Elsisi Alaa E, Elmarhoumy Esraa H, Osman Enass Y
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt.
Toxicol Res (Camb). 2022 Aug 9;11(5):718-729. doi: 10.1093/toxres/tfac045. eCollection 2022 Oct.
Verapamil (VER) and cilostazol (Cilo) are mostly used as cardiovascular drugs; they have beneficial effects on different organs toxicities.
we investigated whether the Nuclear factor erythroid 2-related factor 2 (Nrf2), Glycogen synthase kinase-3β (GSK-3β), and Nuclear factor-kappa B (NF-κB) pathway involved in the protective role of these drugs against Thioacetamide (TAA) induced hepatotoxicity.
male rats were randomized divided into five groups, each group ( = 10): control, TAA, VER+TAA, Cilo+TAA, and VER+Cilo+TAA groups. Hepatotoxicity induced in rats by TAA injection once on the 7th day of the experiment.
TAA-induced hepatotoxicity indicated by a significant elevated in serum markers (Alanine aminotransferases (ALT), Aspartate aminotransferases (AST), and bilirubin), oxidative stress markers (Malondialdehyde (MDA), and Nitric oxide (NO)), and protein levels markers (NF-κB, and S100 calcium-binding protein A4 (S100A4)). Also, TAA decreased Nrf2, and increased GSK-3β genes expression. Histopathological alterations in the liver also appeared as a response to TAA injection. On the other hand VER and/or Cilo significantly prevented TAA-induced hepatotoxicity in rats through significantly decreased in ALT, AST, bilirubin, MDA, NO, NF-κB, and S100A4 protein levels. Also, they increased Nrf2 and decreased GSK-3β genes expression which caused improvement in the histopathological changes of the liver.
the addition of verapamil to cilostazol potentiated the hepatoprotective activity, and inhibited the progression of hepatotoxicity caused by TAA through the Nrf2/GSK-3β/NF-κBpathway and their activity on oxidative stress, inflammation, and NF-κB protein expression.
维拉帕米（VER）和西洛他唑（Cilo）主要用作心血管药物；它们对不同器官的毒性具有有益作用。
我们研究了核因子红细胞2相关因子2（Nrf2）、糖原合酶激酶-3β（GSK-3β）和核因子κB（NF-κB）通路是否参与了这些药物对硫代乙酰胺（TAA）诱导的肝毒性的保护作用。
将雄性大鼠随机分为五组，每组（n = 10）：对照组、TAA组、VER+TAA组、Cilo+TAA组和VER+Cilo+TAA组。在实验第7天一次性注射TAA诱导大鼠肝毒性。
TAA诱导的肝毒性表现为血清标志物（丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）和胆红素）、氧化应激标志物（丙二醛（MDA）和一氧化氮（NO））以及蛋白质水平标志物（NF-κB和S100钙结合蛋白A4（S100A4））显著升高。此外，TAA降低了Nrf2，并增加了GSK-3β基因表达。肝脏的组织病理学改变也表现为对TAA注射的反应。另一方面，VER和/或Cilo通过显著降低ALT、AST、胆红素、MDA、NO、NF-κB和S100A4蛋白水平，显著预防了大鼠TAA诱导的肝毒性。此外，它们增加了Nrf2并降低了GSK-3β基因表达，从而改善了肝脏的组织病理学变化。
西洛他唑中加入维拉帕米可增强肝保护活性，并通过Nrf2/GSK-3β/NF-κB通路及其对氧化应激、炎症和NF-κB蛋白表达的作用，抑制TAA引起的肝毒性进展。
