The Nrf2 Activator RTA-408 Protects Against Retinal Ischemia-Reperfusion Injury by Reprogramming Microglia-Bipolar Cell Communication Networks (PRJCA049109)
Retinal ischemia-reperfusion (I/R) injury is a major cause of vision loss, and while the Nrf2 activator RTA-408 shows therapeutic potential, systemic administration has been limited by hepatotoxicity. This study investigated whether intravitreal delivery of RTA-408 could circumvent systemic toxicity while providing retinal neuroprotection. A mouse model of retinal I/R injury was established, followed by intravitreal injection of RTA-408 or saline. Safety evaluation demonstrated that intravitreal RTA-408 avoided hepatotoxicity, with normal liver histology and biochemistry. Histological analysis revealed significant preservation of retinal thickness and protection of inner retinal layers following RTA-408 treatment. Single-cell RNA sequencing of 32,544 cells revealed that microglia were the primary cellular targets, exhibiting the most extensive transcriptional changes and strongest Nrf2 pathway activation. Crucially, intercellular communication network analysis showed that I/R injury disrupted microglia-bipolar cell interactions, while RTA-408 treatment dramatically enhanced these communications. These findings demonstrate that intravitreal RTA-408 provides safe and effective retinal neuroprotection by reprogramming microglia to establish enhanced communication networks with vulnerable neurons, offering a promising therapeutic strategy for ischemic retinal diseases.