• Chuandi Zhou, Dawei Luo, Wenwen Xia, Chufeng Gu, Tashi Lahm, Xiaofang Xu, Qinghua Qiu, and Zhenzhen Zhang.
• Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, China.
• Neuroscience. 2019 Oct 15; 418: 25-36.

AbstractHistone deacetylase inhibitors (HDACis) have displayed neuroprotective effects in animal models of retinal ischemia/reperfusion (I/R) injury. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a redox-sensitive transcription factor responds to oxidative damage. We investigated the role of Nrf2 in retinal I/R injury, and further explored the mechanisms underlying Nrf2-mediated neuroprotection exerted by HDACi. High intraocular pressure was used to establish retinal I/R model in wild type (WT) and Nrf2 knockout (KO) mice. Nrf2 KO mice displayed more severe retinal damage after I/R. Trichostatin A (TSA) was administered to both WT and Nrf2 KO mice with retinal I/R damage. TSA significantly diminished the retinal ganglion cell degeneration in WT mice but offered no notable protection in Nrf2 KO mice. TSA markedly promoted Nrf2 nuclear translocation and its acetylation. In addition, TSA upregulated Nrf2 downstream proteins, such as Ho-1 and Nqo1, in retinal tissues. In the retinal neuronal cell line 661W, TSA reduced the expression of proinflammatory cytokines, Il-1β, Il-6, Tnf-α and Mmp-9, and it upregulated Bdnf under oxidative stress. However, this trend was not continued after silencing Nrf2. Chromatin immunoprecipitation assay demonstrated that Nrf2 at the Ho-1 promoter significantly increased transcriptional activity after oxidative stress induction. Nrf2, which is dispensable in HDACi-mediated neuroprotection, plays a major neuroprotective role in retinal I/R injury.Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.

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