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Jena J. Steinle, Kimberly P. Williams-Guy, Jayaprakash Pagadala, Duane D. Miller, C R. Yates; Compound 49b Therapy Prevents Diabetes-Induced Complications Associated with Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5971.
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The goal of this study was to investigate whether topical application of a novel specific beta-adrenergic receptor agonist, Compound 49b, can prevent the retinal damage caused by diabetic retinopathy.
Male rats were made diabetic with a streptozotocin injection (60mg/kg). Two days after the injection, glucose measurements were obtained, and diabetic+Compound 49b rats were started on daily 1mM Compound 49b eye drops for 2 or 8 months. The study consisted of three treatment groups; control, diabetic only, and diabetic+49b, which were evaluated monthly by measuring ERG analyses, blood pressure, intraocular pressure, and body weight. At 2 months, retinal samples were analyzed for neuronal changes, and 8-month retinas were analyzed for vascular changes. At both time pints, retinal lysates were analyzed for TNFα levels, cleaved caspase 3 levels, and insulin and Akt phosphorylation. Heart samples were analyzed after 8 months for left ventricular hypertrophy and plasma samples were analyzed by mass spectrophotometry to measure whether topical Compound 49b reached the systemic circulation.
1mM Compound 49b treatment returned ERG amplitudes to control levels, while preventing retinal thinning and cell loss in the ganglion cell layer after 2 months. Compound 49b prevented degenerate capillary formation at 8 months. Protein levels of TNFα and cleaved caspase 3 were increased in the diabetic retina at both time points, but were returned to normal values following Compound 49b treatment. Since we have previously found that topical isoproterenol produced left ventricular hypertrophy, we wanted to investigate whether Compound 49b could overcome this obstacle. Compound 49b was not detected in the plasma of rats treated with 1mM topical Compound 49b, suggesting that Compound 49b does not reach the systemic circulation. Left ventricular samples from diabetes+Compound 49b-treated rats were not significantly different than diabetes alone rats.
Data suggest that Compound 49b eye drops reduced TNFα levels and cleaved caspase 3 levels, while maintaining insulin receptor signal transduction in the diabetic retina. Additionally, Compound 49b improved retinal functional, as measured by ERG. Compound 49b does not reach the systemic circulation, nor cause changes in blood pressure or IOP, suggesting that it may represent a novel topical therapy for diabetic retinopathy.
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