title: Topical Administration of GLP-1 Receptor Agonists Prevents Retinal Neurodegeneration in Experimental Diabetes.
abstract: Retinal neurodegeneration is an early event in the pathogenesis of diabetic retinopathy (DR). Since glucagon-like peptide 1 (GLP-1) exerts neuroprotective effects in the central nervous system and the retina is ontogenically a brain-derived tissue, the aims of the current study were as follows: 1) to examine the expression and content of GLP-1 receptor (GLP-1R) in human and db/db mice retinas; 2) to determine the retinal neuroprotective effects of systemic and topical administration (eye drops) of GLP-1R agonists in db/db mice; and 3) to examine the underlying neuroprotective mechanisms. We have found abundant expression of GLP-1R in the human retina and retinas from db/db mice. Moreover, we have demonstrated that systemic administration of a GLP-1R agonist (liraglutide) prevents retinal neurodegeneration (glial activation, neural apoptosis, and electroretinographical abnormalities). This effect can be attributed to a significant reduction of extracellular glutamate and an increase of prosurvival signaling pathways. We have found a similar neuroprotective effect using topical administration of native GLP-1 and several GLP-1R agonists (liraglutide, lixisenatide, and exenatide). Notably, this neuroprotective action was observed without any reduction in blood glucose levels. These results suggest that GLP-1R activation itself prevents retinal neurodegeneration. Our results should open up a new approach in the treatment of the early stages of DR.
authors.affiliation: Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain cristina.hernandez@vhir.org.
authors.forename: Cristina
authors.initials: C
authors.lastname: Hernández
authors.affiliation: Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Bogdanov
authors.affiliation: Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Lidia
authors.initials: L
authors.lastname: Corraliza
authors.affiliation: Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: García-Ramírez
authors.affiliation: Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Solà-Adell
authors.affiliation: Unidad de Metabolopatías, Laboratorios Clínicos, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Arranz
authors.affiliation: CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas/Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Arroba
authors.affiliation: CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas/Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Valverde
authors.affiliation: Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Simó
mesh_terms: D060433:Administration, Ophthalmic; D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism*; D003930:Diabetic Retinopathy / Q000209:etiology / Q000517:prevention & control*; D004596:Electroretinography; D000077270:Exenatide; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000187:drug effects / Q000378:metabolism; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D000069450:Liraglutide / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D012160:Retina / Q000187:drug effects / Q000473:pathology; D055351:Retinal Neurons / Q000187:drug effects* / Q000473:pathology; D014688:Venoms / Q000494:pharmacology*; D000097789:Glucagon-Like Peptide-1 Receptor Agonists; D000067758:Glucagon-Like Peptide-2 Receptor
chemical_list: D000077270:Exenatide; D005904:Glial Fibrillary Acidic Protein; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D000069450:Liraglutide; D018696:Neuroprotective Agents; D010455:Peptides; D014688:Venoms; D000097789:Glucagon-Like Peptide-1 Receptor Agonists; C479460:lixisenatide; D000067758:Glucagon-Like Peptide-2 Receptor