Georgiev Tsvetelin, Nikolova Galina, Dyakova Viktoriya, Karamalakova Yanka, Georgieva Ekaterina, Ananiev Julian, Ivanov Veselin, Hadzhibozheva Petya
Department of Physiology, Pathophysiology and Pharmacology, Medical Faculty, Trakia University, 6000 Stara Zagora, Bulgaria.
Department of Chemistry and Biochemistry, Medical Faculty, Trakia University, 6000 Stara Zagora, Bulgaria.
Pharmaceuticals (Basel). 2023 Sep 27;16(10):1365. doi: 10.3390/ph16101365.
Aminoglycoside antibiotics and gentamicin (GN), in particular, are still widely used in clinical practice. It is a well-known fact that GN causes nephrotoxicity, and redox disturbances are discussed as a factor in its side effects. Recently, a new type of cell oxidative death, named ferroptosis, was discovered; it is associated with iron accumulation in the cell, glutathione (GSH) depletion and inactivation of glutathione peroxidase-4 (GPX4), reactive oxygen species (ROS) increment with concomitant lipid peroxidation. In this regard, a possible connection between GN-induced renal damage, ferroptosis and the overall antioxidant status of the organism could be investigated. Moreover, due to its beneficial effects, GN is still one of the main choices as a therapeutic agent for several diseases, and the possible reduction of its side effects with the application of certain antioxidants will be of important clinical significance. The study was conducted with adult male white mice divided into several groups (n = 6). GN nephrotoxicity was induced by the administration of GN 100-200 mg/kg i.p. for 10 days. The control group received only saline. The other groups received either Vitamin E (400 mg/kg p.o.) or Silymarin (200 mg/kg p.o.) applied alone or together with GN for the same period. After the end of the study, the animals were sacrificed, and blood and tissue samples were taken for the assessment of biochemical parameters and antioxidant status, as well as routine and specific for GPX4 histochemistry examination. The experimental results indicate that GN-induced nephrotoxicity negatively modulates GPX4 activity and is associated with increased production of ROS and lipid peroxidation. The groups treated with antioxidants demonstrated preserved antioxidant status and better GPX4 activity. In conclusion, the inhibition of ROS production and especially the suppression of ferroptosis, could be of clinical potential and can be applied as a means of reducing the toxic effects of GN application.
氨基糖苷类抗生素，尤其是庆大霉素（GN），在临床实践中仍被广泛使用。众所周知，GN会导致肾毒性，氧化还原紊乱被认为是其副作用的一个因素。最近，一种名为铁死亡的新型细胞氧化死亡被发现；它与细胞内铁积累、谷胱甘肽（GSH）耗竭、谷胱甘肽过氧化物酶-4（GPX4）失活、活性氧（ROS）增加以及伴随的脂质过氧化有关。在这方面，可以研究GN诱导的肾损伤、铁死亡与机体整体抗氧化状态之间的可能联系。此外，由于其有益作用，GN仍然是几种疾病治疗药物的主要选择之一，应用某些抗氧化剂可能降低其副作用具有重要的临床意义。本研究以成年雄性白色小鼠为实验对象，分为几组（n = 6）。通过腹腔注射100 - 200 mg/kg的GN，持续10天来诱导GN肾毒性。对照组仅给予生理盐水。其他组分别单独或与GN一起在同一时期口服维生素E（400 mg/kg）或水飞蓟素（200 mg/kg）。研究结束后，处死动物，采集血液和组织样本，用于评估生化参数和抗氧化状态，以及进行GPX4的常规和特异性组织化学检查。实验结果表明，GN诱导的肾毒性对GPX4活性产生负向调节，并与ROS生成增加和脂质过氧化有关。用抗氧化剂处理的组显示出保留的抗氧化状态和更好的GPX4活性。总之，抑制ROS生成，尤其是抑制铁死亡，可能具有临床潜力，并可作为降低GN应用毒性作用的一种手段。
