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 7 (C24-R) and 8 (C24-S) were most active. To
enhance their water solubility, sustained release, and biocompatibility,
compounds 7 and 8 were encapsulated into
liposomes for in vivo activity and mechanistic studies. In vivo studies indicated that compounds 7 and 8 protected normal retinal structure and physiological function
after RIR injury, reversed damage to retinal ganglion cells, and the S-configuration exhibited significantly stronger activity
compared with the R-configuration. Mechanistic studies
showed that compound 8 exerted a therapeutic effect on
RIR injury by activating the Keap1/Nrf2/ARE signaling pathway; compound 7 did not influence this pathway. We also demonstrated that
differential isomerization at the C-24 position influenced protection
against RIR injury.