Abstract
Purpose: :
Studies have shown that protein acetylation plays a central role in the pathogenesis of neurodegeneration regulating the actions of inflammatory cytokines and gene expression. The purpose of these studies was to investigate the neuroprotective action of nonselective histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), in a retinal ischemic model.
Methods: :
To evaluate the neuroprotective actions of TSA, electroretinogram (ERG) a- and b-waves were evaluated 7 days following ischemic retinal injury to Brown Norway rats. Retinal ischemia was induced by elevating IOP to 160 mmHg for 45 minutes. Selected animals were euthanized and retinae collected to assay changes in TNF and HDAC expression. To evaluate if HDACs regulate signaling of TNF, primary cultures of human astrocyte were established and PI3-kinase/AKT pathway activation and MMP secretion induced by TNF (10 ng/ml) were assessed by Western blot analysis.
Results: :
PCR analyses identified HDAC1, 2, 3, 6, 9 and 11 as the principle HDACs expressed in retinae and astrocytes. In control animals, 7 days following ischemic retinal injury, ERG a- and b-wave amplitudes were significantly reduced from control levels by 23 and 45%, respectively. In rats treated with TSA (5 mg/kg) 1 hour prior to ischemic injury and BID for 3 days post injury, neither ERG a- nor b-wave amplitudes were significantly different from control levels. Four hours following ischemic injury TNF was significantly elevated when compared to controls, 1186 +12, 45 +7 pg/mg, respectively. Incubation of astrocytes with TNF induced significant activation of the PI3-kinase/AKT pathway within 10 minutes, followed by a significant increase in MMP-3 secretion at 24 hours. Pretreatment with TSA produced a dose-related inhibition (IC50 21 nM) of the activation of the PI3-kinase/Akt pathway and the secretion of MMP-3 induced by TNF.
Conclusions: :
Protein acetylation/deacetylation appears to play a role in ischemic retinal injury, and HDAC inhibition can protect the retina from ischemic injury. The neuroprotective response to HDAC inhibition appears to involve the suppression of retina TNF signaling. The use of HDAC inhibitors may provide a novel approach for the treatment of ischemic retinal injury.
Keywords: ischemia • neuroprotection • retina