Azouz Amany A, Abdel-Nassir Abdel-Razek Esraa, Abo-Youssef Amira M
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
Saudi Pharm J. 2020 Nov;28(11):1317-1325. doi: 10.1016/j.jsps.2020.08.022. Epub 2020 Sep 2.
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.
Amlodipine (5 mg/kg, ) was administered to rats for 14 successive days. On the 10 day, nephrotoxicity was induced by a single dose of cisplatin (6.5 mg/kg, ). 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.
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.
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.
有效的化疗药物顺铂的治疗效用因其肾毒性作用而受到阻碍。我们开展本研究旨在探讨氨氯地平通过抑制γ-谷氨酰转肽酶（GGT）对顺铂肾毒性的可能保护作用。
连续14天给大鼠施用氨氯地平（5毫克/千克）。在第10天，通过单剂量顺铂（6.5毫克/千克）诱导肾毒性。在最后一天，采集血样以评估肾功能，同时采集肾组织样本用于测定GGT活性、氧化应激、炎症和凋亡标志物，并进行组织病理学评估。
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著降低。氨氯地平抑制了GGT酶，该酶参与细胞外谷胱甘肽（GSH）和铂-GSH结合物代谢为反应性毒性硫醇。此外，氨氯地平降低了肾脏中NADPH氧化酶的mRNA表达，同时通过激活Nrf2/HO-1信号增强了抗氧化防御。此外，它通过降低p38丝裂原活化蛋白激酶（p38 MAPK）和核因子-κB（NF-κB）的表达显示出显著的抗炎反应，随后肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）和血管细胞黏附分子-1（VCAM-1）表达下调。此外，氨氯地平降低了Bax/Bcl-2比值并提高了肝细胞生长因子（HGF），从而有利于肾细胞存活。
氨氯地平有效抑制GGT，同时增强抗氧化防御并抑制炎症信号传导和细胞凋亡，支持了我们的观点，即氨氯地平可替代毒性GGT抑制剂来预防顺铂肾毒性。
