title: Acetylation preserves retinal ganglion cell structure and function in a chronic model of ocular hypertension.
abstract: OBJECTIVE
  The current studies investigate if the histone deacetylase (HDAC) inhibitor, valproic acid (VPA), can limit retinal ganglion cell (RGC) degeneration in an ocular-hypertensive rat model.
  
  
  METHODS
  Intraocular pressure (IOP) was elevated unilaterally in Brown Norway rats by hypertonic saline injection. Rats received either vehicle or VPA (100 mg/kg) treatment for 28 days. Retinal ganglion cell function and number were assessed by pattern electroretinogram (pERG) and retrograde FluoroGold labeling. Western blotting and a fluorescence assay were used for determination of histone H3 acetylation and HDAC activity, respectively, at 3-day, 1-week, and 2-week time points.
  
  
  RESULTS
  Hypertonic saline injections increased IOPs by 7 to 14 mm Hg. In vehicle-treated animals, ocular hypertension resulted in a 29.1% and 39.4% decrease in pERG amplitudes at 2 and 4 weeks, respectively, and a 42.9% decrease in mean RGC density at 4 weeks. In comparison, VPA treatment yielded significant amplitude preservation at 2 and 4 weeks and showed significant RGC density preservation at 4 weeks. No significant difference in RGC densities or IOPs was measured between control eyes of vehicle- and VPA-treated rats. In ocular-hypertensive eyes, class I HDAC activity was significantly elevated within 1 week (13.3 ± 2.2%) and histone H3 acetylation was significantly reduced within 2 weeks following the induction of ocular hypertension.
  
  
  CONCLUSIONS
  Increase in HDAC activity is a relatively early retinal event induced by elevated IOP, and suppressing HDAC activity can protect RGCs from ocular-hypertensive stress. Together these data provide a basis for developing HDAC inhibitors for the treatment of optic neuropathies.
authors.affiliation: Storm Eye Institute, Department of Ophthalmology, Medical University of South Carolina, Charleston, South Carolina, United States.
authors.forename: Oday
authors.initials: O
authors.lastname: Alsarraf
authors.affiliation: Storm Eye Institute, Department of Ophthalmology, Medical University of South Carolina, Charleston, South Carolina, United States.
authors.forename: Jie
authors.initials: J
authors.lastname: Fan
authors.affiliation: Storm Eye Institute, Department of Ophthalmology, Medical University of South Carolina, Charleston, South Carolina, United States.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Dahrouj
authors.affiliation: Storm Eye Institute, Department of Ophthalmology, Medical University of South Carolina, Charleston, South Carolina, United States.
authors.forename: C James
authors.initials: CJ
authors.lastname: Chou
authors.affiliation: Storm Eye Institute, Department of Ophthalmology, Medical University of South Carolina, Charleston, South Carolina, United States.
authors.forename: Phillip W
authors.initials: PW
authors.lastname: Yates
authors.affiliation: Storm Eye Institute, Department of Ophthalmology, Medical University of South Carolina, Charleston, South Carolina, United States.
authors.forename: Craig E
authors.initials: CE
authors.lastname: Crosson
mesh_terms: D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002908:Chronic Disease; D004195:Disease Models, Animal; D004596:Electroretinography; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D007429:Intraocular Pressure; D008297:Male; D009798:Ocular Hypertension / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D011914:Rats, Inbred BN; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D014635:Valproic Acid; D000123:Acetyltransferases
keywords: acetylation; neuroprotection; ocular hypertension; retina