Doehmen S., Poulaki V., Koizumi K., Kirchhof B., Joussen A. M.

Dept. of Vitreoretinal Surgery, University of Cologne, Germany and Massachusetts Eye and Ear Infirmary, Harvard Medical School; Boston MA, USA

Introduction: Leukocyte adhesion to the diabetic retinal vasculature results in early blood-retinal barrier breakdown, capillary non-perfusion and endothelial cell death. Previous work has shown that intercellular adhesion molecule-1 (ICAM-1) and CD18 are required these processes. We now investigate the effect of the TNF-alpha inhibitor Enbrel on retinal leukostasis and vascular leakage.
Methods: Long Evans rats were made diabetic with streptozotocin. Confirmed diabetic animals were treated subcutaneously with the TNFinhibitor Enbrel. In vivo static leukocytes were identified in the retinal vasculature by concanavalin A lectin. Vascular leakage was measured using Evans Blue. ENOS and Nf-KB were quantified using Elisa techniques.
Results: Enbrel potently suppressed diabetic leukocyte adhesion in retinal arterioles (47%, n=11, P< 0.0001), venules (36%, n=11, P< 0.0005), and capillaries (36%, n=11, P< 0.001). Furthermore Enbrel was able to significantly reduce diabetic vascular leakage. The expression of eNOS, a likely downstream mediator of VEGF activity, was increased in diabetic retina, but was potently suppressed with the TNFa inhibitor (n=8, P<0.005). Enbrel reduced Nf-KB activity.
Conclusion: Taken together, these data identify the anti-inflammatory drug Enbrel as an important and useful treatment approach to prevent diabetes associated vascular alterations in the earliest stages of diabetic retinopathy.
JDFI Jo 3-2000-192, Ernst-und-Berta-Grimmke Stiftung and Meyer-Schwarting Stiftung

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