title: Epigenetic intervention with a BET inhibitor ameliorates acute retinal ganglion cell death in mice.
abstract: The bromo and extraterminal (BET) epigenetic "reader" family is becoming an appealing new therapeutic target for several common diseases, yet little is known of its role in retinal neurodegeneration. We explored the potential of BET inhibition in the protection of retinal ganglion cells (RGCs).
  
  
  
  To test the therapeutic effect of JQ1, an inhibitor highly selective for the BET family of proteins, we used an acute RGC damage model induced by N-methyl-D-aspartic acid (NMDA) excitotoxicity. Adult C57BL/6 mice received an intravitreal injection of NMDA with (or without) JQ1 in one eye and vehicle control in the contralateral eye; RGC loss was assessed on retinal sections and whole mounts. Gene expression and apoptosis were analyzed by quantitative real time (RT)-PCR and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), respectively. For counting RGCs, immunostaining of the marker protein BRN3A was performed on whole mounts.
  
  
  
  NMDA treatment eliminated RGCs (day 7 and day 14 post injection) and diminished the expression (mRNAs) of RGC-selective genes, includingThy1, Nrn1, Sncg, andNfl(day 3 and day 7). In contrast, co-injection with JQ1 maintained the number and gene expression of RGCs at ~2 fold of the control (NMDA only, no JQ1), and it decreased NMDA-induced TUNEL-positive cells in the RGC layer by 35%. While NMDA treatment dramatically upregulated mRNAs of inflammatory cytokines (TNFα, IL-1β, MCP-1, RANTES) in retinal homogenates, co-injection with JQ1 suppressed their upregulation by ~50%.
  
  
  
  Intravitreal injection of a BET inhibitor (JQ1) ameliorates NMDA-induced RGC death, revealing the RGC-protective potential of pharmacological blockage of the BET family. This new strategy of epigenetic intervention may be extended to other retinal degenerative conditions.
authors.affiliation: Department of Ophthalmology, The First Hospital of China Medical University, Shenyang, China; Department of Ophthalmology, The 3rd People's Hospital of Dalian, Dalian, China; Department of Surgery, 5151 Wisconsin Institute for Medical Research, University of Wisconsin-Madison, Madison, WI.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Surgery, 5151 Wisconsin Institute for Medical Research, University of Wisconsin-Madison, Madison, WI.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Surgery, 5151 Wisconsin Institute for Medical Research, University of Wisconsin-Madison, Madison, WI.
authors.forename: Go
authors.initials: G
authors.lastname: Urabe
authors.affiliation: Department of Surgery, 5151 Wisconsin Institute for Medical Research, University of Wisconsin-Madison, Madison, WI; Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yingmei
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Department of Surgery, 5151 Wisconsin Institute for Medical Research, University of Wisconsin-Madison, Madison, WI; McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, WI; Department of Surgery and Department of Physiology & Cell Biology, Davis Heart and Lung Research Institute, the Ohio State University, Columbus, OH.
authors.forename: Lian-Wang
authors.initials: LW
authors.lastname: Guo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001381:Azepines / Q000494:pharmacology*; D002452:Cell Count; D016207:Cytokines / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D016202:N-Methylaspartate / Q000633:toxicity; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D014230:Triazoles / Q000494:pharmacology*
chemical_list: C561695:(+)-JQ1 compound; D001381:Azepines; D016207:Cytokines; D009687:Nuclear Proteins; D014230:Triazoles; D016202:N-Methylaspartate