Protective effects of selectin ligands/inhibitor (SKK-60060) against retinal ischemia-reperfusion injury

A newly developed selectin ligand inhibitor (SKK-60060) has been shown to b lock P- and L-selectins in vitro. We examined its inhibition of leukocyte-e ndothelial 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 60 min in anesthetized pigmented rats. SKK-60060 was administered 5 min bef ore reperfusion and 4, 12, 24 and 48 hr thereafter, and leukocyte dynamics in the retinal microcirculation were evaluated using acridine orange digita l fluorography. After 7 days of reperfusion, ischemia-induced retinal damag e was also assessed histologically. SKK-60060 treatment suppressed leukocyte rolling during the reperfusion per iod: 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 24 hr, respectively. The subsequent l eukocyte accumulation was also inhibited in SKK-60060-treated rats: accumul ated leukocytes in the SKK-60060-treated rats were reduced by 72.8% (P < 0. 01) and 53.4% (P < 0.01) at 12 and 24 hr, respectively. Retinal venous vaso dilation in SKK-60060-treated rats were significantly suppressed at each ti me point (P < 0.05). Histological examination demonstrated protective effec ts of SKK-60060 on ischemia-induced retinal damage, which were more substan tial in the inner retina (P < 0.01). SKK-60060 significantly inhibits the leukocyte rolling along the major reti nal veins and their accumulation during the reperfusion period. These resul ts suggest therapeutic potential of SKK-60060 for ischemia-reperfusion inju ry. (C) 2000 Academic Press.