Psalmotoxin-1, a novel TRPM2 channel antagonist, reduces age-related macular degeneration-caused mitochondrial oxidative damage and apoptosis in human retinal pigment epithelial (ARPE-19) cells.

PURPOSE: Age-related macular degeneration (AMD) develops as a result of mitochondrial reactive oxygen species (mitROS) and apoptosis caused by increased Ca2+ influx via the overstimulation of transient receptor potential melastatin 2 (TRPM2). Psalmotoxin-1 (PSTX) has acid-sensing ion channel (ASIC) inhibitor and antioxidant actions in several cells. PSTX has been shown to modulate hypoxia-induced oxidative cytotoxicity and cell death in mouse eye cells by inhibiting ASIC-mediated Ca2+ influx; however, this mechanism does not apply to AMD. In this study, we investigated how PSTX inhibits TRPM2 to protect human retinal pigment epithelium - 19 (ARPE-19) cells against mitROS damage and apoptosis caused by sodium iodate (SoI).

MATERIALS AND

METHODS

Control (CONT), 20 nM PSTX for 24 h, 10 mM SoI for 24 h, SoI + PSTX, and SoI + TRPM2 antagonist (25 µM N-(p-amylcinnamoyl) anthranilic acid, ACA) groups were induced in the ARPE-19 cells.

RESULTS

The ADP-ribose-induced TRPM2 current density, Fe2+, and H2O2-induced cytosolic Ca2+ concentrations were elevated by the SoI treatment. Additionally, its treatment increased the markers of apoptosis, caspases (caspase-3, -8, and - 9), oxidative stress, and mitochondrial membrane dysfunction while lowering glutathione (GSH), glutathione peroxidase (GSH-Px), and cell viability number. GSH, GSH-Px, and cell viability were enhanced, whereas oxidative stress and cell death indicators were decreased via TRPM2 inhibition by the treatments of PSTX and ACA.

CONCLUSION

The results of the preliminary study indicated that PSTX incubation blocked TRPM2-mediated Ca2+ signaling, reducing AMD-induced mitochondrial oxidant injury and cell death. PSTX, a new TRPM2 antagonist, may be utilized to treat oxidative stress and aberrant Ca2+ influx induced by AMD.