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George Trichonas, George Hoppe, Tamara J. Lee, Jonathan E. Sears; Prolyl Hydroxylase Inhibition during Hyperoxia Prevents Oxygen-induced Retinopathy in the Rat 50/10 Model. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2534.
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To study the effect of systemic prolyl hydroxylase inhibition (PHDi) in the rat oxygen-induced retinopathy (OIR) model.
Litters of Sprague-Dawley rat pups and their mothers were transferred within 10 h after birth to oxygen exposure chambers (BioSpherix) where they were subjected to alternating 24-h periods of 50% oxygen and 10% oxygen for 14 days. Control rats were raised simultaneously in room air. On postnatal day (P) 14, the oxygen-exposed rats were returned to room air. OIR animals received intraperitoneal injections of dimethyloxalylglycine (DMOG, 200μg/g), an antagonist of α-ketoglutarate cofactor and inhibitor for PHD, on P3, P5, P7 and P9. Control animals received intraperitoneal injections of PBS. On P14 and P21, animals were anesthetized with Ketamine (80 mg/kg) and Xylazine (8 mg/kg) and were perfused through the left ventricle with 0.5 ml of 0.1% Evans Blue dye. Eye cups were dissected to prepare retinal flat-mounts which were examined under fluorescent microscopy. Neovascularization and avascular areas were assessed on retinal flat-mounts by computerized image analysis.
Alternating hyperoxia/hypoxia in untreated rats led to peripheral as well as central vascular obliteration on day P14. Rats that were treated with systemic DMOG by intraperitoneal injections had less posterior ischemia and greater peripheral vascularity than control animals treated with PBS injections. DMOG administration had no adverse effect on retinal vasculature of rats reared in room air.
We have previously demonstrated that PHDi prevents OIR in mice exposed to 5 days of 75% oxygen followed by 5 days of 21% oxygen. The 50/10 rat experiments demonstrate that PHDi is also effective in a 24-h alternating hyperoxia/hypoxia model. The rat OIR model further validates the therapeutic value of PHDi to prevent retinopathy of prematurity, because it reduces oxygen-induced vascular obliteration and retinovascular growth attenuation in prolonged and/or alternating hyperoxia.
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