Clinical Pharmacology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt.
PLoS One. 2022 Jul 18;17(7):e0271591. doi: 10.1371/journal.pone.0271591. eCollection 2022.
Amikacin (AK) has the largest spectrum of aminoglycosides. However, its use is constrained because of nephrotoxicity and ototoxicity. Ellagic acid (EA) is a polyphenol present in plants. It has antioxidant, anticarcinogenic, and antimutagenic characteristics. Cilostazol (CTZ) is a phosphodiesterase Ш inhibitor, it is a potent vasodilator and antiplatelet drug. CTZ has an inhibitory effect on reactive oxygen species and superoxide generation in addition to hydroxyl radicals scavenging action. This study determines whether EA and cilostazol have a protective effect against AK-induced nephrotoxicity. Forty-nine rats were divided into seven equal groups: control normal; AK 400 mg/kg; EA 10 mg/kg; CTZ 10 mg/kg; AK 400 mg/kg plus EA 10 mg/kg; AK 400 mg/kg plus CTZ 10 mg/kg; AK 400 mg/kg plus EA 10 mg/kg and CTZ 10 mg/kg. For seven days, drugs were administered using gavage one hour before intramuscular injection of AK. Twenty-four hours after the last AK dosage, blood samples were collected to determine blood urea nitrogen and creatinine levels. Kidneys were removed for histopathological examination and measurement of: malondialdehyde (MDA), catalase (CAT), decreased glutathione (GSH), superoxide dismutase (SOD), interleukin 6 (IL6), tumor necrosis factor-alpha (TNFα), nuclear factor kappa B (NFκB), and Bcl-2 associated x protein (BAX). AK caused kidney damage, inflammatory mediator elevation, and oxidative stress and apoptotic markers. Rats receiving EA or CTZ indicated significant improvement in kidney function, decrease in oxidative stress and inflammation through NF-kB down-regulation and BAX expression. The combination of EA and CTZ showed a synergistic effect. In conclusion, EA and CTZ might play a beneficial role in preventing nephrotoxicity induced by AK partially by inhibition of tissue inflammation and apoptosis.
阿米卡星（AK）具有氨基糖苷类药物中最广泛的谱。然而，由于其肾毒性和耳毒性，其使用受到限制。鞣花酸（EA）是一种存在于植物中的多酚。它具有抗氧化、抗癌和抗突变特性。西洛他唑（CTZ）是一种磷酸二酯酶Ш抑制剂，它是一种有效的血管扩张剂和抗血小板药物。CTZ 除了具有清除羟自由基的作用外，还具有抑制活性氧和超氧化物生成的作用。本研究旨在确定 EA 和西洛他唑是否对 AK 诱导的肾毒性具有保护作用。49 只大鼠分为 7 组：正常对照组；AK400mg/kg；EA10mg/kg；CTZ10mg/kg；AK400mg/kg+EA10mg/kg；AK400mg/kg+CTZ10mg/kg；AK400mg/kg+EA10mg/kg 和 CTZ10mg/kg。七天内，通过灌胃给药，在肌肉注射 AK 前一小时给药。最后一次 AK 剂量后 24 小时，采集血样以测定血尿素氮和肌酐水平。取出肾脏进行组织病理学检查和测定：丙二醛（MDA）、过氧化氢酶（CAT）、还原型谷胱甘肽（GSH）、超氧化物歧化酶（SOD）、白细胞介素 6（IL6）、肿瘤坏死因子-α（TNFα）、核因子 kappa B（NFκB）和 Bcl-2 相关 X 蛋白（BAX）。AK 导致肾脏损伤、炎症介质升高和氧化应激和凋亡标志物。给予 EA 或 CTZ 的大鼠表明，通过 NF-kB 下调和 BAX 表达，肾功能显著改善，氧化应激和炎症减轻。EA 和 CTZ 的联合具有协同作用。总之，EA 和 CTZ 可能通过抑制组织炎症和凋亡，在预防 AK 诱导的肾毒性方面发挥有益作用。
