Protective Effect of a GLP-1 Analog on Ischemia-Reperfusion Induced Blood-Retinal Barrier Breakdown and Inflammation

• Published in: Investigative ophthalmology & visual science Vol. 57; no. 6; pp. 2584 - 2592
• Main Authors: Gonçalves, Andreia, Lin, Cheng-Mao, Muthusamy, Arivalagan, Fontes-Ribeiro, Carlos, Ambrósio, António F, Abcouwer, Steven F, Fernandes, Rosa, Antonetti, David A
• Format: Journal Article
• Language: English
• Published: United States The Association for Research in Vision and Ophthalmology 01.05.2016
• Subjects: Animals; Blood-Retinal Barrier - drug effects; Cattle; Cells, Cultured; Disease Models, Animal; Glucagon-Like Peptide 1 - analogs & derivatives; Immunoblotting; Immunohistochemistry; Incretins - pharmacology; Inflammation - metabolism; Inflammation - prevention & control; Ischemia - etiology; Ischemia - metabolism; Ischemia - prevention & control; Male; Peptides - pharmacology; Physiology and Pharmacology; Rats; Rats, Long-Evans; Reperfusion Injury - complications; Reperfusion Injury - metabolism; Retinal Diseases - etiology; Retinal Diseases - metabolism; Retinal Diseases - prevention & control; Venoms - pharmacology
• ISSN: 1552-5783; 0146-0404; 1552-5783
• DOI: 10.1167/iovs.15-19006

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.