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Radouil T. Tzekov, Wensheng Li, Jialing Liang, Yi Wang, Shalesh Kaushal; Structural and Functional Changes in Mertk -/- Mouse Retina after Systemic Administration of Valproic Acid. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4345.
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Mice homozygous for the targeted disruption of the Mertk gene exhibit early photoreceptor degeneration resulting in apoptosis, loss of ERG signal and thinning of the retina. The purpose of the study was to evaluate whether the course of the degeneration was affected by systemic administration of valproic acid (VPA), a neuroprotective agent and an approved FDA drug.
Male and female mertk-/- mice (n=12) were treated daily with an intraperitoneal injection of valproic acid solution (250 mg/kg) from P25-P30 until P65-P67. Mice of the same age dosed in the same manner with saline served as a control group (n=12). At the end of the treatment, central retinal thickness at ~500 microns nasally and temporally from the optic disc was measured with ultrahigh resolution OCT (Bioptigen Inc.). Vision function was evaluated by full-field ERG recordings. A small subgroup (n=4 VPA; n=3 control) was followed without any treatment until P96-P97.
Both temporal and nasal central retinal full-thickness measurements demonstrated significantly thicker retina in the VPA-treated group (~33% difference; p<0.001; Mann-Whitney test). Presence of outer nuclear layer (ONL) containing more than 1 row of nuclei was observed in the majority of the VPA-treated mice (21 out of 24 eyes, or 87.5%), and in a few of the control mice (7 out of 24 eyes, or 29.2%). At P96-P97, 5 out of 8 eyes (62.5%) in the VPA-treated group and 0 out of 6 eyes (0%) in the control group maintained preserved ONL. Correspondingly, photopic ERG b-wave amplitude was ~80% larger in the VPA-treated group (p<0.05) at P65, while photopic b-wave peak time was ~16% faster with VPA treatment (p<0.05) and much closer to a value usually found in C57BL/6 mice of the same age (mean time: control = ~87 msec, VPA-treated = ~74 msec, C57BL/6 = ~60 msec). At the time of second follow-up (P97), one animal from the VPA-treated group had a recordable photopic ERG.
The observed pattern of protection of retinal structure and vision function as a result of the systemic administration of valproic acid supports the therapeutic potential of the drug in retinal degenerative diseases and expands on previous similar observations for other retinal disease animal models from our group. It is also consistent with our pilot clinical experience in patients with retinitis pigmentosa (Clemson et al., 2010, Br J Opthalmol).
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