Ocotillol Derivatives\nMitigate Retinal Ischemia-Reperfusion\nInjury by Regulating the Keap1/Nrf2/ARE Signaling Pathway

Retinal ischemia-reperfusion (RIR) injury can lead to\nvarious retinal\ndiseases. Oxidative stress is considered an important pathological\nevent in RIR injury. Here, we designed and synthesized 34 ocotillol\nderivatives, then examined their antioxidant and anti-inflammatory\ncapacities; we found that compounds <b>7</b> (C24-<i>R</i>) and <b>8</b> (C24-<i>S</i>) were most active. To\nenhance their water solubility, sustained release, and biocompatibility,\ncompounds <b>7</b> and <b>8</b> were encapsulated into\nliposomes 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\nafter RIR injury, reversed damage to retinal ganglion cells, and the <i>S</i>-configuration exhibited significantly stronger activity\ncompared with the <i>R</i>-configuration. Mechanistic studies\nshowed that compound <b>8</b> exerted a therapeutic effect on\nRIR injury by activating the Keap1/Nrf2/ARE signaling pathway; compound <b>7</b> did not influence this pathway. We also demonstrated that\ndifferential isomerization at the C-24 position influenced protection\nagainst RIR injury.