The study was done to investigate whether Necrostatin-1#Nec-1# would protect photoreceptors from cell death and improve functional outcome after experimental retinal detachment. Experimental retinal detachment models were created in Sprague-Dawley rats by subretinal injection of sodium hyaluronate and received intravitreal injections of Necrostatin-1, its inactive analogue: Necrostatin-1i#Nec-1i# or vehicle. The rat eyes were observed and sacrificed at various time points. Structural and morphologic changes were observed by light microscopy and electron microscopy. Neuronal functional outcome was assessed by electroretinogram#ERG# recordings. In other animals, retinas were subjected to propodium iodide staining or Western Blotting and probed with anti-RIP1 and anti-phosphoserine antibody. Pretreatment with Necrostatin-1 led to significant preservation in outer nuclear layer thickness and histoarchitecture compared with vehicle-treated controls 7 days after retinal detachment. Pretreatment with Necrostatin-1 inhibited the induction of RIP1 phosphorylation and reduced the number of PI-labelled cells 3 days after retinal detachment. Electron microscope results indicated Necrostatin-1 treatment inhibited necroptotic-like cell death, but not affect apoptotic cell death, 3 days after retinal detachment. Pretreatment with Necrostatin-1i did not provide histological or functional protection. Necrostatin-1 also
significantly attenuated the ERG a-wave and b-wave reduction compared with vehicle controls 7 days after retinal detachment. The data suggest that necrostatin-1, the specific necroptosis inhibitor, is promising therapeutic agent to protect photoreceptors from necroptosis and improve functional outcome. |
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