Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India.
Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.
J Biochem Mol Toxicol. 2021 Jan;35(1):e22614. doi: 10.1002/jbt.22614. Epub 2020 Sep 4.
The use of cyclosporine A (CsA) as an immunosuppressive agent is often limited owing to its hepatotoxic and nephrotoxic properties. The present study was designed to evaluate the protective effect of metformin and silymarin in a rat model of CsA induced hepatorenal toxicity. The study included seven groups of Wistar albino rats (n = 6 per group): normal control, experimental control (CsA alone, 25 mg/kg), CsA + metformin (50 and 500 mg/kg), CsA + silymarin (50 and 200 mg/kg) and CsA + vitamin E (100 mg/kg). All the drugs were given daily for a period of 21 days by oral gavage and their effect was evaluated on serum levels of organ function markers (serum glutamate pyruvate transaminase, serum glutamate oxaloacetate transaminase, bilirubin, urea/blood urea nitrogen, creatinine), markers of oxidative stress (thiobarbituric acid reactive substances, glutathione, superoxide dismutase), inflammation (nitrite, myeloperoxidase, tumour necrosis factor-alpha, prostaglandin E ), apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labelling positivity) in addition to tissue histology, cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) immunoreactivity. Administration of metformin and silymarin along with CsA ameliorated functional damage to liver and kidneys in a dose-dependent manner. Significant and comparable improvement in the tissue levels of oxidative stress, inflammation, apoptotic markers was also observed following treatment with both the test drugs. Normalization of histology scores, as well as COX-2 and iNOS immunoreactivity scores, further strengthened these findings. The hepatoprotective and nephroprotective effects of metformin and silymarin were comparable and matched with that of reference drug, vitamin E. The findings of the present study suggest that both metformin and silymarin have a potential for clinical use in patients receiving long-term CsA treatment to maintain their liver and kidney functions.
环孢素 A（CsA）作为一种免疫抑制剂的应用常因其肝毒性和肾毒性而受到限制。本研究旨在评估二甲双胍和水飞蓟素在 CsA 诱导的肝肾功能毒性大鼠模型中的保护作用。研究包括 7 组 Wistar 白化大鼠（每组 6 只）：正常对照组、实验对照组（单独 CsA，25mg/kg）、CsA+二甲双胍（50 和 500mg/kg）、CsA+水飞蓟素（50 和 200mg/kg）和 CsA+维生素 E（100mg/kg）。所有药物均通过口服灌胃给药，每天一次，共 21 天，并评估其对血清器官功能标志物（血清谷氨酸丙酮酸转氨酶、血清谷氨酸草酰乙酸转氨酶、胆红素、尿素/血尿素氮、肌酐）、氧化应激标志物（硫代巴比妥酸反应物质、谷胱甘肽、超氧化物歧化酶）、炎症标志物（亚硝酸盐、髓过氧化物酶、肿瘤坏死因子-α、前列腺素 E）、细胞凋亡标志物（末端脱氧核苷酸转移酶 dUTP 缺口末端标记阳性）的影响，以及组织学、环氧化酶（COX）-2 和诱导型一氧化氮合酶（iNOS）免疫反应性。CsA 联合二甲双胍和水飞蓟素给药可改善肝肾功能损伤，呈剂量依赖性。两种试验药物治疗后，组织氧化应激、炎症、细胞凋亡标志物水平也有显著且可比的改善。组织学评分、COX-2 和 iNOS 免疫反应性评分的正常化进一步加强了这些发现。二甲双胍和水飞蓟素的肝保护和肾保护作用与参考药物维生素 E 相当。本研究结果表明，二甲双胍和水飞蓟素均具有在长期接受 CsA 治疗的患者中应用以维持其肝肾功能的潜力。
