Protective Effects of Selectin Ligands/Inhibitor (SKK-60060) against Retinal Ischemia-Reperfusion Injury

Abstract

A newly developed selectin ligand inhibitor (SKK-60060) has been shown to block P- and L-selectins in vitro. We examined its inhibition of leukocyte–endothelial interactions in vivo against retinal ischemia-reperfusion injury and protective effects on ischemia-induced retinal damage.Retinal ischemia was induced by temporary ligation of the optic sheath for 60min in anesthetized pigmented rats. SKK-60060 was administered 5min before reperfusion and 4, 12, 24 and 48hr thereafter, and leukocyte dynamics in the retinal microcirculation were evaluated using acridine orange digital fluorography. After 7 days of reperfusion, ischemia-induced retinal damage was also assessed histologically.SKK-60060 treatment suppressed leukocyte rolling during the reperfusion period; their numbers in the SKK-60060-treated rats were reduced by 67.0% (P<0.01) and 53.2% (P<0.01) at 12 and 24hr, respectively. The subsequent leukocyte accumulation was also inhibited in SKK-60060-treated rats; accumulated leukocytes in the SKK-60060-treated rats were reduced by 72.8% (P<0.01) and 53.4% (P<0.01) at 12 and 24hr, respectively. Retinal venous vasodilation in SKK-60060-treated rats were significantly suppressed at each time point (P<0.05). Histological examination demonstrated protective effects of SKK-60060 on ischemia-induced retinal damage, which were more substantial in the inner retina (P<0.01).SKK-60060 significantly inhibits the leukocyte rolling along the major retinal veins and their accumulation during the reperfusion period. These results suggest therapeutic potential of SKK-60060 for ischemia-reperfusion injury.