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D.P. Bingaman, Z.–Y. Wei, K.P. Thomas, S. Stacy, N. Lin; AL–39324, A Selective RTKi, Prevents VEGF–Induced Retinal Vascular Permeability in Adult Rats . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1742.
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© ARVO (1962-2015); The Authors (2016-present)
Receptor tyrosine kinases (RTKs), such as VEGFRs, likely mediate critical signal transduction in ischemic retinopathies, e.g., diabetic retinopathy. Therefore, we evaluated the dose–response effect of the small molecule, RTK inhibitor, AL–39324 (KDR IC50=4nM), against enhanced retinal vascular permeability in a surrogate model of diabetic macular edema (DME).
AL–39324 was administered using either a single intravitreal injection (ivt) or oral gavage and extravasation of Evans blue dye was used as the primary outcome measure to estimate retinal vascular permeability (RVP). Local (0.3–3% 10 µL ivt) or systemic (3, 10, 20mg/kg/d p.o.) treatment was initiated 72 hours prior to VEGF exposure in adult Sprague–Dawley rats. Each rat then received an ivt injection of 500ng (10µL) hrVEGF OU. Twenty–four hours post–VEGF exposure, retinas were harvested following systemic perfusion with Evans blue dye and RVP was determined using the mean±s.e.m. of net ABS/wet weight/plasma ABS. One way ANOVA or nonparametric analyses were used to define differences between groups depending on the normality of the data; P≤0.05 was considered significant.
Eyes injected with 1–3% AL–39324 showed significant and dose–dependent prevention of enhanced RVP (P=0.02 and P<0.001, respectively), ranging from 50–70% inhibition, compared to vehicle–treated controls. Moreover, rats treated with 20 mg/kg/d p.o. showed a >50% reduction in enhanced RVP vs. vehicle–treated controls (P=0.009).
AL–39324 was potent and efficacious against VEGF–induced RVP in these studies, providing significant protection against VEGF–induced blood–retinal barrier breakdown. Both local and systemic delivery of AL–39324 provided dose–dependent inhibition, where similar studies in the STZ–diabetic rat have been initiated. Based upon the premise that VEGF is a key pathologic mediator in human diabetic retinopathy, these results suggest that AL–39324 may be useful for the treatment of human DME.
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