Tempol Mitigates Cisplatin-Induced Retinopathy by Modulating ER Stress, Enhancing Autophagy, and Preserving Neurotrophic Support.

The-state-of-the-art literature is eagerly searching for protective strategies of chemotherapy-induced retinal neurotoxicity, driven by oxidative stress, ER stress, mitochondrial dysfunction, and autophagy impairment. We investigated the neuroprotective effects of tempol, a stable nitroxide antioxidant, capable of crossing biological barriers and mitigating cisplatin-induced cytomolecular insult. Forty-eight Wistar rats were divided into control, cisplatin-treated, tempol-treated, and CIS + TEM-cotreated groups. Retinal tissues were analyzed through histological, immunohistochemical, and biomolecular oxidative profile and NGF expression techniques. Autophagy, ER stress markers, and ultrastructural changes were evaluated. Cisplatin induced severe retinal degeneration, characterized by photoreceptor disorganization, mitochondrial damage, impaired redox path-ways, impaired autophagy (LC3↓, p62↑), downregulated NGF, and ER stress activation (CHOP↑, JNK↑, XBP1↑, BiP↑). Tempol pre- and co-treatment restored the high baseline level of retinal autophagy as proved by immunohistochemical and mRNA upregulation of LC3 and downregulation of p62 in ganglion cell, inner nuclear, and outer nuclear layers as well as Beclin 1 gene expression restoration. Furthermore, tempol alleviated ER stress and preserved mitochondrial ultrastructure driven by NGF upregulation and restored redox sensitive pathways, leading to improved retinal ganglion and RPE cell architecture and neuroprotection. This study provides critical insights into the molecular mechanisms of cisplatin-induced retinopathy, emphasizing oxidative stress, ER stress, autophagy inhibition, and apoptosis. It highlights tempol's therapeutic potential as a neuroprotective agent targeting oxidative-apoptotic pathways and restoring ER-mitochondrial-autophagy-neurotrophic retinal homeostasis.