Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura University, 35516 Mansoura, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, 35516 Mansoura, Egypt.
Int Immunopharmacol. 2021 Jan;90:107125. doi: 10.1016/j.intimp.2020.107125. Epub 2020 Nov 13.
Cardiotoxicity is one of the most commonly encountered adverse effects observed alongside the therapeutic use of doxorubicin (DOX), thus curbing its therapeutic utility.
The current study was conducted to evaluate the cardioprotective effect of gabapentin (Gaba), a Ca + 2 channel blocker with emerging pharmacological merits, against DOX-induced cardiotoxicity. Gaba was orally administered at two dose levels (10 and 30 mg/kg) for 21 days parallel to DOX injection.
DOX induced significant functional, biochemical, and histopathological injury to the myocardium. Gaba treatment revealed a cardioprotective effect as manifested in the significant restoration of electrocardiogram parameters, including the heart rate, ST segment elevation, QRS and T wave amplitudes, and QT and PR intervals. The biomarkers of myocardial injury, namely serum creatine kinase, aspartate aminotransferase, and lactate dehydrogenase activities, significantly declined as well as the concomitant improvement of the myocardial oxidative status. Mechanistically, Gaba treatment significantly reduced the myocardial contents of c-Jun N-terminal kinase (JNK), the major modulator of inflammatory/apoptotic signaling. However, the myocardial contents of the apoptotic biomarkers caspase-8 and TRAIL also significantly declined. In isolated cardiomyocytes, Gaba treatment maintained the morphological characteristics of the cardiomyocytes and preserved their spontaneous beating characteristics. Nevertheless, the protein expression of caspase-8, JNK 1/2, and CD95L significantly declined with Gaba treatment.
Gaba confers cardioprotective effects against DOX-induced myocardial injury and cardiotoxicity by modulating the inflammatory/apoptotic signaling pathway.
心脏毒性是多柔比星（DOX）治疗应用中最常见的不良反应之一，因此限制了其治疗用途。
本研究旨在评估钙通道阻滞剂加巴喷丁（Gaba）对 DOX 诱导的心脏毒性的心脏保护作用。Gaba 以两个剂量水平（10 和 30mg/kg）口服给药，与 DOX 注射同时进行 21 天。
DOX 对心肌引起显著的功能、生化和组织病理学损伤。Gaba 治疗表现出心脏保护作用，表现为心电图参数（包括心率、ST 段抬高、QRS 和 T 波幅度以及 QT 和 PR 间隔）的显著恢复。心肌损伤的生物标志物，即血清肌酸激酶、天冬氨酸转氨酶和乳酸脱氢酶活性也显著降低，同时心肌氧化状态得到改善。机制上，Gaba 治疗显著降低了 c-Jun N 末端激酶（JNK）的心肌含量，JNK 是炎症/凋亡信号的主要调节剂。然而，凋亡标志物 caspase-8 和 TRAIL 的心肌含量也显著下降。在分离的心肌细胞中，Gaba 治疗维持了心肌细胞的形态特征，并保持了它们自发跳动的特征。然而，Gaba 治疗后 caspase-8、JNK1/2 和 CD95L 的蛋白表达显著下降。
Gaba 通过调节炎症/凋亡信号通路对 DOX 诱导的心肌损伤和心脏毒性具有心脏保护作用。
