The Potential Role of Small-Molecule PERK Inhibitor LDN-0060609 in Primary Open-Angle Glaucoma Treatment (2021)
Primary open-angle glaucoma (POAG) constitutes the most common type of glaucoma.Emerging evidence suggests that Endoplasmic Reticulum (ER) stress and the protein kinase RNAlike endoplasmic reticulum kinase (PERK)-mediated Unfolded Protein Response (UPR) signalingpathway play a key role in POAG pathogenesis. Thus, the main aim of the study was to evaluate theeffectiveness of the PERK inhibitor LDN-0060609 in cellular model of glaucoma using primary humantrabecular meshwork (HTM) cells. To evaluate the level of the ER stress marker proteins, Westernblotting and TaqMan gene expression assay were used. The cytotoxicity was measured by XTT, LDHassays and Giemsa staining, whereas genotoxicity via comet assay. Changes in cell morphologywere assessed by phase-contrast microscopy. Analysis of apoptosis was performed by caspase-3assay and flow cytometry (FC), whereas cell cycle progression by FC. The results obtained havedemonstrated that LDN-0060609 triggered a significant decrease of ER stress marker proteins withinHTM cells with induced ER stress conditions. Moreover, LDN-0060609 effectively increased viability,reduced DNA damage, increased proliferation, restored normal morphology, reduced apoptosis andrestored normal cell cycle distribution of HTM cells with induced ER stress conditions. Thereby,PERK inhibitors, such as LDN-0060609, may provide an innovative, ground-breaking treatmentstrategy against POAG.
Keywords: nauki medyczne