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Kai Dong, Xiaodong Sun, Genjie Ke; Involvement of Autophagy in z-VAD-FMK Induced Photoreceptor Necroptosis, a Caspase-Independent Cell Death, after Experimental Retinal Detachment. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2854.
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Necroptosis is a recently discovered, caspase-independent cell death and necroptosis signaling can accompany autophagy, which may also contribute to neuronal damage. We investigated whether necroptosis induced by z-VAD-FMK was involved the activation of autophagy and whether Necrostatin-1, a specific necroptosis inhibitor, could inhibit this induction of autophagy after experimental retinal detachment.
Experimental retinal detachment models were created in Sprague-Dawley rats by subretinal injection of sodium hyaluronate. Subretinal injections of z-VAD-FMK, DMSO or z-VAD-FMK combined with Necrostatin-1 were performed at the time of the retinal detachment induction, respectively.
Three days after retinal detachment, z-VAD-FMK treatment led to significant reduction of TUNEL-positive photoreceptors but increase of PI-labelled cells compared with DMSO-treated controls. Transmission electron microscope results indicated that z-VAD-FMK induced photoreceptor necroptosis accompanied with extensive vacuolization. Western Blotting further proved LC-3II expression and the activation of autophagy. Western Blotting results showed z-VAD-FMK promotes necroptosis and autophagy by inhibiting caspase-8 activation, promoting RIP1 phosphorylation and LC-3(II) induction. Necrostatin-1 combined with z-VAD-FMK treatment provided significant protection of photoreceptors by simultaneous inhibition of RIP phosphorylation, LC-3(II) induction and caspase activation.
The results of this study for the first time provided evidence that the activation of autophagy was involved in necroptosis induced by z-VAD-FMK, which could be inhibited by Necrostatin-1 in experimental retinal detachment. These results suggest combination therapy is a potential way to prevent neuronal damage in various retinal disorders associated with photoreceptor loss.
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