Protection mechanism of epalrestat on glutamate-induced retinal excitotoxicity model based on network pharmacology

This study aimed to investigate the protective effect of epalrestat (EPS) and the molecular mechanisms that underlie its treatment of retinal excitotoxicity.

The corresponding targets of drug and disease were obtained from relevant databases, respectively. By constructing and analyzing connected networks, the targets, primary molecular function, biological processes, and signaling pathways associated with EPS were found. The binding affinity between EPS and potential targets was confirmed by molecular docking. Establishing an excitotoxicity model with glutamate to further evaluate network pharmacology results by gathering samples from R28 cells and measuring inflammatory factor levels, cell viability, oxidative stress indicators, and Nrf2/HO-1 signaling pathway expression.

138 targets, including the NFE2L2 and HMOX1 that encode HO-1 and Nrf2, were shown to overlap between drug and disease by network pharmacology analysis. Molecular docking results revealed that EPS exerts therapeutic effects through multiple targets like Nrf2 and HO-1. In vitro experiments have shown that EPS reversed the effects of glutamate-induced apoptosis, which included a decrease in superoxide dismutase (SOD) and an increase in intracellular reactive oxygen species (ROS), malondialdehyde (MDA), TNF-α, IL-1β, and IL-6, by regulating the Nrf2/HO-1 signaling. Furthermore, by reducing glutamate-induced cell damage, the Nrf2 inhibitor ML385 further supports the important roles of Nrf2/HO-1 signaling in R28 cell antioxidant and anti-inflammatory responses.

EPS inhibits retinal excitotoxicity by acting as an antioxidant and anti-inflammatory through the Nrf2/HO-1 signaling pathway. EPS may have some clinical benefits in reducing retinal excitotoxicity-related retinopathy.