# Evaluation of Ototoxic Effects of Cisplatin in a Rat Model: A Dose-Response Study
## 4 Discussion
The product of this nitration, 3-nitrotyrosine, is considered a biological marker of oxidative stress, more specifically termed \"nitrative stress\" [24; 82]. The expression of nitrotyrosine was evaluated in both organs involved in our investigation, the cochlea and the kidney. Although protein nitration could occur under basal physiological conditions, it increases significantly after ROS and RNS elevation, and it could only be observed in regions that experienced oxidative stress [24; 87]. In control rats, nitrotyrosine was observed in certain areas of the cochlea, such as the spiral ligament and the organ of Corti cells, while absent in the stria vascularis and kidney. After CDDP administration, nitrotyrosine expression was observed to increase in all tissues, particularly in the stria vascularis, renal tubular epithelium, and cells detached from the tubular lumen. Previous studies in the cochleae and kidneys of animals treated with CDDP have documented an increase in nitrotyrosine expression, suggesting a key role for protein nitration in CDDP-induced ototoxicity and nephrotoxicity [39; 63; 64; 71; 88]. SOD1 is a Cu/Zn enzyme that is generally found in the cellular cytoplasm [89] but has been observed to move into the nucleus when ROS levels increase, allowing it to regulate genes involved in the control of oxidative stress [23]. In the NT group, we found that SOD1 was present in the stria vascularis, almost everywhere in the spiral ligament, and in the cytoplasm of spiral ganglion neurons, as indicated by other studies, which also noticed high expression in the Corti organ [90]. Treatment with CDDP resulted in the presence of SOD1 in the nuclei of hair cells instead. The different distribution of SOD1 in cochlear tissues might suggest a varying sensitivity to oxidative stress. Treatment with CDDP caused a significant reduction in this protein throughout the spiral ligament and localized labeling in the basal marginal cells of the stria vascularis. Due to its highly vascularized tissue, the stria vascularis is the first to be affected by CDDP treatment and oxidative stress, ahead of all other cochlear structures, but it was also the tissue with the highest activity of SOD1 [90], which could explain its readiness to respond to oxidative stress. Furthermore, the stria vascularis has a high level of CAT and GSH, which prevents the formation of superoxides when SOD1 levels are reduced [91; 92]. However, hair cells could be more susceptible to oxidative stress. In rats treated with CDDP, nuclear staining disappeared in hair cells damaged by exposure to chemotherapy. This suggests that CDDP caused oxidative stress in hair cells, which caused the depletion of endogenous antioxidant defenses, leading to morphological and functional damage and cell death. Previous data have shown that SOD1 was crucial for hair cell survival, which was consistent with this hypothesis [84; 93]. In the kidney, SOD1, which has two isoforms, has been studied in different tissues of rat [94]. These experiments revealed that SOD was mainly active in the glomeruli and has reduced activity in the epithelial cells of the DCT, collecting ducts, Henle's loops, and the brush border of PCT epithelial cells. During these studies, it was discovered that SOD activity and immunodalization of the two isoforms differed significantly, with SOD1 and SOD2 staining appearing mild in all nephron structures but absent in glomeruli [94]. It has been suggested that the differences may be attributed to the presence of another extracellular SOD, SOD3. Recent studies on the nephrotoxic effects of cisplatin confirmed a reduction in SOD expression in rats treated with the drug [76; 95; 96]. Our investigation revealed that SOD1 was absent from the glomeruli but was present in the nuclei of PT cells, especially in the region that borders the medulla. The terminal part of the PT was more sensitive to harmful stimuli than the initial part, which was closer to the glomerulus and the middle part [97].