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S. Kaushal, S. M. Noorwez, R. Tzekov, D. Huang, Y. Li, R. Wen; The Effect of Valproic Acid in Mouse Models of RP. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3735.
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To determine the effect of valproic acid (VPA) on the amounts of folded rhodopsin in a P23H mouse model and assess VPA’s neuroprotective effect in the S334ter-3 rat model.
Heterozygous P23H opsin mice and S334ter-3 rats were produced by previously published methods. VPA (200 mg/kg) or a placebo was administered daily (i.p.) to P23H mice, littermate controls, or C57/B6 mice every other day for two weeks. The mice were dark-adapted overnight and their eyes were then harvested in dim red light. The total folded rhodopsin was purified from each eye and quantified by UV/visible spectroscopy using our previously published methods. Separately, in the S334ter rats, either VPA (300 mg/ml) or a placebo was administered via i.p. daily, starting at PD 9. Eyes were collected at PD 21, embedded in an Epon/Araldite mixture, and sectioned at 1 µm thickness to display the entire retina along the vertical meridian. Retinal sections were examined by light microscopy and evaluated independently by three observers.
When compared to the retinas receiving a placebo, the P23H mice treated with VPA had an approximately 30-40% increase in the amounts of folded rhodopsin, which was statistically significant. There was no substantial effect of VPA on the littermate controls or the C57/B6 mice. In the retinas of the S334ter rats treated with VPA, the outer nuclear layer (ONL) had 2-3 rows of photoreceptor nuclei in the superior retina. In contrast, animals treated with PBS had only 1 row of nuclei in the ONL of the same retinal region. Separate quantitative data showed that the ONL thickness in treated animals was significantly higher than the controls.
Systemically delivered VPA in P23H mice resulted in increased folded rhodopsin levels and in modest but significant preservation of photoreceptors in the S334ter-3 rats.
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