title: Tenilsetam prevents early diabetic retinopathy without correcting pericyte loss.
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 (< or = 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.
authors.affiliation: 3rd Medical Department, Justus-Liebig University Giessen, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hoffmann
authors.forename: Alex
authors.initials: A
authors.lastname: Alt
authors.forename: Jihong
authors.initials: J
authors.lastname: Lin
authors.forename: Günther
authors.initials: G
authors.lastname: Lochnit
authors.forename: Uwe
authors.initials: U
authors.lastname: Schubert
authors.forename: Erwin
authors.initials: E
authors.lastname: Schleicher
authors.forename: Triantaphyllos
authors.initials: T
authors.lastname: Chavakis
authors.forename: Michael
authors.initials: M
authors.lastname: Brownlee
authors.forename: Fokko J
authors.initials: FJ
authors.lastname: Van der Woude
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Preissner
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hammes
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003930:Diabetic Retinopathy / Q000188:drug therapy / Q000517:prevention & control*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D020286:Pericytes / Q000166:cytology*; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013876:Thiophenes / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D002614:Chelating Agents; D010879:Piperazines; D013876:Thiophenes; D042461:Vascular Endothelial Growth Factor A; C059511:tenilsetam