Abdelaala Nashwa, El-Shoura Ehab A M, Khalaf Marwa M, Zafaar Dalia, A N Ahmed Ahmed, Atwa Ahmed M, Abdel-Wahab Basel A, Ahmed Yasmine H, Abomandour Ahmed, Salem Esraa A
GI Medical Oncology Department, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Clinical Pharmacy Department, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt.
Immunopharmacol Immunotoxicol. 2025 Jun;47(3):287-304. doi: 10.1080/08923973.2025.2469220. Epub 2025 Feb 27.
Amikacin (AMC), an aminoglycoside antibiotic known for its rapid and potent bactericidal activity, is also associated with nephrotoxicity. Diosmin and perindopril have been reported to improve renal function and hold promise as therapeutic agents for preventing drug-induced nephrotoxicity. This study aimed to investigate the protective effect of Diosmin and perindopril, either alone or in combination, against renal damage induced by AMC toxicity and to elucidate the underlying mechanisms.
The researchers evaluated the impact of Diosmin (50 mg/kg, orally) and perindopril (2 mg/kg, intraperitoneally) on AMC-induced kidney injury (1.2 g/kg, intraperitoneally) in rats. Invasive blood pressure, serum kidney function and toxicity parameters, oxidative stress biomarkers, and inflammatory cytokine levels in serum and renal tissue were assessed. Histopathological changes in the kidney were examined using hematoxylin and eosin (H&E) staining, electron microscopy, and immunohistochemical analysis. The molecular mechanisms underlying the protective effect of the combination pretreatment on kidney injury were investigated using enzyme-linked immunosorbent assay (ELISA) and Western blotting techniques.
The findings demonstrated that the combination therapy improved kidney function by attenuating pathological changes observed in H&E staining including tubular necrosis and glomerular damage, in addition to reducing levels of kidney function including serum levels of creatinine compared to the AMC group, blood urea nitrogen (BUN) uric acid, and albumin. Mean arterial blood pressure, and toxicity markers including Kidney Injury Molecule-1 (KIM-1), Cystatin-c were also decreased in samples of combination group compared to AMC group. Furthermore, the protective combination therapy downregulated NF-κB-p65, P53, Keap-1, and C-FOS, while upregulating Mammalian sirtuin 1 (SIRT1), inhibitor of nuclear factor kappa B (Iκβ), nuclear factor erythroid 2-related factor 2 (Nrf2), and Heme oxygenase-1 (HO-1) levels.
The findings reveal the potential clinical application of combining Diosmin and perindopril to reduce AMC-induced nephrotoxicity, which requires further research in clinical settings.
阿米卡星（AMC）是一种以快速强效杀菌活性著称的氨基糖苷类抗生素，但也与肾毒性相关。据报道，地奥司明和培哚普利可改善肾功能，有望作为预防药物性肾毒性的治疗药物。本研究旨在探讨地奥司明和培哚普利单独或联合使用对AMC毒性诱导的肾损伤的保护作用，并阐明其潜在机制。
研究人员评估了地奥司明（50mg/kg，口服）和培哚普利（2mg/kg，腹腔注射）对大鼠AMC诱导的肾损伤（1.2g/kg，腹腔注射）的影响。评估了有创血压、血清肾功能和毒性参数、氧化应激生物标志物以及血清和肾组织中的炎性细胞因子水平。使用苏木精和伊红（H&E）染色、电子显微镜和免疫组织化学分析检查肾脏的组织病理学变化。使用酶联免疫吸附测定（ELISA）和蛋白质印迹技术研究联合预处理对肾损伤保护作用的分子机制。
研究结果表明，与AMC组相比，联合治疗通过减轻H&E染色中观察到的病理变化（包括肾小管坏死和肾小球损伤）改善了肾功能，此外还降低了肾功能水平，包括血清肌酐水平、血尿素氮（BUN）、尿酸和白蛋白。与AMC组相比，联合组样本中的平均动脉血压以及包括肾损伤分子-1（KIM-1）、胱抑素-c在内的毒性标志物也有所降低。此外，保护性联合治疗下调了NF-κB-p65、P-53、Keap-1和C-FOS，同时上调了哺乳动物沉默调节蛋白1（SIRT1）、核因子κB抑制剂（Iκβ）、核因子红细胞2相关因子2（Nrf2）和血红素加氧酶-1（HO-1）水平。
研究结果揭示了联合使用地奥司明和培哚普利降低AMC诱导的肾毒性的潜在临床应用价值，这需要在临床环境中进一步研究。
