Titre du document / Document title

Tenilsetam prevents early diabetic retinopathy without correcting pericyte loss

Auteur(s) / Author(s)

HOFFMANN Jennifer ^{(1 2)} ; ALT Alex ⁽¹⁾ ; JIHONG LIN ⁽³⁾ ; LOCHNIT Günther ⁽²⁾ ; SCHUBERT Uwe ⁽²⁾ ; SCHLEICHER Erwin ⁽⁴⁾ ; CHAVAKIS Triantaphyllos ⁽⁵⁾ ; BROWNLEE Michael ⁽⁶⁾ ; VAN DERWOUDE Fokko J. ⁽³⁾ ; PREISSNER Klaus T. ⁽²⁾ ; HAMMES Hans-Peter ⁽³⁾ ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

⁽¹⁾ 3, Giessen, ALLEMAGNE
⁽²⁾ Institute of Biochemistry, Justus-Liebig University, Giessen, ALLEMAGNE
⁽³⁾ 5, Mannheim, ALLEMAGNE
⁽⁴⁾ Department of Internal Medicine IV, University of Tuebingen, Tuebingen, ALLEMAGNE
⁽⁵⁾ Experimental Immunology Branch, NCI, NIH, Bethesda, Maryland, ETATS-UNIS
⁽⁶⁾ Albert Einstein College of Medicine, Bronx, New York, ETATS-UNIS

Résumé / 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 (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 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.

Revue / Journal Title

Thrombosis and haemostasis   ISSN 0340-6245   CODEN THHADQ 

Source / Source

2006, vol. 95, n^o4, pp. 689-695 [7 page(s) (article)] (45 ref.)

Langue / Language

Anglais

Editeur / Publisher

Schattauer, Stuttgart, ALLEMAGNE  (1976) (Revue)

Mots-clés anglais / English Keywords

Eye disease ; Endocrinopathy ; Retinopathy ; Pericyte ; Diabetes mellitus ; Early ; Prevention ; Tenilsetam ;

Mots-clés français / French Keywords

Oeil pathologie ; Endocrinopathie ; Rétinopathie ; Péricyte ; Diabète ; Précoce ; Prévention ; Ténilsétam ;

Mots-clés espagnols / Spanish Keywords

Ojo patología ; Endocrinopatía ; Retinopatía ; Pericito ; Diabetes ; Precoz ; Prevención ; Tenilsetam ;

Mots-clés d'auteur / Author Keywords

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

Localisation / Location

INIST-CNRS, Cote INIST : 10255, 35400015296974.0150