Department of Pharmacology and Toxicology, Faculty of Pharmacy, South Valley University, Qena, 83523, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 83523, Egypt.
Pharmazie. 2024 Oct 1;79(9):187-194. doi: 10.1691/ph.2024.4566.
Antioxidant and anti-inflammatory effects of lixisenatide (LX) and ticagrelor (TC) have been previously identified in type 2 diabetes mellitus (T2DM). Diabetic nephropathy is one of the major complications of T2DM. In the current study, we examined the potential protective effects of LX and TC on experimentally induced diabetic nephropathy in T2DM rats and their possible molecular mechanisms. To examine this possibility, rats were fed a high-fat diet (HFD) for 12 weeks, followed by a single injection of 35 mg/kg streptozotocin (STZ) to induce T2DM. 10 μg/kg LX and 25 mg/kg TC were given alone or in combination to T2DM rats for 4 weeks. The kidney examination of T2DM rats showed clear deterioration. T2DM rats exhibited significantly higher body weight, blood glucose, hemostatic model assessment for insulin resistance (HOMA-IR), blood urea nitrogen (BUN), serum creatinine, kidney reactive oxygen species (ROS), nuclear factor-κ B (NF-κ B), and transforming growth factor-β (TGF-β ), and significantly lower serum insulin, urine creatinine, creatinine clearance (CRCL), kidney superoxide dismutase (SOD), glutathione reduced (GSH), nuclear factor erythroid 2 (NrF₂ ), heme oxygenase-1 (HO-1), and endothelial nitric oxide synthase (eNOS) when compared to control rats. Single treatment with LX or TC showed obvious ameliorative effects on kidney complications in T2DM rats, with more ameliorative effects with the combined administration of both drugs. Conclusion: Our investigation found that both LX and TC could significantly ameliorate the development of diabetic nephropathy via stimulating NrF₂ /HO-1 antioxidant pathway in addition to increasing eNOS and decreasing NF-κ B renal tissue concentrations, and these effects were markedly augmented by their combined administration.
利西那肽（LX）和替格瑞洛（TC）的抗氧化和抗炎作用已在 2 型糖尿病（T2DM）中得到证实。糖尿病肾病是 T2DM 的主要并发症之一。在本研究中，我们研究了 LX 和 TC 对 T2DM 大鼠实验性糖尿病肾病的潜在保护作用及其可能的分子机制。为了研究这种可能性，大鼠接受高脂肪饮食（HFD）喂养 12 周，然后单次注射 35mg/kg 链脲佐菌素（STZ）诱导 T2DM。10μg/kg LX 和 25mg/kg TC 分别或联合给予 T2DM 大鼠 4 周。T2DM 大鼠的肾脏检查显示明显恶化。T2DM 大鼠的体重、血糖、胰岛素抵抗止血模型评估（HOMA-IR）、血尿素氮（BUN）、血清肌酐、肾脏活性氧（ROS）、核因子-κB（NF-κB）和转化生长因子-β（TGF-β）明显升高，而血清胰岛素、尿肌酐、肌酐清除率（CRCL）、肾脏超氧化物歧化酶（SOD）、还原型谷胱甘肽（GSH）、核因子红细胞 2（NrF₂）、血红素加氧酶-1（HO-1）和内皮型一氧化氮合酶（eNOS）明显降低。与对照组相比，LX 或 TC 单一治疗对 T2DM 大鼠肾脏并发症有明显改善作用，联合两种药物治疗的改善作用更为明显。结论：我们的研究发现，LX 和 TC 均可通过刺激 NrF₂/HO-1 抗氧化途径，增加 eNOS 和降低 NF-κB 肾组织浓度，显著改善糖尿病肾病的发生，且联合用药效果更为明显。
