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

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

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 and a 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 (60mg/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 AGE-inhibitor 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.

Original languageEnglish (US)
Pages (from-to)689-695
Number of pages7
JournalThrombosis and Haemostasis
Volume95
Issue number4
DOIs
StatePublished - Apr 1 2006

Keywords

  • Endothelial survival
  • Experimental diabetic retinopathy
  • Pericytes
  • Tenilsetam
  • VEGF

ASJC Scopus subject areas

  • Hematology

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  • Cite this

    Hoffmann, J., Alt, A., Lin, J., Lochnit, G., Schubert, U., Schleicher, E., Chavakis, T., Brownlee, M., Van der Woude, F. J., Preissner, K. T., & Hammes, H. P. (2006). Tenilsetam prevents early diabetic retinopathy without correcting pericyte loss. Thrombosis and Haemostasis, 95(4), 689-695. https://doi.org/10.1160/TH05-11-0725