Bakhdar Fatmah A, Abdel Kawy Hala S, Magadmi Rania M, El-Kordy Eman A, Alamri Abdulhakeem S
Pharmacology Department, Faculty of Medicine, King Abdulaziz University, KSA.
Pharmacology and Toxicology Department, Faculty of Pharmacy, Umm Al-Qura University, KSA.
J Taibah Univ Med Sci. 2022 Jul 21;18(1):9-18. doi: 10.1016/j.jtumed.2022.07.004. eCollection 2023 Feb.
The immunosuppressant tacrolimus is a major cause of new-onset diabetes after transplantation. The aim of this study was to evaluate whether a low dose of the histone-deacetylase inhibitor (vorinostat) might ameliorate tacrolimus-induced new-onset diabetes.
Thirty 8-week-old male Wistar rats were randomly divided into five groups: a control group, tacrolimus group (1.5 mg/kg intraperitoneally for 28 days), vorinostat group (15 mg/kg orally for 28 days), a group receiving tacrolimus with vorinostat for 28 days; and a group receiving coadministration of tacrolimus for 28 days and vorinostat for 14 days. Diabetes development was assessed on the basis of serum glucose, insulin, HOMA-IR and C-peptide. To investigate the mechanism of vorinostat, we assessed inflammatory markers (tumor necrosis factor-α and interleukin-1β), an antioxidant marker (glutathione), an oxidant marker (nicotinamide adenine dinucleotide phosphate hydrogen oxidase) and an apoptosis marker (caspase-3). Kidney functions (creatinine and blood urea nitrogen) were also assessed.
The administration of tacrolimus for 28 days resulted in significantly increased serum glucose and decreased C-peptide and insulin levels than those in the control group. However, coadministration of vorinostat significantly decreased hyperglycemia and increased C-peptide and insulin levels. Moreover, combined treatment with tacrolimus and vorinostat, compared with tacrolimus treatment alone, resulted in significantly reduced inflammatory and oxidant markers, and increased glutathione. Additionally, vorinostat improved the kidney parameters.
Vorinostat at a low dose (15 mg/kg) induces anti-inflammatory and antioxidative effects that protect the pancreas and kidney against the development of new-onset diabetes due to tacrolimus in rats. This experimental study provides insights supporting further clinical trials to improve the post-kidney transplantation protocol through addition of vorinostat to the immunosuppressive regimen.
免疫抑制剂他克莫司是移植后新发糖尿病的主要病因。本研究旨在评估低剂量组蛋白去乙酰化酶抑制剂（伏立诺他）是否可改善他克莫司诱导的新发糖尿病。
将30只8周龄雄性Wistar大鼠随机分为五组：对照组、他克莫司组（腹腔注射1.5mg/kg，共28天）、伏立诺他组（口服15mg/kg，共28天）、他克莫司与伏立诺他联合给药28天组；以及他克莫司给药28天和伏立诺他给药14天联合给药组。根据血清葡萄糖、胰岛素、稳态模型评估胰岛素抵抗（HOMA-IR）和C肽评估糖尿病的发展情况。为研究伏立诺他的作用机制，我们评估了炎症标志物（肿瘤坏死因子-α和白细胞介素-1β）、抗氧化标志物（谷胱甘肽）、氧化标志物（烟酰胺腺嘌呤二核苷酸磷酸氢氧化酶）和凋亡标志物（半胱天冬酶-3）。还评估了肾功能（肌酐和血尿素氮）。
与对照组相比，给予他克莫司28天导致血清葡萄糖显著升高，C肽和胰岛素水平降低。然而，伏立诺他联合给药显著降低了高血糖，并提高了C肽和胰岛素水平。此外，与单独使用他克莫司治疗相比，他克莫司与伏立诺他联合治疗显著降低了炎症和氧化标志物，并提高了谷胱甘肽水平。此外，伏立诺他改善了肾脏参数。
低剂量（15mg/kg）的伏立诺他具有抗炎和抗氧化作用，可保护大鼠胰腺和肾脏免受他克莫司诱导的新发糖尿病的影响。这项实验研究为进一步的临床试验提供了见解，支持通过在免疫抑制方案中添加伏立诺他来改进肾移植后方案。
