Selenium Nanoparticles Protect Retinal Pigment Epithelial Cells Against Experimental Age‐Related Macular Degeneration‐Induced Mitochondrial Oxidative Toxicity and Apoptosis Through the Modulation of the TRPM2 Channel

Excessive Ca²⁺ influx leads to mitochondrial oxidative injury and cell death, contributing to the development of age-related macular degeneration (AMD). The protective role of selenium nanoparticle (SeNPs), through inhibition of ADP-ribose- and hydrogen peroxide (H₂O₂)-induced TRPM2 cation channel stimulation, was recently reported in human retinal pigment epithelial 19 (ARPE-19) cells for hypoxia-induced oxidative cytotoxicity and cell death, but not for AMD. We aimed to investigate the protective effects of SeNPs through inhibition of TRPM2 on AMD (sodium iodate [NaI])-induced oxidative injury, cell death, and apoptosis in ARPE-19 cells. The ARPE-19 cells were divided into four main groups: control (CNT), SeNPs (2.5 μg/mL for 24 h), AMD (10 mM NaI for 24 h) and AMD + SeNPs. The AMD treatment increased TRPM2 current density and cytosolic Ca²⁺ and Zn²⁺ fluorescence intensities, as well as the percentage of cell death. It also elevated apoptotic markers (caspases 3, 8, and 9) and oxidative stress markers (mitochondrial membrane dysfunction, oxygen free radicals, and lipid peroxidation), while decreasing antioxidants (glutathione and glutathione peroxidase), cell viability and the number of live cells. TRPM2 stimulation further increased these markers. When SeNPs and TRPM2 antagonists were used to treat the AMD-induced increase in TRPM2 activation, they increased antioxidants and cell viability while decreasing oxidative stress and cell death markers. In conclusion, SeNP treatment reduced AMD-induced mitochondrial oxidative cytotoxicity and cell death by inhibiting TRPM2-mediated Ca²⁺ signaling. SeNP represents a potential therapeutic option for AMD-induced retinal disorders linked to abnormal oxygen free radical production and Ca²⁺ influx.