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O. Alsarraf, S. K. Mani, D. R. Menick, C. E. Crosson; Reduced Histone Deacetylase Activity Protects the Retina From Ischemic Injury. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4714.
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Protein acetylation is an essential mechanism for regulating transcriptional and inflammatory events. The current studies investigate if reduced histone deacetylase (HDAC) activity via administration of exogenous inhibitors or endogenous events can limit ischemic retinal injury.
To investigate if administration of HDAC inhibitors can reduce ischemic retinal injury, rats were treated with valproic acid (100 mg/kg; i.p.), trichostatin-A (TSA) (2.5 mg/kg; i.p.), or vehicle, 1 hour prior to and 3 hours following, 45 minutes of retinal ischemia. To investigate if endogenous events can alter HDAC activity and reduce ischemic injury, retinal neuroprotection was induced by 5 minutes of an ischemic preconditioning (IPC) event, 24 hours prior to the ischemic injury. Morphometric and electroretinogram (ERG) analyses were used to assess differences in retinal structure and function, 7 days following ischemic injury. Protein acetylation, HDAC expression and TNF-α levels were evaluated by Western blot analysis.
In vehicle-treated animals, ERG a- and b-waves from ischemic eyes were significantly reduced compared to contralateral responses by 46.3% and 67.4%, respectively. Histologic examination of these eyes demonstrated extensive degeneration of the ganglion cell and inner plexiform layers. In rats treated with valproic acid or TSA, ERG a- and b-waves from ischemic eyes were significantly increased, and normal inner retina morphology was preserved. Ischemia also increased retinal TNF-α, which was blocked by pretreatment with HDAC inhibitors. Both neuroprotection and reduced TNF-α were associated with an increase in retina protein acetylation. In animals receiving a preconditioned stimulus, retinas exhibited significant preservation in functional and structural endpoints. Preconditioning also increased retina protein acetylation and the down regulation of HDAC-5 expression.
These studies provide evidence that reductions in histone deacetylase activity with the resulting hyper-acetylation of retina proteins can protect the retina from ischemic injury. Decrease in HDAC activity and expression also plays a role in the development of ischemic preconditioning in the retina.
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