Aldose Reductase Inhibitor Attenuates Leukocyte-Endothelial Interaction in Experimental Diabetic Retina in vivo

Abstract

Purpose: : Increased activity of polyol pathway has been implicated in the pathogenesis of diabetic retinopathy. Aldose reductase inhibitor is expected to prevent or improve diabetic retinopathy. Recently, it has been reported that aldose reductase inhibitor (fidarestat) prevent retinal oxidative stress and vascular endothelial growth factor overexpression in diabetic rats. Moreover, increased leukocyte entrapment has been suggested to be involved in blood flow disturbances in the early diabetic retina. In this study, we investigate the effect of fidarestat on leukocyte-endothelial interaction in experimental diabetic retina in vivo.

Methods: : Diabetes was induced in male Long-Evans rats by intraperitoneal injection of streptozotocin (STZ: 75mg/kg). Fidarestat (4 or 16mg/kg/day) was administered orally during 4-week diabetic period. Retinal sorbitol and fructose concentrations were measured by LC/MS/MS method. Accumulated leukocytes in the retinal microcirculation were quantitatively evaluated in vivo with acridine orange digital fluorography.

Results: : Retinal sorbitol and fructose concentrations were approximately 3-fold higher in untreated diabetic rats than in the control rats. High dose of fidarestat completely normalized retinal sorbitol concentration, whereas retinal fructose concentration was reduced by 80%. The number of leukocytes trapped in the retinal microcirculation of diabetic rats (9.8 ± 3.9 cells/mm²) was significantly increased, compared with nondiabetic control rats (3.4 ± 2.1 cells/mm²; P < 0.01). Oral administration of fidarestat significantly decreased the number of leukocytes trapped in the retinal microcirculation of diabetic rats (6.1 ± 3.5 and 5.2 ± 3.2 cells/mm² with low dose and high dose fidarestat, respectively; P < 0.01).

Conclusions: : Oral administration of fidarestat attenuated the increase of leukocyte entrapment in the retinal microcirculation during the period of early diabetes. These results suggest a therapeutic potential of fidarestat on diabetic retinopathy.

Keywords: diabetic retinopathy