June 2013
Volume 54, Issue 15
Free
ARVO Annual Meeting Abstract  |   June 2013
Quinic Acid Derivative, KZ-41 Protects Against Radiation-Induced Retinal Endothelial Cell Dysfunction: An Early - to - Late Stage Treatment of Radiation Retinopathy
Author Affiliations & Notes
  • Jordan Toutounchian
    Pharmaceutical Sciences, Univ of Tennessee Hlth Sci Ctr, Memphis, TN
  • Qiuhua Zhang
    Ophthalmology, Univ of Tennessee Hlth Sci Ctr, Memphis, TN
  • Jayaprakash Pagadala
    Pharmaceutical Sciences, Univ of Tennessee Hlth Sci Ctr, Memphis, TN
  • Duane Miller
    Pharmaceutical Sciences, Univ of Tennessee Hlth Sci Ctr, Memphis, TN
  • Jena Steinle
    Ophthalmology, Univ of Tennessee Hlth Sci Ctr, Memphis, TN
  • Charles Yates
    Pharmaceutical Sciences, Univ of Tennessee Hlth Sci Ctr, Memphis, TN
  • Footnotes
    Commercial Relationships Jordan Toutounchian, None; Qiuhua Zhang, None; Jayaprakash Pagadala, None; Duane Miller, None; Jena Steinle, None; Charles Yates, RxBio, Inc (C), RxBio, Inc (P), RxBio, Inc (R)
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 1965. doi:
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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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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: 670 radiation damage: light/UV • 557 inflammation • 700 retinal neovascularization  
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