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AC Clermont, HI Salti, LE Goddard, GL King, LP Aiello; Diabetes-Induced Retinal Vascular Permeability is Both Prevented and Reversed In Vivo by Oral Administration of PKC-ß Selective Inhibitor LY333531 . Invest. Ophthalmol. Vis. Sci. 2002;43(13):3863.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Since diabetes-induced retinal vascular permeability may be mediated by activation of protein kinase C (PKC), we examined whether primary and/or secondary intervention with orally-administered PKC-ß isoform-selective inhibitor LY333531 could prevent or reverse retinal vascular permeability in diabetic animals. Methods: STZ-induced diabetic (DM) and non-diabetic (NDM) Sprague-Dawley rats were assigned to a primary intervention (1°) group (treatment initiated at onset of DM with evaluation 2 weeks later) or a secondary (2°) intervention group (treatment begun 2w after onset of DM with evaluation 2w later). DM and NDM 1° groups were provided access to normal chow or chow containing 0.06% LY333531. The 2° groups received control chow for 2w followed by LY333531 or control chow for the subsequent 2w. Retinal vascular permeability was measured using the Evans-blue albumin permeation. Results: DM increased retinal vascular permeability as compared to NDM controls by 2.3±0.8 fold (n=8, p=0.042) and 2.5±0.7 fold (n=5, p=0.006) in the 1° and 2° groups, respectively. Preventative treatment with LY333531 reduced retinal vascular permeability by 92±50% (n=6, p=0.014) while interventional therapy resulted in a 100±32% (n=5, p=0.007) reduction as compared to untreated DM controls (1.3±0.8 vs 2.8±1.0 and 1.96±0.94 vs 4.85±1.35 µL/g/hr for 1o and 2o studies, respectively). LY333531 treatment of NDM groups did not alter retinal vascular permeability as compared to NDM controls (1.35±0.46 vs 1.21±1.25 and 2.27±0.67 vs 1.96±0.43 µL/g/hr for 1° and 2° studies, respectively). Conclusion: Two weeks of oral therapy with PKC-ß selective inhibitor LY33531 prevents diabetes-induced retinal vascular permeability and reverses the retinal vascular permeability already established after two weeks of diabetes. These data further suggest that the inhibition of PKC-ß in vivo may be a useful therapeutic approach for treatment of diabetic macular edema and similar disorders.
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