Inhibition of Histone Deacetylase Protects the Retina from Ischemic Injury

Abstract

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.

Inhibition of class I histone deacetylase activity represses matrix metalloproteinase-2 and -9 expression and preserves LV function postmyocardial infarction

“…On the other hand, HDACs could affect MMP-2 and MMP-9 expression indirectly, possibly by regulating the levels of inflammatory cytokines expressed and released in the infarct and border zones. We have shown that TSA treatment represses the induction of retinal TNF-␣ levels in rats subjected to retinal ischemia (13). Another study (24) has shown that long-term treatment with SAHA reduced circulating levels of multiple inflammatory cytokines, including TNF-␣, IL-1␤, and IL-6, in the rat DOCA-salt model of hypertensive cardiomyopathy.…”

Histone Deacetylase (HDAC) Inhibition as a Novel Treatment for Diabetes Mellitus

“…This review includes a short overview of genetic associations between HDACs and the etiology of diabetes followed by a discussion of the potential for HDACi as an oral therapy with respect to modulation of the immune system, insulin resistance, β-cell development, differentiation and function, and pathogenetic events relevant for β-cell failure and destruction and islet graft rejection. Of note, HDACi also hold promise with respect to treatment of late diabetic complications such as diabetic nephropathy (28,29) and retinal ischemia playing a central role in diabetic retinopathy (30). HDACi and late diabetic complications will not be discussed further here, and readers are referred to the aforementioned references.…”

Diosmin Protects Rat Retina from Ischemia/Reperfusion Injury

“…23 Briefly, we photographed 3 standard rectangular areas (0.2 · 0.2 mm; 0.04 mm 2 ) at 1, 2, and 3 mm, respectively, from the optic disc in the central region of each retinal quadrant (superotemporal, inferotemporal, superonasal, and inferonasal). Thus, for each retina, 12 rectangles were evaluated, for a total area of 0.48 mm 2 (12 · 0.04 mm 2 ), which is *1% of the total area of the retina, 24 assuming an average area of 50 mm. 2 To determine the density of FG-positive RGCs as cells/mm, 2 we multiplied the number of cells per 0.04 mm 2 by 25.…”