title: Protective Effect of a GLP-1 Analog on Ischemia-Reperfusion Induced Blood-Retinal Barrier Breakdown and Inflammation.
abstract: Inflammation associated with blood-retinal barrier (BRB) breakdown is a common feature of several retinal diseases. Therefore, the development of novel nonsteroidal anti-inflammatory approaches may provide important therapeutic options. Previous studies demonstrated that inhibition of dipeptidyl peptidase-IV, the enzyme responsible for the degradation of glucagon-like peptide-1 (GLP-1), led to insulin-independent prevention of diabetes-induced increases in BRB permeability, suggesting that incretin-based drugs may have beneficial pleiotropic effects in the retina. In the current study, the barrier protective and anti-inflammatory properties of exendin-4 (Ex-4), an analog of GLP-1, after ischemia-reperfusion (IR) injury were examined.
  
  
  
  Ischemia-reperfusion injury was induced in rat retinas by increasing the intraocular pressure for 45 minutes followed by 48 hours of reperfusion. Rats were treated with Ex-4 prior to and following IR. Blood-retinal barrier permeability was assessed by Evans blue dye leakage. Retinal inflammatory gene expression and leukocytic infiltration were measured by qRT-PCR and immunofluorescence, respectively. A microglial cell line was used to determine the effects of Ex-4 on lipopolysaccharide (LPS)-induced inflammatory response.
  
  
  
  Exendin-4 dramatically reduced the BRB permeability induced by IR injury, which was associated with suppression of inflammatory gene expression. Moreover, in vitro studies showed that Ex-4 also reduced the inflammatory response to LPS and inhibited NF-κB activation.
  
  
  
  The present work suggests that Ex-4 can prevent IR injury-induced BRB breakdown and inflammation through inhibition of inflammatory cytokine production by activated microglia and may provide a novel option for therapeutic intervention in diseases involving retinal inflammation.
authors.affiliation: Institute for Biomedical Imaging and Life Sciences (IBILI) Faculty of Medicine, University of Coimbra, Coimbra, Portugal 3CNC.IBILI, University of Coimbra, Coimbra, Portugal.
authors.forename: Andreia
authors.initials: A
authors.lastname: Gonçalves
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Michigan Kellogg Eye Center, Ann Arbor, Michigan, United States.
authors.forename: Cheng-Mao
authors.initials: CM
authors.lastname: Lin
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Michigan Kellogg Eye Center, Ann Arbor, Michigan, United States.
authors.forename: Arivalagan
authors.initials: A
authors.lastname: Muthusamy
authors.affiliation: Institute for Biomedical Imaging and Life Sciences (IBILI) Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Carlos
authors.initials: C
authors.lastname: Fontes-Ribeiro
authors.affiliation: Institute for Biomedical Imaging and Life Sciences (IBILI) Faculty of Medicine, University of Coimbra, Coimbra, Portugal 3CNC.IBILI, University of Coimbra, Coimbra, Portugal 4Association for Innovation and Biomedical Research on Light, Coimbra, Portugal.
authors.forename: António F
authors.initials: AF
authors.lastname: Ambrósio
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Michigan Kellogg Eye Center, Ann Arbor, Michigan, United States.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Abcouwer
authors.affiliation: Institute for Biomedical Imaging and Life Sciences (IBILI) Faculty of Medicine, University of Coimbra, Coimbra, Portugal 3CNC.IBILI, University of Coimbra, Coimbra, Portugal.
authors.forename: Rosa
authors.initials: R
authors.lastname: Fernandes
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Michigan Kellogg Eye Center, Ann Arbor, Michigan, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: Antonetti
mesh_terms: D000818:Animals; D001813:Blood-Retinal Barrier / Q000187:drug effects*; D002417:Cattle; D002478:Cells, Cultured; D004195:Disease Models, Animal; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives*; D015151:Immunoblotting; D007150:Immunohistochemistry; D054795:Incretins / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism / Q000517:prevention & control*; D007511:Ischemia / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans; D015427:Reperfusion Injury / Q000150:complications* / Q000378:metabolism; D012164:Retinal Diseases / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D014688:Venoms / Q000494:pharmacology*
chemical_list: D054795:Incretins; D010455:Peptides; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide