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Heather Schmitt, Cassandra Schlamp, Robert W Nickells; Small molecule inhibition of Histone Deacetylase 3 (HDAC3) reduces RGC damage and apoptosis induced by acute optic nerve injury. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2425.
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Histone deacetylase (HDAC) activity mediates nuclear atrophy and apoptosis in retinal ganglion cells (RGCs) following acute optic nerve injury. An important role in these processes may be played by HDAC3, which exhibits nuclear translocation in ganglion cells shortly after optic nerve injury. Amelioration of histone deacetylation, heterochromatin formation, and apoptosis was found in the ganglion cell layer where Hdac3 was conditionally knocked out prior to optic nerve injury. The purpose of this study was to test the hypothesis that small molecule inhibition of HDAC3 leads to protection of retinal ganglion cells from histone deacetylation-related chromatin condensation and death following acute injury.
C57BL/6 mice were given an intravitreal injection of the HDAC3-specific inhibitor RGFP-966 or vehicle into the OS eye immediately following optic nerve crush. Five days after optic nerve crush, eyes were harvested and analyzed for histone H4 deacetylation, heterochromatin formation, and Caspase-3 (CASP3) activation using Western blotting, fluorescence microscopy, and TEM imaging. Eyes were also harvested at 14 days post optic nerve crush for analysis of total RGC loss using fluorescence microscopy. Similar studies are being conducted in the microbead model of ocular hypertension.
Selective inhibition of HDAC3 leads to amelioration of histone deacetylation and heterochromatin formation following acute optic nerve damage. RGC cell death, as a function of CASP3 activation and soma loss is also attenuated. Further studies using a model of experimental glaucoma, combined with systemic application of this inhibitor, are ongoing.
RGFP-966 mimics the effects of Hdac3 conditional knock-out in RGCs. HDAC3 inhibitors may be a viable therapeutic option to prevent RGC damage and loss following optic nerve injury.
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