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.

Objectives: The current study focused on the kidney protection and antioxidant properties along with the potential anti-ferroptotic activity of Geranium macrorrhizum L. (G. macrorrhizum) oil to ameliorate the acute renal oxidative tissue damage and toxicity of the aminoglycoside antibiotic gentamicin (GM) in an experimental murine model. Methods: The research was carried out with mature Balb/c mice distributed into four groups (n = 6). Application of GM (200 mg kg⁻¹ intraperitoneal injection for 10 days) was performed to induce kidney injury. Only saline was administered to the controls. The remaining groups were administered G. macrorrhizum oil (50 mg kg⁻¹ per dose) either used alone or in combination with GM. To assess the renal antioxidant status, the activities of specific antioxidant enzymes, indicators of lipid and DNA peroxidation and renal functional damage were examined using standard commercial kits, ELISA and EPR spectroscopy. Results: G. macrorrhizum oil analysis revealed 20 organic components belonging to mono- and sesquiterpenoids and long-chain hydrocarbons. The antioxidant and anti-inflammatory effects of G. macrorrhizum oil were demonstrated by reduced malondialdehyde, ROS, 8-hydroxy-2′-deoxyguanosine and cytokine levels (especially interleukin-1β) compared with GM. Furthermore, increased activation of superoxide dismutase, catalase and glutathione (GSH) were observed in the kidney homogenates of the animals which received GM in combination with G. macrorrhizum oil compared with the GM group. Additional changes in the GSH/glutathione peroxidase-4 axis were detected, suggesting the possible anti-ferroptotic potential of the oil. Nephroprotection was also demonstrated by elevated PGC-1α expression (peroxisome proliferator-activated receptor γ coactivator 1-alpha) and reduced KIM-1 levels (kidney injury molecule-1) following application of the oil. Conclusions: The preserved kidney antioxidant and functional properties in the groups treated with oil suggest that Geranium macrorrhizum L. could be utilized clinically to mitigate the toxic effects of GM application.