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Jordan Toutounchian, Qiuhua Zhang, Jayaprakash Pagadala, Duane Miller, Jena Steinle, Charles Yates; Quinic Acid Derivative, KZ-41 Protects Against Radiation-Induced Retinal Endothelial Cell Dysfunction: An Early - to - Late Stage Treatment of Radiation Retinopathy. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1965.
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Radiation-induced damage to the vascularized retinal segments of the posterior portion of the eye triggers an exuberant pro-inflammatory response resulting in leukocyte adhesion, vessel blockage, decreased oxygen supply, and retinal endothelial cell (REC) death. In this study we evaluated the effect of KZ-41 on radiation-induced leukocyte adhesion to human RECs and retinal neovascularization (RNV) in a murine oxygen-induced retinopathy (OIR) model.
Leukocyte Adhesion: Human primary RECs were grown to confluence onto 75x38mm glass slides. Irradiated RECs (single dose 30 Gy; 137Cs at ~3 Gy/min) were placed into a parallel-plate flow chamber and treated with either KZ-41 (10μM) or vehicle (PBS). U937 (human monocytic) cells were then perfused over RECs and digital images were obtained every 30 min over two hours. OIR: Mouse pups (n=5/group) were exposed to 75% oxygen at post-natal day (P)7 for 5 days and then returned to normal oxygen (P12). Mice received daily ocular administration of either KZ-41-loaded nanoemulsion (100 mg/kg) or vehicle on P12-17. Eyes were enucleated at P17 and retinal whole-mounts stained using the endothelial cell specific marker isolectin B4-594. Images were acquired using a Nikon Eclipse 80i confocal microscope with Nikon-NIS elements software. Vaso-obliteration was determined by comparing vascular regrowth to avascular area around the optic nerve. Image analysis was performed using Adobe Photoshop.
Radiation increased leukocyte-REC adhesion as early two hours post-exposure as compared to unirradiated controls (2 ± 2 vs. 87 ± 18 adhered cells; P < 0.05). Whereas, KZ-41 treatment reduced leukocyte adhesion to irradiated RECs (25 ± 12 vs. 87 ± 18 adhered cells; P < 0.05). In the murine OIR model, KZ-41 reduced the avascular area by two-fold as compared to vehicle treated mice (P < 0.05). Histologic examination of retinal whole mounts revealed a more organized microvasculature with less extensive neovascular tufting in KZ-41 treated mice.
Leukocyte-REC adhesion is a hallmark of radiation-induced retinopathy. Subsequent vaso-occlusion and ischemia leads to pathologic RNV. Attenuation of radiation-induced adhesion and pathologic RNV by KZ-41 suggests that quinic acid derivatives may have therapeutic benefit in radiation retinopathy or other inflammatory diseases of the eye.
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