Targeting the AGE-RAGE/GSK-3β axis in diabetic retinopathy: Wound-healing effects of trans-anethole and FPS-ZM1 and putative GSK-3β inhibitory activity of FPS-ZM1

Diabetic retinopathy (DR) causes retinal detachment, capillary degeneration, and diabetic macular edema. Chronic hyperglycemia leads to the formation of advanced glycation end products (AGEs). This activates the receptor for advanced glycation end-products (RAGE) signaling pathway, resulting in inflammation, oxidative stress, and cellular issues in the retina. The AGE-RAGE axis and signaling pathways are attractive therapeutic targets. This study investigated the protective effects of trans-anethole (TA) and the RAGE inhibitor FPS-ZM1 in an in vitro model of high glucose-induced retinal injury. Both compounds were initially evaluated by molecular docking against GSK-3β. As FPS-ZM1 demonstrated higher predicted binding affinity than TA, further computational analyses, including molecular dynamics simulations and MM/GBSA binding free energy calculations, were performed only for FPS-ZM1. Both only TA and its combination with FPS-ZM1 greatly improved the healing response when glucose levels were high. This suggests that TA may have considerable therapeutic potential for wound healing. In addition, molecular docking and molecular dynamics simulations revealed that FPS-ZM1 may interact with GSK-3β ligand binding site. Further investigations utilizing in vivo models are necessary to validate the inhibitory impact of FPS-ZM1 on GSK-3β and to elucidate the molecular mechanisms responsible for the protective benefits of trans-anethole.