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Shenghai Zhang, Xinghuai Sun, Jihong Wu; Valproate Exerts Pleiotropic Neuroprotective Effects on Retinal Ganglion Cells in vivo Through Epigenetic Modulation in an Experimental Model of Glaucoma. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6583.
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Valproate (VPA) is a well-established treatment for epilepsy and bipolar disorder. Although it has been recently shown to mediate neuronal protection, little is known about its effects on retinal ganglion cell (RGC) during glaucomatous neuropathy. This study examined whether VPA promotes RGC survival in an experimental glaucoma. And the precise mechanism was further investigated.
Unilateral glaucoma was induced in adult male Norwegian Brown rats by anterior chamber injection of paramagnetic polystyrene microspheres. Norwegian Brown rats received intravitreal injections of VPA after IOP elevation induction. RGC survival was evaluated from flat-mounted whole retinas by counting retrograde FG-labeled cells. Potential molecular targets and Global and Gene Promoter-Specific Chromatin modifications involved in VPA-mediated protection were analyzed using chip-seq.
VPA treatment significantly delayed RGC death at 4 weeks after IOP elevation (P<0.01; vs. PBS-treated groups), and had the following expressional effects: it up-regulated bcl-2, bcl-xl, survivin, catenin, HSP70, BDNF, but down-regulated bax, α-synuclein, TNF-α. VPA induced the strongest global chromatin modifications, including histone H3/H4 hyperacetylation, 2MeH3K9 hypomethylation, and DNA demethylation. Locally, Distinct CpG sites in the distal part of the GLT-1 promoter were demethylated and enriched in acetylated histone H4 in response to VPA. These chromatin modifications may regulate multiple gene expressions involved in neuroprotection.
The present results first demonstrate that VPA exerts pleiotropic neuroprotective effects on RGCs in experimental model of glaucoma involving in enhancing transcription of cell-protective genes and down-regulating detrimental genes through VPA-mediated chromatin modifications.
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