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Kenneth P. Mitton, Edward E. Guzman, David Byrd, Trung Tran, Jason Sotzen; Rescue Of Photoreceptor Degeneration In Rd1 Mice By Systemic Treatment With Valproic Acid. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5585.
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© ARVO (1962-2015); The Authors (2016-present)
Valproic acid (VPA) is an anticonvulsant, and a histone deacetylase inhibitor, that will be evaluated for neuroprotection in new RP clinical trials in the United States and Korea. Unfortunately, few studies exist to evaluate the effects of systemic VPA, good or bad, with animal models of retinal degeneration. We examined photoreceptor loss and neurotrophic gene expression in retinas of Rd1 mice treated with systemic VPA .
Rd1 mice were treated with daily doses of VPA (IP) during the post natal period of rapid photoreceptor (rod) loss that is characteristic of this model. To determine if systemic VPA (non-ocular) can change retinal gene expression, we measured the expression of Bdnf, Gdnf and Cntf after single and multiple doses of VPA in Rd1 and wild-type mice.
A single IP injection of VPA, caused a substantial increase and decrease in retinal neurotrophic factor gene expression (Gdnf, Cntf) in the post-natal retina within 18 hrs. There were no apparent differences in neurotrophic factor gene expression in the normal maturing neural retina after multiple days of dosing. Expression of these genes were not affected in the normal adult neural retina after a single VPA dose (IP). Daily injections with VPA (P9-P19) rescued a significant number of rod photoreceptors in Rd1 mice. At P20, VPA injected mice had several extra rows of photoreceptor nuclei, compared to their PBS injected litter mates that had a single row of nuclei at P20. Dosing much later from P14 to P19 also rescued a significant number of photoreceptors.
Single doses of VPA (IP), can cause significant changes to neurotrophic factor gene expression within in the neural retina. These differences vanish after multiple daily dosing. Systemic daily dosing with VPA significantly slowed the loss of photoreceptors in the Rd1 model of rapid retinal degeneration. Thus systemic VPA might have beneficial effects for specific forms of retinal degeneration. VPA can increase or decrease the expression of different neurotrophic genes in the neural retina. Thus, we must also caution that VPA's effects on individual genes are clearly unpredictable, may vary in context (normal or disease), and should be explored for all genes and in many available RP models.
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