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C.V. Patel, A. Clermont, D. Bursell, D.P. Bingaman, L.P. Aiello; Receptor Tyrosine Kinase (RTK) Inhibition With AL–39324 Ameliorates Diabetes–Induced Retinal Vascular Permeability (RVP) in vivo . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1741.
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Diabetes–induced increases in retinal vascular permeability (RVP) and leukocyte adhesion have been linked to the up–regulation of growth factors such as vascular endothelial growth factor (VEGF). RTKs such as VEGF receptor 2 (KDR) mediate growth factor actions upon the retinal vasculature. This study determines whether the RTK selective inhibitor AL–39324 can normalize diabetes–induced increases in retinal vascular permeability and leukostasis in vivo.
Diabetes was induced in male Long–Evans rats with 65 mg/kg streptozotocin (STZ) after an overnight fast. Upon confirmation of diabetes (blood glucose > 250 mg/dl), treatment was initiated by oral gavage. Non–diabetic (NDM) and diabetic (DM) rats received oral gavage of either vehicle or AL–39324 at 1.5 or 5 mg/kg/d BID. After 2 weeks, jugular vein catheters were implanted 1 day prior to experimentation for the infusion of indicator dyes. Retinal leukostasis was assessed by acridine orange infusion and imaged with a scanning laser ophthalmoscope. RVP was measured using Evan’s blue albumin permeation (45 mg/kg) after a 2 hour circulation period.
Treatment with the oral RTKi was well tolerated by both NDM and DM groups with no observed systemic or ERG side effects. Blood glucose levels and body weights were not different between DM control and DM treatment groups. Diabetes increased RVP (38.1+33.4 µl/g/hr, n=9) as compared with NDM control (7.3+2.5 µl/g/hr, n=5, p<0.001). RVP was reduced in DM animals treated with AL–39324 at 1.5mg/kg/d (11.4±4.1 µl/g/hr, n=6, p<0.05) and at 5 mg/kg/d (8.9±3.1 µl/g/hr, n=7, p<0.01) as compared to DM control. RVP was unchanged in NDM treated at 5 mg/kg/d. Retinal leukostasis was increased in DM control as compared to NDM control (7.86 vs 2.80 cells/pixel2). In DM animals treated with 5 mg/kg/d, no statistically significant difference in leukostasis was observed compared with DM control. Intervention and further dose–response studies are in progress.
In this preliminary prevention study, treatment with an oral RTK inhibitor was well tolerated over a 2 week interval and reduced diabetes–induced retinal vascular permeability but not retinal leukostasis. These data suggest that, at least in some cases, RTK inhibition may prevent the diabetes–induced breakdown of the blood retina barrier independently of leukocyte activation.
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