Ali Maha Ismail Mohammed, Imbaby Samar, Arafat Horeya Erfan Korayem, Maher Shymaa Ahmed, Kolieb Eman, Ali Shrouk Mohamed
Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Suez Canal University, 41522 Ismailia, Egypt.
Clinical Pharmacology Department, Faculty of Medicine, Suez Canal University, 41522 Ismailia, Egypt.
Life Sci. 2023 May 1;320:121561. doi: 10.1016/j.lfs.2023.121561. Epub 2023 Mar 8.
The current work aims to demonstrate the potential defensive function of venlafaxine (VLF) in cardiotoxicity and nephrotoxicity caused by cisplatin (CP), that could be by modulating extracellular signal-regulated kinase (ERK)1/2 and nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase NOX4 pathways.
Five groups of rats were used, as follow: three control groups (control, carboxymethyl cellulose, and VLF), CP group got CP once (7 mg/kg, intraperitoneally, i.p.), and (CP+ VLF) group got CP once then after 1 h they got VLF {50 mg/kg daily, orally for 14 days}. At the end of the study; electrocardiogram (ECG) was recorded for anaesthized rats then blood samples and tissues were taken for biochemical and histopathological investigations. Caspase 3, a marker of cellular damage and apoptosis was detected by immunohistochemistry.
CP treatment significantly impaired cardiac functions as evidenced by changes in rats' ECG. Cardiac enzymes, renal markers and inflammatory markers were increased with decreased activities of the total antioxidant capacity, superoxide dismutase and glutathione peroxidase. Also, ERK1/2 and NOX4 were upregulated with histopathological and immunohistochemical alterations of heart and kidney. While, VLF markedly alleviated CP-induced functional cardiac abnormalities and improved ECG pattern. It reduced both cardiac and renal biomarkers, oxidative stress, proinflammatory cytokine with ERK1/2 and NOX4 downregulation, improved the histopathological and immunohistochemical changes induced by cisplatin in heart and kidney.
VLF treatment impedes cardiotoxicity and nephrotoxicity caused by CP. This beneficial effect was mediated through reduction of oxidative stress, inflammation, and apoptosis by targeting the ERK1/2 and NOX4.
当前研究旨在证明文拉法辛（VLF）在顺铂（CP）所致心脏毒性和肾毒性中的潜在保护作用，其机制可能是通过调节细胞外信号调节激酶（ERK）1/2和烟酰胺腺嘌呤二核苷酸磷酸（NAPDH）氧化酶NOX4信号通路。
使用五组大鼠，如下：三个对照组（对照组、羧甲基纤维素组和VLF组），CP组一次性腹腔注射CP（7 mg/kg），（CP + VLF）组一次性腹腔注射CP后1小时开始口服VLF（50 mg/kg，每日一次，共14天）。研究结束时，记录麻醉大鼠的心电图（ECG），然后采集血样和组织进行生化及组织病理学检查。通过免疫组织化学检测细胞损伤和凋亡的标志物半胱天冬酶3。
CP治疗显著损害心脏功能，大鼠心电图出现变化。心脏酶、肾脏标志物和炎症标志物升高，而总抗氧化能力、超氧化物歧化酶和谷胱甘肽过氧化物酶活性降低。此外，ERK1/2和NOX4上调，心脏和肾脏出现组织病理学和免疫组织化学改变。而VLF显著减轻CP诱导的心脏功能异常，改善心电图模式。它降低了心脏和肾脏生物标志物、氧化应激、促炎细胞因子，下调了ERK1/2和NOX4，改善了顺铂诱导的心脏和肾脏组织病理学和免疫组织化学变化。
VLF治疗可减轻CP所致的心脏毒性和肾毒性。这种有益作用是通过靶向ERK1/2和NOX4降低氧化应激、炎症和细胞凋亡来实现的。
