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Ed Guzman, Mrinalini Despande, David W Byrd, Camryn DeLooff, Paul A Zlojutro, Keriah Abd, Kenneth P Mitton; Systemic Valproic Acid can Accelerate Photoreceptor Loss in rd10 mice. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1281.
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Clinical trials are recruiting patients to evaluate Valproic Acid’s (VPA) therapeutic potential for AD-RP. As a potent Histone Deacetylase Inhibitor (HDACi), VPA does have the potential to alter gene expression. However, VPA’s effects on gene expression are non-specific; therefore, it is possible that VPA’s effect on the rate of photoreceptor loss could vary between families with different causative genetic mutations. Recently, we found that systemic VPA treatment dramatically slows photoreceptor loss in rd1 mice but failed to benefit rd10 mice. Additional analysis has revealed that VPA treatment actually exacerbates photoreceptor loss in rd10 mice.
Expression of neurotrophic factor genes (Bdnf, Gdnf, Cntf, Fgf2) were measured by real-time PCR after single doses in Pde6brd10/rd10mice. Rd10 mice were also treated with daily doses (IP injection) of VPA for 10 days and compared to PBS-treated control liter mates. Retinal morphology was assessed with virtual microscopy of H&E stained paraffin sections. Retinal function was monitored by focal and ganzfeld-ERG.
In contrast to the rd1 model, a single dose of VPA during the later stage of retinal maturation, did not result in a relative decrease in Cntf and Fgf2 gene expression in rd10 mice. In contrast to rd1 mice, daily VPA-treatment of rd10 mice failed to reduce the rate of photoreceptor loss in the rd10 model. Both, focal-ERG and ganzfeld-ERG showed a reduced B-wave response in VPA-treated animals compared to their PBS-treated liter mates. Consistent with ERG results, subsequent morphological analysis revealed a slight reduction in the number of surviving photoreceptors in the VPA-treated animals.
While systemic VPA treatment dramatically slows the rate of photoreceptor loss in rd1 mice, it can slightly accelerate the rate of photoreceptor loss in the rd10 model. While both of these models harbor different mutations of the same gene, it is clear that differences in the timing of photoreceptor loss, and differences in their photoreceptor physiology result in opposite effects of VPA treatment on photoreceptor loss. If one considers rd10 a better model of RP because substantial degeneration occurs in mature retina, then our results suggest that some human RP patients might not be good candidates for VPA treatment. It is possible that VPA could benefit or accelerate vision loss depending on a patient's specific genetic defect.
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