Abstract
Retinal leukostasis, mediated by intracellular adhesion molecule-1 (ICAM-1) and vascular endothelial growth factor (VEGF), has been implicated in the pathogenesis of early diabetic retinopathy. Phosphomannopentaose sulfate (PI-88) is a highly sulfonated oligosaccharide which inhibits heparanase activity and competes with heparan sulfate binding to growth factors. In this study, we evaluated whether PI-88 could inhibit retinal leukostasis in strepotzotocin(STZ)-induced diabetic rat and elucidated the possible mechanisms. Diabetes was induced in Sprague-Dawley rats by intraperitoneal injection (i.p.) of STZ. Three months after induction, diabetic rats were administered PI-88 (25 mg/kg body weight) or vehicle solution daily via i.p. for 14 consecutive days. Leukostasis was analyzed on retinal flatmounts by concanavalin A and CD45 immunofluorescence staining. Retinal function was analyzed by electroretinography (ERG). ICAM-1 and VEGF levels in retinas were studied by Western blot and enzyme-linked immunosorbent assay (ELISA) respectively. The systemic administration of PI-88, but not vehicle, significantly decreased the number of adherent leukocytes in retinas by 52.24% (P<0.001) and led to significant preservation (about 50%, P<0.001) of scotopic ERG a- and b-wave amplitudes in treated diabetic rats as compared to those of diabetic control rats. These changes were associated with downregulation of ICAM-1 (45%, P<0.001) and VEGF (26.83+/-2.01 versus 40.8+/-3.24 pg/mg, P<0.01) in retinas of PI-88 treated diabetic rats as compared to those of diabetic control rats. PI-88 significantly inhibited retinal leukostasis and reversed retinal dysfunction by a mechanism that may include decreased ICAM-1 and VEGF expression in diabetic rats. Our data suggests that PI-88 is a promising agent for the treatment of diabetic retinopathy.