Saudi Pharmaceutical Journal ( IF 3.0 ) Pub Date : 2020-09-02 , DOI: 10.1016/j.jsps.2020.08.022 Amany A Azouz 1 , Esraa Abdel-Nassir Abdel-Razek 1 , Amira M Abo-Youssef 1
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Background
The therapeutic utility of the effective chemotherapeutic agent cisplatin is hampered by its nephrotoxic effect. We aimed from the current study to examine the possible protective effects of amlodipine through gamma-glutamyl transpeptidase (GGT) enzyme inhibition against cisplatin nephrotoxicity.
Methods
Amlodipine (5 mg/kg, po) was administered to rats for 14 successive days. On the 10th day, nephrotoxicity was induced by a single dose of cisplatin (6.5 mg/kg, ip). On the last day, blood samples were collected for estimation of kidney function, while kidney samples were used for determination of GGT activity, oxidative stress, inflammatory, and apoptotic markers, along with histopathological evaluation.
Results
Amlodipine alleviated renal injury that was manifested by significantly diminished serum creatinine and blood urea nitrogen levels, compared to cisplatin group. Amlodipine inhibited GGT enzyme, which participates in the metabolism of extracellular glutathione (GSH) and platinum-GSH-conjugates to a reactive toxic thiol. Besides, amlodipine diminished mRNA expression of NADPH oxidase in the kidney, while enhanced the anti-oxidant defense by activating Nrf2/HO-1 signaling. Additionally, it showed marked anti-inflammatory response by reducing expressions of p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor-kappa B (NF-κB), with subsequent down-regulation of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and vascular cell adhesion molecule-1 (VCAM-1). Moreover, amlodipine reduced Bax/Bcl-2 ratio and elevated hepatocyte growth factor (HGF), thus favoring renal cell survival.
Conclusions
Effective GGT inhibition by amlodipine associated with enhancement of anti-oxidant defense and suppression of inflammatory signaling and apoptosis support our suggestion that amlodipine could replace toxic GGT inhibitors in protection against cisplatin nephrotoxicity.
中文翻译：
氨氯地平通过抑制 γ-谷氨酰转肽酶 (GGT) 减轻顺铂诱导的大鼠肾毒性，该酶抑制与 Nrf2/HO-1、MAPK/NF-κB 和 Bax/Bcl-2 信号传导相关
背景
有效化疗剂顺铂的治疗效用因其肾毒性作用而受到阻碍。我们的目的是通过当前的研究来检查氨氯地平通过抑制γ-谷氨酰转肽酶（GGT）对顺铂肾毒性可能产生的保护作用。
方法
连续 14 天给大鼠施用氨氯地平（5 mg/kg，口服）。第10天，单剂量顺铂（6.5 mg/kg，腹膜内注射）诱导肾毒性。最后一天，采集血液样本用于评估肾功能，同时使用肾脏样本测定GGT活性、氧化应激、炎症和凋亡标志物以及组织病理学评估。
结果
与顺铂组相比，氨氯地平减轻了肾损伤，表现为血清肌酐和血尿素氮水平显着降低。氨氯地平抑制 GGT 酶，该酶参与细胞外谷胱甘肽 (GSH) 和铂-GSH 缀合物代谢为活性有毒硫醇。此外，氨氯地平可降低肾脏中 NADPH 氧化酶的 mRNA 表达，同时通过激活 Nrf2/HO-1 信号传导增强抗氧化防御。此外，它通过减少 p38 丝裂原激活蛋白激酶 (p38 MAPK) 和核因子-κ B (NF-κB) 的表达，以及随后下调肿瘤坏死因子-α (TNF-α) 的表达，表现出明显的抗炎反应。 )、白细胞介素-6 (IL-6) 和血管细胞粘附分子-1 (VCAM-1)。此外，氨氯地平降低了 Bax/Bcl-2 比率并升高了肝细胞生长因子 (HGF)，从而有利于肾细胞存活。
结论
氨氯地平有效抑制 GGT 与增强抗氧化防御以及抑制炎症信号和细胞凋亡相关，支持我们的建议，即氨氯地平可以替代有毒的 GGT 抑制剂来预防顺铂肾毒性。
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