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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
1   3rd Medical Department, Justus-Liebig University Giessen, Giessen, Germany
3   Institute of Biochemistry, Justus-Liebig University, Giessen, Germany
,
Alex Alt
1   3rd Medical Department, Justus-Liebig University Giessen, Giessen, Germany
,
Jihong Lin
2   5th Medical Department, Faculty of Clinical Medicine, University of Heidelberg, Mannheim, Germany
,
Günther Lochnit
3   Institute of Biochemistry, Justus-Liebig University, Giessen, Germany
,
Uwe Schubert
3   Institute of Biochemistry, Justus-Liebig University, Giessen, Germany
,
Erwin Schleicher
4   Department of Internal Medicine IV, University of Tuebingen, Tuebingen, Germany
,
Triantaphyllos Chavakis
5   Experimental Immunology Branch, NCI, NIH, Bethesda, Maryland, USA
,
Michael Brownlee
6   Albert Einstein College of Medicine, Bronx, New York, New York, USA
,
Fokko J. Van der Woude
2   5th Medical Department, Faculty of Clinical Medicine, University of Heidelberg, Mannheim, Germany
,
Klaus T. Preissner
3   Institute of Biochemistry, Justus-Liebig University, Giessen, Germany
,
Hans-Peter Hammes
2   5th Medical Department, Faculty of Clinical Medicine, University of Heidelberg, Mannheim, Germany
› Author AffiliationsFinancial support: This work was supported by grants from the Deutsche Forschungsgemeinschaft (GRK 534; Ha 1755/4–2).
Further Information

Publication History

Received 06 November 2005

Accepted after revision 25 February 2006

Publication Date:
30 November 2017 (online)

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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

Footnote: The paper is part of the doctoral thesis by J. Hoffmann.


 

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