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 E₂), 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.

中文翻译：

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二甲双胍和水飞蓟素通过调节氧化还原状态和炎症，在环孢素A诱导的大鼠肝肾毒性中提供保护。

由于环孢素A（CsA）的肝毒性和肾毒性，因此常常受到限制。本研究旨在评估二甲双胍和水飞蓟素在CsA诱导的肝肾毒性大鼠模型中的保护作用。该研究包括7组Wistar白化病大鼠（每组n = 6）：正常对照组，实验对照组（仅CsA，25 mg / kg），CsA +二甲双胍（50和500 mg / kg），CsA +水飞蓟素（50和200 mg / kg）和CsA +维生素E（100 mg / kg）。每天通过管饲法给予所有药物，为期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）水平的影响。氧化应激（硫代巴比妥酸反应性物质，₂），细胞凋亡（末端脱氧核苷酸转移酶dUTP缺口末端标记阳性）以及组织组织学，环氧化酶（COX）-2和诱导型一氧化氮合酶（iNOS）免疫反应性。二甲双胍和水飞蓟素以及CsA的给药以剂量依赖的方式减轻了对肝和肾的功能损害。两种测试药物治疗后，氧化应激，炎症，细胞凋亡标记物的组织水平也得到了显着和相当的改善。组织学评分以及COX-2和iNOS免疫反应性评分的标准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相当，并且与参考药物维生素E相当。