Tacrolimus (FK506) Attenuates Leukocyte Accumulation After Transient Retinal Ischemia

Abstract

Background and Purpose-Tacrolimus, an immunosuppressant agent, has been shown to reduce tissue injury and leukocyte accumulation after transient ischemia. This study was designed to evaluate quantitatively the inhibitory effects of tacrolimus on leukocyte rolling and on subsequent leukocyte accumulation in vivo after transient retinal ischemia and the protective effects of tacrolimus on ischemia-induced neural damage. Methods-Retinal ischemia was induced for 60 minutes in anesthetized pigmented rats by temporary ligation of the optic sheath. Tacrolimus was administered at 10 minutes after ischemic induction. At 4, 12, 24, and 48 hours after reperfusion, leukocyte behavior in the retinal microcirculation was evaluated in vivo with acridine orange digital fluorography. After 7 days of reperfusion, ischemia-induced retinal damage was evaluated histologically. Results-Treatment with tacrolimus suppressed leukocyte rolling; the maximum number of rolling leukocytes was reduced by 60.1% at 12 hours after reperfusion (PϽ0.05). In tacrolimus-treated rats, the velocity of rolling leukocytes was significantly faster than in vehicle-treated rats (PϽ0.01). The subsequent leukocyte accumulation was reduced by 61.6% at 24 hours after reperfusion (PϽ0.01). Histological examination demonstrated the protective effect of tacrolimus on ischemia-induced retinal damage, which was more substantial in the inner retina (PϽ0.01). Conclusions-The present study demonstrated the inhibitory effect of tacrolimus on leukocyte rolling and on subsequent leukocyte accumulation and the therapeutic potency to neural injury after transient retinal ischemia. (Stroke.

Evaluation of Leukocyte-Endothelial Interactions in Retinal Diseases

“…c Two leukocytes can be seen rolling along the venous wall (arrowheads), and one was adhered to the venous wall (arrow). This figure was previously published in Stroke [85]. …”

“…Significant reduction in leukocyte accumulation was observed in tacrolimus-treated rats at 12 h ( e ) and 24 h ( f ) after reperfusion. This figure was previously published in Stroke [85]. …”

“…On the basis of the results of these experiments, many investigators have studied various agents that can attenuate tissue damage by suppressing leukocyte-endothelial interactions in the postischemic retina. Antithrombin III [83,84], tacrolimus (FK506) [85], argatroban (direct thrombin inhibitor) [86], statin [87,88], Rho-associated protein kinase inhibitor [89], superoxide dismutase [90], thalidomide [91], selectin ligands/inhibitor (SKK-60060) [92], triamcinolone acetonide [93], ischemic preconditioning [94,95], platelet depression [81], and 17β-estradiol [96] are reported to reduce leukocyte accumulation in the postischemic retina and thereby reduce neural damage.…”

Argatroban Attenuates Leukocyte– and Platelet–Endothelial Cell Interactions After Transient Retinal Ischemia

“…10,25 Male pigmented Long-Evans rats (200 to 220 g; nϭ342) (KIWA Laboratory Animals Co, Ltd) were anesthetized with xylazine hydrochloride (4 mg/kg) and ketamine hydrochloride (10 mg/kg). The pupils were dilated with 0.5% tropicamide and 2.5% phenylephrine hydrochloride.…”

“…10,24,25 In brief, a scanning laser ophthalmoscope (SLO; Rodenstock Instruments), coupled with a computer-assisted image analysis system, made continuous, high-resolution images of the fundus stained by metachromatic fluorochrome AO (Wako Pure Chemicals). 28 For further analysis, the obtained images were recorded on an S-VHS videotape at a rate of 30 frames/s.…”