chemotherapy due to its cardiotoxicity, finding new strategies to reduce DOX challenge and improve patients' outcomes is crucial. Due to positive cardiovascular impacts of troxerutin (TXR), here we have investigated the effect of TXR on DOX-induced cardiotoxicity by evaluating the myocardial oxidative stress and expression of genes regulating mitochondrial biogenesis. Male Wistar rats (250-300 g) were randomly allocated into four groups: control, TXR, DOX, and TXR + DOX. Troxerutin (150 mg/kg) was orally administrated once a day through a gavage tube for 4 weeks before DOX challenge. The TXR-treated and time-matched control rats received intraperitoneal injection of DOX (20 mg/kg). Three days after DOX challenge, the left ventricular samples were obtained to determine the expression of genes regulating mitochondrial biogenesis via real-time PCR. Myocardial creatine kinase (CK-mB), oxidative stress markers, and mitochondrial function (generation of reactive oxygen species or ROS and ATP levels) were also evaluated using commercial kits and spectrophotometric and fluorometric methods. DOX administration significantly increased the levels of CK-mB, malondialdehyde (MDA), and mitochondrial ROS levels, while reduced the cellular ATP production and expression levels of SIRT-1, PGC-1α, and NRF-2 as well as superoxide dismutase, glutathione peroxidase, and catalase activity in comparison to control group (P < 0.05 to P < 0.01). Pretreatment of DOX-received rats with TXR significantly upregulated the expression of all biogenesis genes and antioxidant enzymes with non-significant effect on catalase activity, and significantly reduced CK-mB and MDA levels toward control values (P < 0.05 to P < 0.01). Mitochondrial ROS and ATP levels were also restored significantly by pretreatment with TXR (P < 0.05). The data suggested that preconditioning of rats with TXR had protective effect on DOX-induced cardiotoxicity through inducing antioxidative properties and restoring the mitochondrial function and the expression profiles of myocardial SIRT-1/PGC-1α/NRF-2 network.
由于阿霉素（DOX）在化疗中的临床应用因心脏毒性而受到限制，寻找新的策略来降低DOX的不良影响并改善患者预后至关重要。鉴于曲克芦丁（TXR）对心血管有积极影响，我们在此通过评估心肌氧化应激以及调节线粒体生物发生的基因表达，研究了TXR对DOX诱导的心脏毒性的影响。雄性Wistar大鼠（250 - 300克）被随机分为四组：对照组、TXR组、DOX组和TXR + DOX组。在DOX攻击前4周，通过灌胃管每天一次口服给予曲克芦丁（150毫克/千克）。接受TXR治疗的大鼠和时间匹配的对照大鼠腹腔注射DOX（20毫克/千克）。DOX攻击后三天，获取左心室样本，通过实时PCR确定调节线粒体生物发生的基因表达。还使用商业试剂盒以及分光光度法和荧光法评估心肌肌酸激酶（CK - mB）、氧化应激标志物和线粒体功能（活性氧或ROS的产生以及ATP水平）。与对照组相比，给予DOX显著增加了CK - mB、丙二醛（MDA）和线粒体ROS水平，同时降低了细胞ATP产生以及SIRT - 1、PGC - 1α和NRF - 2的表达水平，以及超氧化物歧化酶、谷胱甘肽过氧化物酶和过氧化氢酶活性（P < 0.05至P < 0.01）。用TXR预处理接受DOX的大鼠显著上调了所有生物发生基因和抗氧化酶的表达，对过氧化氢酶活性无显著影响，并使CK - mB和MDA水平显著降低至对照值（P < 0.05至P < 0.01）。用TXR预处理还显著恢复了线粒体ROS和ATP水平（P < 0.05）。数据表明，用TXR对大鼠进行预处理通过诱导抗氧化特性以及恢复线粒体功能和心肌SIRT - 1/PGC - 1α/NRF - 2网络的表达谱，对DOX诱导的心脏毒性具有保护作用。
