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Abstract #99049 Published in IGR 22-4
Inhibition of the NR2B-PSD95 Interaction Exerts Neuroprotective Effects on Retinal Ischemia-Reperfusion Injury
Zhang X; Zhang R; Wu JNeuroscience 2022; 490: 89-99
Glaucoma is a neurodegenerative disease characterized by progressive retinal ganglion cell (RGC) death. Recently, many studies have reported that the N-methyl D-aspartate receptor 2B (NR2B) subunit is excitotoxic in the pathogenesis of glaucoma, but the molecular mechanism should be further explored. In our present study, we investigated the involvement of the NR2B-postsynaptic density protein-95 (PSD95) complex in RGC apoptosis in an experimental glaucoma animal model and determined whether inhibition of the NR2B-PSD95 interaction protected RGCs. We found that levels of NR2B, phosphorylated NR2B (p-NR2B) and PSD95 were significantly increased after 12 h of reperfusion, and the protein expression levels were maintained after 24 h of reperfusion in the ischemia-reperfusion (I/R) injury model. Immunohistochemical staining showed that NR2B and PSD95 partially colocalized in the ganglion cell layer (GCL). Increased levels of NR2B and p-NR2B were also detected in the rat chronic ocular hypertension (COH) model, while decreased PSD95 levels accompanied by severe injury were observed. Tat-NR2B9c treatment significantly increased RGC survival in the I/R injury model by disrupting the NR2B-PSD95 interaction, as confirmed by Brn3A fluorescent labelling and TdT-mediated dUTP nick-end labelling (TUNEL) assays. Levels of the apoptosis-related proteins Bax and cleaved caspase-3 decreased as the number of surviving RGCs increased. Together, our results suggest that the NR2B-PSD95 complex was involved in RGC death in the retinal I/R injury model. Tat-NR2B9c exerted a neuroprotective effect on RGC survival in the retinal I/R injury model by disrupting the NR2B-PSD95 interaction.
Eye Institute, Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, 200031, China; Shanghai Key Laboratory of Visual Impairment and Restoration, Science and Technology Commission of Shanghai Municipality, Shanghai, 200031, China; Key Laboratory of Myopia (Fudan University), Chinese Academy of Medical Sciences, National Health Commission, China.
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