Dopamine Alleviated Diabetic Retinal Neurodegeneration through Protecting Retinal Ganglion Cells from Ferroptosis via the Nrf2/HO‑1 Signaling Pathway.

Diabetic retinopathy (DR) is a major cause of vision impairment, with diabetic retinal neurodegeneration (DRN) identified as an early pathological feature. Although dopamine (DA) has demonstrated protective effects in various neurodegenerative diseases, its role in DRN is inadequately understood. This study provides evidence that DA can alleviate DRN impairment and elucidates the underlying mechanisms. Diabetes was induced in C57BL/6 mice through a single large dose injection of streptozotocin, and the dopamine precursor l-DOPA was administered via intraperitoneal injection daily for 2 weeks to therapeutically supplement dopamine levels. The results indicated that l-DOPA treatment significantly restored retinal thickness, enhanced the amplitude of oscillatory potentials, and alleviated retinal glial cell activation compared to diabetic mice. In vitro, DA treatment of SH-SY5Y cells under high-glucose stress led to a significant increase in superoxide dismutase activity, with a reduction in malondialdehyde levels, lipid peroxide, and iron ion concentration. Additionally, the expression of GPX4, SLC7A11, ferritin, Nrf2, and HO-1 proteins was upregulated, while the expression of NCOA4 was downregulated. Importantly, the protective effects of DA were significantly attenuated by the Nrf2 inhibitor ML385, confirming the involvement of the Nrf2/HO-1 pathway in DA's protective mechanism. These findings suggest that DA alleviates oxidative stress, reduces ferroptosis, and improves the retinal function in DRN through the activation of the Nrf2/HO-1 pathway, indicating that DA may represent a novel therapeutic strategy for treating DRN.