Inhibition of histone deacetylase protects the retina from ischemic injury

Invest Ophthalmol Vis Sci. 2010 Jul;51(7):3639-45. doi: 10.1167/iovs.09-4538. Epub 2010 Feb 17.


PURPOSE. The pathogenesis of retinal ischemia results from a series of events involving changes in gene expression and inflammatory cytokines. Protein acetylation is an essential mechanism in regulating transcriptional and inflammatory events. The purpose of this study was to investigate the neuroprotective action of the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) in a retinal ischemic model. METHODS. To investigate whether HDAC inhibition can reduce ischemic injury, rats were treated with TSA (2.5 mg/kg intraperitoneally) twice daily on days 0, 1, 2, and 3. Seven days after ischemic injury, morphometric and electroretinographic (ERG) analyses were used to assess retinal structure and function. Western blot and immunohistochemical analyses were used to evaluate TSA-induced changes in histone-H3 acetylation and MMP secretion. RESULTS. In vehicle-treated animals, ERG a- and b-waves from ischemic eyes were significantly reduced compared with contralateral responses. In addition, histologic examination of these eyes revealed significant degeneration of inner retinal layers. In rats treated with TSA, amplitudes of ERG a- and b-waves from ischemic eyes were significantly increased, and normal inner retina morphology was preserved. Ischemia also increased the levels of retinal TNF-alpha, which was blocked by TSA treatment. In astrocyte cultures, the addition of TNF-alpha (10 ng/mL) stimulated the secretion of MMP-1 and MMP-3, which were blocked by TSA (100 nM). CONCLUSIONS. These studies provide the first evidence that suppressing HDAC activity can protect the retina from ischemic injury. This neuroprotective response is associated with the suppression of retinal TNF-alpha expression and signaling. The use of HDAC inhibitors may provide a novel treatment for ischemic retinal injury.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Blotting, Western
  • Electroretinography
  • Female
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / metabolism*
  • Histones / metabolism
  • Hydroxamic Acids / pharmacology*
  • Immunohistochemistry
  • Male
  • Matrix Metalloproteinase 1 / metabolism
  • Matrix Metalloproteinase 3 / metabolism
  • Neuroprotective Agents / pharmacology
  • Rats
  • Rats, Inbred BN
  • Reperfusion Injury / enzymology
  • Reperfusion Injury / prevention & control*
  • Retina / drug effects*
  • Retinal Diseases / enzymology
  • Retinal Diseases / prevention & control*
  • Tumor Necrosis Factor-alpha / metabolism


  • Histone Deacetylase Inhibitors
  • Histones
  • Hydroxamic Acids
  • Neuroprotective Agents
  • Tumor Necrosis Factor-alpha
  • trichostatin A
  • Matrix Metalloproteinase 3
  • Matrix Metalloproteinase 1
  • Histone Deacetylases