Tenilsetam prevents early diabetic retinopathy without correcting pericyte loss

Jennifer Hoffmann; Alex Alt; Jihong Lin; Günther Lochnit; Uwe Schubert; Erwin Schleicher; Triantaphyllos Chavakis; Michael Brownlee; Fokko J. Van der Woude; Klaus T. Preissner; Hans-Peter Hammes

doi:10.1160/TH05-11-0725

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2006; 95(04): 689-695
DOI: 10.1160/TH05-11-0725

Cardiovascular Biology and Cell Signalling

Schattauer GmbH

Tenilsetam prevents early diabetic retinopathy without correcting pericyte loss

Jennifer Hoffmann

¹3^rd Medical Department, Justus-Liebig University Giessen, Giessen, Germany

³Institute of Biochemistry, Justus-Liebig University, Giessen, Germany

,

Alex Alt

¹3^rd Medical Department, Justus-Liebig University Giessen, Giessen, Germany

,

Jihong Lin

²5^th Medical Department, Faculty of Clinical Medicine, University of Heidelberg, Mannheim, Germany

,

Günther Lochnit

³Institute of Biochemistry, Justus-Liebig University, Giessen, Germany

,

Uwe Schubert

³Institute of Biochemistry, Justus-Liebig University, Giessen, Germany

,

Erwin Schleicher

⁴Department of Internal Medicine IV, University of Tuebingen, Tuebingen, Germany

,

Triantaphyllos Chavakis

⁵Experimental Immunology Branch, NCI, NIH, Bethesda, Maryland, USA

,

Michael Brownlee

⁶Albert Einstein College of Medicine, Bronx, New York, New York, USA

,

Fokko J. Van der Woude

²5^th Medical Department, Faculty of Clinical Medicine, University of Heidelberg, Mannheim, Germany

,

Klaus T. Preissner

³Institute of Biochemistry, Justus-Liebig University, Giessen, Germany

,

Hans-Peter Hammes

²5^th Medical Department, Faculty of Clinical Medicine, University of Heidelberg, Mannheim, Germany

› Author Affiliations

Abstract

Summary

Hyperglycemia-induced mitochondrial overproduction of reactive oxygen species leads to the activation of different biochemical pathways involved in endothelial damage of the diabetic retina. Tenilsetam [(±)-3-(2-thienyl)-2-piperazinone] is a dicarbonyl scavenger in the millimolar range anda transition metal ion chelator in the micromolar range. We tested its effect on experimental diabetic retinopathy, and on endothelial cell characteristics in vitro. Streptozotocin diabetic male Wistar rats (60 mg/ kg BW) received 50 mg/kg BW tenilsetam (D-T) for 36 weeks, or no treatment (D).The impact of tenilsetam (0–30 mM) on endothelial proliferation, apoptosis, sprouting, cytokine-induced leucocyte-endothelial interaction, and VEGF expression was tested in vitro.Tenilsetam did not affect glycemic control or body weight in diabetic animals. The 3.7 fold increase in acellular capillaries in diabetic rats [p<0.001 vs. non-diabetic controls (N)] was reduced by 70% (p<0.001) through treatment, but pericyte loss (D vs. N –33%; p<0.001) remained unaffected. In vitro, tenilsetam inhibited endothelial proliferation at lower doses, while inducing apoptosis at high doses. Leucocyte adhesion was only inhibited at high doses. Sprouting angiogenesis of bovine retinal endothelial cells was promoted at lower doses (≤ 10 mM). At micromolar concentrations, endothelial VEGF expression was upregulated by 100%. Long-term treatment with the AGEinhibitor and iron-chelating compound tenilsetam inhibits the formation of acellular capillaries without correcting pericyte loss. The compound has dose-dependent effects on endothelial cell function. These data suggest that, independent of known properties, tenilsetam shows important rescue functions on endothelial cells which could be useful for the treatment of early diabetic retinopathy.

Keywords

Experimental diabetic retinopathy - pericytes - endothelial survival - VEGF - tenilsetam

Full Text

References

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