Immunology Department, Theodor Bilharz Research Institute, Warrak El-Hadar, P.O. box 30, Imbaba, 12411, Giza, Egypt.
Pharmacology Department, Theodor Bilharz Research Institute, El-Nile St., Warrak El-Hadar, P.O. box 30, Imbaba, 12411, Giza, Egypt.
Sci Rep. 2024 Oct 1;14(1):22751. doi: 10.1038/s41598-024-72729-w.
Currently, there is a lack of targeted medications for estrogen-induced intrahepatic cholestasis (EIC) and the primary objective in managing this condition is to safeguard liver function. Consequently, this study was conducted to examine the pharmacological efficacy of cilostazol (CTZ) in the management of EIC and explore its underlying mechanisms through the use of an animal model. Thirty female Sprague-Dawley rats were divided into five groups of six animals each: Normal group, 17-ethinylestradiol (EE)-induced intrahepatic cholestasis group, EE + ursodeoxycholic acid (UDCA)-treated group, EE + CTZ (5 mg/kg)-treated group, and EE + CTZ (10 mg/kg)-treated group. It was found that the therapeutic efficacy of UDCA and low dosage of CTZ (5 mg/kg) was comparable. Nevertheless, when CTZ was administered at a dose of 10 mg/kg, it resulted in the normalization of all liver function parameters, oxidative stress, and pro-inflammatory markers, together with improvement in the histopathological derangements and hepatocytic apoptosis. These effects were mediated through the activation of the hepatocyte nuclear factor-1 alpha (HNF1α)/Farnesoid X receptor (FXR) pathway with subsequent down-regulation of the bile acids (BAs) synthesis enzyme; cholesterol 7α-hydroxylase (CYP7A1), and up-regulation of the BAs-metabolizing enzyme; cytochrome P450 (CYP)3A1 and the bile salt export pump; BSEP. Therefore, the administration of CTZ in a dose-dependent manner can protect against EIC through regulating the HNF1α/FXR pathway and anti-apoptotic mechanisms. This implies that CTZ exhibits considerable promise as a therapeutic agent for the treatment of cholestatic liver disorders.
目前，针对雌激素诱导的肝内胆汁淤积症（EIC）尚无特效药物，该疾病的主要治疗目标是保护肝功能。因此，本研究旨在通过动物模型探究西洛他唑（CTZ）在 EIC 管理中的药理作用，并探讨其潜在机制。将 30 只雌性 Sprague-Dawley 大鼠分为五组，每组 6 只：正常组、17-乙炔雌二醇（EE）诱导的肝内胆汁淤积组、EE+熊去氧胆酸（UDCA）治疗组、EE+CTZ（5mg/kg）治疗组和 EE+CTZ（10mg/kg）治疗组。结果表明，UDCA 和低剂量 CTZ（5mg/kg）的治疗效果相当。然而，当 CTZ 剂量为 10mg/kg 时，所有肝功能参数、氧化应激和促炎标志物均恢复正常，组织病理学紊乱和肝细胞凋亡也得到改善。这些作用是通过激活肝细胞核因子-1α（HNF1α）/法尼醇 X 受体（FXR）通路来介导的，随后下调胆汁酸（BAs）合成酶胆固醇 7α-羟化酶（CYP7A1），上调 BAs 代谢酶细胞色素 P450（CYP）3A1 和胆汁盐输出泵；BSEP。因此，CTZ 呈剂量依赖性给药可通过调节 HNF1α/FXR 通路和抗凋亡机制来预防 EIC。这表明 CTZ 作为一种治疗胆汁淤积性肝病的药物具有很大的潜力。
