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S Doehmen, V Poulaki, K Koizumi, B Kirchhof, AM Joussen; The TNF-Inhibitor Enbrel prevents early diabetic retinal changes in vivo . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1332.
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Purpose: 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. In this context we had investigated the effect of the TNF-alpha inhibitor Enbrel on retinal leukostasis. Building upon this data we now investigate the effect of Enbrel on diabetic endothelial cell death and vascular leakage. Methods: Long Evans rats were made diabetic with streptozotocin. Confirmed diabetic animals were treated subcutaneously with the TNF-inhibitor Enbrel. Endothelial injury, apoptosis and death in retina of diabetic rats were evaluated by propidium iodide, TUNEL & CytoDeath, and DNA fragmentation ELISA, respectively. Retinal vascular leakage in vivo was evaluated using Evans blue dye. Results: Enbrel was able to significantly reduce diabetic vascular leakage. Furthermore, in vivo TNF-alpha reduced retinal vascular endothelial cell injury, apoptosis, death and vascular leakage. Evaluation of the endothelial cell death demonstrated a reduction of diabetes associated endothelial cell death by 41%. 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. They suggest a mechanistic role for TNF-alpha in the development of diabetic retinopathy and macular edema and imply that inhibition of the Fas/FasL system may prove beneficial in preventing diabetic endothelial cell death.
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