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J. D. Akula, R. Kubota, R. M. Hansen, R. Tzekov, D. McGee, A. B. Fulton; Effects of a Vitamin-A Derivative (AG-787-14-2) on Retinal Function in Oxygen-Induced Retinopathy. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2629.
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Rats with oxygen-induced retinopathy (OIR) are a common model of human retinopathy of prematurity (ROP). Both OIR and ROP are characterized by abnormal retinal vasculature and by lasting dysfunction of the neural retina. Our recent findings in OIR rats imply a causal role for the rods in the ROP disease process. However, experimental manipulation of rod function is necessary to establish this role conclusively. We hypothesized that Acucela Inc.’s vitamin-A derivative, AG-787-14-2 (the "drug"), would alter rod function in OIR.
OIR was induced in four litters of Sprague-Dawley pups (N=24) by exposure to alternating periods of 50% and 10% oxygen from the day of birth (P0) to P14. The light cycle was 12 hr light (10-30 lux) and 12 hr dark; the light-to-dark transition coincided with each oxygen alternation. For 15 days beginning P7, within one hour of this transition, the first and fourth litters were administered 6 mg/kg drug IP; the second and third litters received only vehicle. At P20-22, when marked retinal vascular abnormality is generally observed, electroretinograms were recorded and receptor and post-receptor function evaluated. Treatment effects were evaluated by ANOVA.
Neither the maximal rod response nor the amplification constant of phototransduction were much changed by the drug treatment. However, the time-constant of deactivation of phototransduction, assessed by a double-flash protocol, was significantly shorter in drug-treated rats. Intriguingly, differences in post-receptoral responses were marked. While post-receptor sensitivity (log σ) was unchanged, maximal scotopic b-wave amplitude was twice as large in drug-treated as vehicle-treated rats. The OFF response to a 400 ms stimulus presented in the presence of a background that suppressed the saturating a-wave by ~90% was likewise 2× larger, as was the cone-driven response to 20 Hz flicker presented on the same background.
There was no evidence of serious, negative alteration of the photoreceptor response after treatment with AG-787-14-2. Importantly, the drug appears to have had a favorable effect on responses originating in the inner retina. The inner retina is supplied by the retinal vasculature; quantitative image analysis of fundus photographs will ascertain if the vascular abnormality associated with OIR was, in turn, reduced.
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