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Boglarka Racz, Konstantin Petrukhin; Effect of the advanced non-retinoid RBP4 antagonist on vascular permeability in the mouse diabetic retinopathy model. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5799.
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Diabetic retinopathy (DR) is the leading cause of blindness and visual impairment among working-aged adults around the world. Current treatment options for different stages of DR include intraocular injections of steroids and anti-VEGF agents as well as focal and panretinal laser photocoagulation. An oral drug that slows or prevents DR progression without destroying photoreceptors by laser or without frequent intravitreal injections would represent a significant innovation. As part of the NIH-supported Blueprint Neurotherapeutics Network project we identified and characterized several novel classes of Retinol-Binding Protein 4 (RBP4) antagonists. Here we report characterization of the advanced RBP4 antagonist CU507 in the mouse model of diabetic retinopathy.
Hyperglycemia was induced in C57BL/6J mice by STZ injections. CU507 was administered orally at a daily dose of 10 mg/kg for a period of 2.5 months. Retinal vascular permeability was assessed by measuring in the retina of FITC-BSA injected into the tail veins of mice. In addition, vascular permeability was independently assessed in a separate treatment group by measuring the concentration of mouse serum albumin in the retina by immunoblotting.
Compound administration induced partial reduction in concentration of serum RBP4 confirming the mechanism of action. STZ-induced hyperglycemia resulted in increased vascular permeability in the mouse retina. Vascular permeability was significantly attenuated by the CU507 treatment as was evidenced by the decreased FITC-BSA leakage and reduced concentration of mouse serum albumin in the retina.
Our study showed that oral administration of the RBP4 antagonist can significantly reduce vascular leakage in the mouse DR model. Potential mechanisms for this beneficial effect may involve direct inhibition of the retinol-independent pro-inflammatory signaling by RBP4 or/and reduction of the energy demand in photoreceptors as a result of modulation of the visual cycle.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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