title: Protective effects of the dipeptidyl peptidase IV inhibitor sitagliptin in the blood-retinal barrier in a type 2 diabetes animal model.
abstract: OBJECTIVE
  The aim of this study was to evaluate the efficacy of sitagliptin, a dipeptidyl peptidase IV inhibitor (DPP-IV), in preventing the deleterious effects of diabetes on the blood-retinal barrier in male Zucker Diabetic Fatty (ZDF) rats.
  
  
  METHODS
  ZDF rats at 20 weeks of age were treated with sitagliptin (10 mg/kg/day) during 6 weeks. The effect of the drug on glycaemia was assessed by evaluating glycated haemoglobin (HbA1c). The content and/or distribution of tight junction (TJ) proteins occludin and claudin-5, as well as nitrotyrosine residues, interleukin (IL)-1β, BAX and Bcl-2 was evaluated in the retinas by western blotting and/or immunohistochemistry. Retinal cell apoptosis was assessed by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) assay. The number of CD34+ cells present in peripheral circulation was assessed by flow cytometry, and endothelial progenitor cells (EPC) adhesion ability to the retinal vessels was evaluated by immunohistochemistry.
  
  
  RESULTS
  Sitagliptin improved glycaemic control as reflected by a significant decrease in HbA1c levels by about 1.2%. Treatment with sitagliptin prevented the changes in the endothelial subcellular distribution of the TJ proteins induced by diabetes. Sitagliptin also decreased the nitrosative stress, the inflammatory state and cell death by apoptosis in diabetic retinas. Diabetic animals presented decreased levels of CD34+ cells in the peripheral circulation and decreased adhesion ability of EPC to the retinal vessels. Sitagliptin allowed a recovery of the number of CD34+ cells present in the bloodstream to levels similar to their number in controls and increased the adhesion ability of EPC to the retinal vessels.
  
  
  CONCLUSIONS
  Sitagliptin prevented nitrosative stress, inflammation and apoptosis in retinal cells and exerted beneficial effects on the blood-retinal barrier integrity in ZDF rat retinas.
authors.affiliation: Laboratory of Pharmacology and Experimental Therapeutics, Institute of Biomedical Research in Light and Image (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: A
authors.initials: A
authors.lastname: Gonçalves
authors.forename: E
authors.initials: E
authors.lastname: Leal
authors.forename: A
authors.initials: A
authors.lastname: Paiva
authors.forename: E
authors.initials: E
authors.lastname: Teixeira Lemos
authors.forename: F
authors.initials: F
authors.lastname: Teixeira
authors.forename: C F
authors.initials: CF
authors.lastname: Ribeiro
authors.forename: F
authors.initials: F
authors.lastname: Reis
authors.forename: A F
authors.initials: AF
authors.lastname: Ambrósio
authors.forename: R
authors.initials: R
authors.lastname: Fernandes
mesh_terms: D000818:Animals; D017209:Apoptosis; D001813:Blood-Retinal Barrier / Q000187:drug effects* / Q000378:metabolism*; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003930:Diabetic Retinopathy / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D006442:Glycated Hemoglobin / Q000187:drug effects; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D011924:Rats, Zucker; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D006442:Glycated Hemoglobin; D011719:Pyrazines; D000068900:Sitagliptin Phosphate; D014230:Triazoles