The Effects And Mechanism Of Rapamycin On Photoreceptor Cell Death After Experimental Retinal Detachment

Purpose After experimental retinal detachment(RD),the applications of caspase inhibitor z-vadfmk(a pan caspase inhibitor)could inhibit apoptosis,but increased receptor interacting protein(RIP)-mediated necroptosis.In this study,we investigated whether rapamycin could inhibit necroptosis and cooperate with z-vad-fmk to protect the retina after RD.Methods RD animal models were established in Sprague–Dawley rats by subretinal injection of sodium hyaluronate and treated with subretinal injections of z-vad-fmk or z-vad-fmk combined with rapamycin.On day 3 after RD,retinas were collected and analyzed by transmission electron microscopy(TEM),ROS assay,and western blot(for beclin-1,LC-3,RIP-1,AIF).On day 7 after RD,retinas were observed by H&E staining.Vision-dependent behavior of rats was tested by the modified Morris water maze.Results TEM and H&E staining indicated that rapamycin combined with z-vad-fmk could reduce photoreceptor necrosis and preserve the ONL thickness after RD.The modified Morris water maze test showed that vision-dependent behavior was also significantly improved in the rapamycin + z-vad-fmk group.Western Blotting results demonstrated that rapamycin promoted the activation of autophagy by promoting beclin-1 and LC-3 induction and inhibited z-vad-fmk-induced necroptosis by inhibiting RIP-1 expression.In addition,rapamycin could also inhibit ROS production and AIF release.Conclusions Rapamycin could inhibit ROS production and AIF release and prevent z-vad-fmk-induced necroptosis by activation of autophagy after experimental retinal detachment.The combination of z-vad-fmk and rapamycin may be a promising therapeutic regimen for maximally inhibiting cell death after RD.