Ocotillol Derivatives Mitigate Retinal Ischemia-Reperfusion Injury by Regulating the Keap1/Nrf2/ARE Signaling Pathway

Retinal ischemia-reperfusion (RIR) injury can lead to various retinal diseases. Oxidative stress is considered an important pathological event in RIR injury. Here, we designed and synthesized 34 ocotillol derivatives, then examined their antioxidant and anti-inflammatory capacities; we found that compounds <b>7</b> (C24-<i>R</i>) and <b>8</b> (C24-<i>S</i>) were most active. To enhance their water solubility, sustained release, and biocompatibility, compounds <b>7</b> and <b>8</b> were encapsulated into liposomes for <i>in vivo</i> activity and mechanistic studies. <i>In vivo</i> studies indicated that compounds <b>7</b> and <b>8</b> protected normal retinal structure and physiological function after RIR injury, reversed damage to retinal ganglion cells, and the <i>S</i>-configuration exhibited significantly stronger activity compared with the <i>R</i>-configuration. Mechanistic studies showed that compound <b>8</b> exerted a therapeutic effect on RIR injury by activating the Keap1/Nrf2/ARE signaling pathway; compound <b>7</b> did not influence this pathway. We also demonstrated that differential isomerization at the C-24 position influenced protection against RIR injury.