Department of Pharmacology & Toxicology, Faculty of Pharmacy, Nahda University, Beni-Suef 62514, Egypt.
Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.
Biomed Pharmacother. 2022 Jun;150:113026. doi: 10.1016/j.biopha.2022.113026. Epub 2022 Apr 28.
Non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastric ulcers represent a significant clinical concern and adversely affect the quality of life. Inducible nitric oxide synthase/endothelial nitric oxide synthase (iNOS/eNOS) and asymmetric dimethylarginine/ dimethylarginine dimethylaminohydrolase-1 (ADMA/DDAH-1) signaling are key players in gastric ulcer pathogenesis. This work was planned to explore the role of iNOS/eNOS and ADMA/DDAH-1 signaling in rats with indomethacin-induced gastric ulcer, as potential pathways for the gastro-protective effect of tadalafil. Split into 5 separate groups, rats were assigned to control, tadalafil (10 mg/kg, p.o), indomethacin (single oral dose of 60 mg/kg), indomethacin + pantoprazole (40 mg/kg, p.o), and indomethacin + tadalafil (10 mg/kg, p.o). The results indicated that pretreatment with tadalafil significantly reduced ulcer index (UI), increased preventive index (PI), and counteracted indomethacin-induced histopathological aberrations. Tadalafil significantly reduced the gastric content of NO while it significantly elevated that of GSH and enhanced SOD activity. It significantly reduced the gastric expression of TNF-α and ADMA while it significantly elevated that of COX-2, PGE-2, and DDAH-1. Western blot analysis revealed that pretreatment with tadalafil significantly reduced iNOS protein expression while it significantly elevated that of eNOS. Collectively, these data suggest that tadalafil exerts potential protective effect against indomethacin-induced ulcer through suppression of inflammation, attenuation of oxidative stress, and boosting of antioxidants. Moreover, tadalafil protective effects are mediated via upregulation of PGE-2 with modulating the signaling pathways of ADMA/DDAH-1, and iNOS/eNOS. As a result, the current evidence corroborates the use of tadalafil in controlling gastric ulcers and preventing NSAID gastric side effects.
非甾体抗炎药（NSAIDs）引起的胃溃疡是一个重要的临床关注点，会降低生活质量。诱导型一氧化氮合酶/内皮型一氧化氮合酶（iNOS/eNOS）和不对称二甲基精氨酸/二甲基精氨酸二甲氨基水解酶-1（ADMA/DDAH-1）信号通路是胃溃疡发病机制中的关键因素。本研究旨在探讨 iNOS/eNOS 和 ADMA/DDAH-1 信号通路在吲哚美辛诱导的大鼠胃溃疡中的作用，以及它可能是他达拉非发挥胃保护作用的途径。将大鼠分为 5 组：对照组、他达拉非（10mg/kg，po）组、吲哚美辛（单次口服 60mg/kg）组、吲哚美辛+泮托拉唑（40mg/kg，po）组和吲哚美辛+他达拉非（10mg/kg，po）组。结果表明，他达拉非预处理可显著降低溃疡指数（UI），增加预防指数（PI），并拮抗吲哚美辛引起的组织病理学异常。他达拉非显著降低胃内容物中的一氧化氮（NO）水平，同时显著增加谷胱甘肽（GSH）水平和超氧化物歧化酶（SOD）活性。他达拉非显著降低肿瘤坏死因子-α（TNF-α）和 ADMA 的胃表达，同时显著增加环氧化酶-2（COX-2）、前列腺素 E-2（PGE-2）和 DDAH-1 的胃表达。Western blot 分析显示，他达拉非预处理可显著降低 iNOS 蛋白表达，同时显著增加 eNOS 蛋白表达。综上所述，这些数据表明，他达拉非通过抑制炎症、减轻氧化应激和增强抗氧化剂来发挥对吲哚美辛诱导的溃疡的潜在保护作用。此外，他达拉非的保护作用是通过上调 PGE-2 来调节 ADMA/DDAH-1 和 iNOS/eNOS 信号通路来介导的。因此，目前的证据支持使用他达拉非来控制胃溃疡和预防 NSAID 的胃部副作用。
