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Beatrice M. Tam, Zusheng Zong, Shalesh Kaushal, Orson L. Moritz; Amelioration Of Retinal Degeneration In A X. Laevis Model Of RP By Treatment With Valproic Acid. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1220.
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The rhodopsin P23H mutation is the most common cause of autosomal dominant RP in North America, and causes instability of opsin in the biosynthetic pathway. Using X. laevis models of retinitis pigmentosa (RP), we have previously demonstrated that retinal degeneration caused by P23H rhodopsin can be partially rescued by dark rearing due to stabilization of the protein by the 11-cis retinal chromophore. In this study, we treated X. laevis tadpoles expressing P23H rhodopsin with the drug valproic acid (VPA), a proposed therapy for RP, to examine its efficacy and mechanism of action.
Transgenic tadpoles expressing human P23H rhodopsin were treated with varying concentrations of VPA beginning 5 days after fertilization, and concluding 14 days after fertilization, under conditions of either cyclic light or constant darkness. Tadpole eyes were subsequently processed for dot blot assay for total rhodopsin and confocal microscopy.
We observed highly significant rescue of P23H rhodopsin-induced retinal degeneration by VPA. This rescue was dose dependent, but never complete. We further investigated the effect of combined dark rearing and VPA treatment. We found that VPA treatment + dark rearing did not result in significantly greater rescue than VPA treatment alone, suggesting a common mechanism of action of these two therapies. Confocal microscopy further indicated that both dark rearing and VPA treatment result in a reduction in the quantity of full length P23H rhodopsin present in rod inner segments.
Our results indicate that VPA treatment is effective in at least one animal model of RP. Furthermore, rescue of retinal degeneration by dark-rearing and VPA treatment likely share a common mechanism. However, our results also suggest at least two mechanisms underlie retinal degeneration in this model of RP, one of which is not addressed by either dark rearing or VPA treatment.
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