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Oday Alsarraf, Phillip W. Yates, Craig E. Crosson; Valproic Acid Reduces Retinal Ganglion Cell Degeneration in Ocular-Hypertensive Rats. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3401.
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The dysregulation of protein acetylation is an integral event in the pathogenesis of several neurodegenerative diseases. The current studies investigate if the histone deacetylase (HDAC) inhibitor, valproic acid, can limit retinal ganglion cell (RGC) degeneration in an ocular-hypertensive rat model.
Intraocular pressure (IOP) was elevated unilaterally in Brown Norway rats by hypertonic saline injection, and the rats divided into vehicle and valproic acid (100 mg/kg) treatment groups. Valproic acid or vehicle was administered (i.p.) twice-daily for 28 days. At the end of the treatment period, RGC function and number was assessed by pattern electroretinogram (pERG) and retrograde FluoroGold-labeling. Contralateral eyes served as controls.
Hypertonic saline injections increased IOPs by 8-14 mmHg in the ipsilateral eyes during the 28-day study. No significant differences in IOPs of the hypertensive or control eyes were measured between the valproic acid and vehicle groups. In vehicle-treated animals, mean pERG amplitudes from ocular-hypertensive eyes were significantly reduced by 31% when compared to control values. In animals treated with valproic acid, pERG amplitudes in hypertensive eyes were not significantly different from control values. Analysis of FluoroGold-labeling from vehicle-treated animals revealed a mean cell density of 1964 ±60 (cells/mm2) for the control eyes, and a significant decrease to 1155 ±49 (cells/mm2) in hypertensive eyes. In valproic acid-treated rats, a mean cell density of 2049 ±64 and 1746 ±95 (cells/mm2) was measured in the control and hypertensive eyes, respectively. A significant increase in labeled cells was measured in hypertensive eyes from rats receiving valproic acid compared to the vehicle-treated group. In addition, administration of valproic acid increased histone-H3 acetylation levels in all layers of the retina.
These studies provide evidence that valproic acid provides structural and functional protection to retinal ganglion cells during ocular-hypertensive stress. This protective action appears to be associated with the inhibition of retinal HDAC activity, and provides a basis for development of HDAC inhibitors in the treatment of optic neuropathies.
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