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Elizabeth J. Crandall, Sandeep S. Samudre, Patricia B. Williams, Frank A. Lattanzio, Jr.; Cannabinoid Treatment Increases Choroidal Neovascularization in a Mouse Model of Exudative Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4015.
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Exudative age-related macular degeneration (AMD) is characterized by the growth of abnormal blood vessels under the retina, known as choroidal neovascularization (CNV). Cannabinoids are speculated to inhibit rampant growth of blood vessels. In this study, the ability of WIN55-212-2 (WIN), a synthetic endocannabinoid, to mitigate CNV was evaluated in a mouse laser model. Also its ability to reduce proliferation was tested in human retinal vascular endothelial cells (hRVE).
To test vascular cell growth inhibition, WIN (50 µg/ml), or anti-VEGF antibodies, bevacizumab (2500 µg/ml) or ranibizumab (10 µg/ml), were applied to hRVE cells during the log growth phase over 24 hrs, +/- 10nM VEGF. For in vivo experiments, WIN (1.0%), or vehicle (Tocrisolve®) were administered as topical eye drops twice daily in C57BL/6J mouse laser CNV model (n=10 eyes/group). CNV was induced using an argon laser with a 50µm spot size at 260 W for 0.1 sec (3 spots). Drug treatment was initiated 4 days prior to laser photocoagulation and continued for 2 weeks after laser. Mice were then perfused with FITC labelled dextran (50mg/ml) euthanized and eyes enucleated for microscopy. The eyes were visualized in cup without flat mounting and CNV area per spot was calculated using SigmaPlot. Visual evaluation for toxicity was performed daily for the duration of the experiment.
Ranibizumab or bevacizumab reduced cell growth only in the presence of VEGF. WIN half maximally inhibited cell growth +/- VEGF. In the mouse model, hyperfluorescent areas indicating rampant vessel growth were observed at the sites of laser induction after 2 weeks. The mean CNV area per spot was 0.92±0.3 and 1.8±0.4 mm2 for vehicle and WIN respectively after 2 weeks of treatment. WIN treatment significantly increased CNV compared to vehicle (p=0.04, n=10). During the treatment period no signs of toxicity were noted by visual assessment.
Cell culture results did not correlate with in vivo studies. After 2 weeks, WIN treatment increased CNV area. All treatments were well tolerated as there were no indications of ocular irritation. Although these initial results are promising, further experimentation is necessary to explore their mechanisms of action and potential use in humans.
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