title: Activation of Melanocortin Receptors MC 1 and MC 5 Attenuates Retinal Damage in Experimental Diabetic Retinopathy.
abstract: We hypothesize that melanocortin receptors (MC) could activate tissue protective circuit in a model of streptozotocin- (STZ-) induced diabetic retinopathy (DR) in mice. At 12-16 weeks after diabetes induction, fluorescein angiography (FAG) revealed an approximate incidence of 80% microvascular changes, typical of DR, in the animals, without signs of vascular leakage. Occludin progressively decreased in the retina of mice developing retinopathy. qPCR of murine retina revealed expression of two MC receptors, Mc1r and Mc5r. The intravitreal injection (5 μL) of the selective MC1 small molecule agonist BMS-470539 (33 μmol) and the MC5 peptidomimetic agonist PG-901 (7.32 nM) elicited significant protection with regular course and caliber of retinal vessels, as quantified at weeks 12 and 16 after diabetes induction. Mouse retina homogenate settings indicated an augmented release of IL-1α, IL-1β, IL-6, MIP-1α, MIP-2α, MIP-3α, and VEGF from diabetic compared to nondiabetic mice. Application of PG20N or AGRP and MC5 and MC1 antagonist, respectively, augmented the release of cytokines, while the agonists BMS-470539 and PG-901 almost restored normal pattern of these mediators back to nondiabetic values. Similar changes were quantified with respect to Ki-67 staining. Finally, application of MC3-MC4 agonist/antagonists resulted to be inactive with respect to all parameters under assessment.
authors.affiliation: Multidisciplinary Department of Medical-Surgical and Dental Specialties, Second University of Naples, 80138 Naples, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Rossi
authors.affiliation: Department of Experimental Medicine, Second University of Naples, 80138 Naples, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Maisto
authors.affiliation: Multidisciplinary Department of Medical-Surgical and Dental Specialties, Second University of Naples, 80138 Naples, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Gesualdo
authors.affiliation: Department of Experimental Medicine, Second University of Naples, 80138 Naples, Italy.
authors.forename: M C
authors.initials: MC
authors.lastname: Trotta
authors.affiliation: Department of Clinical, Public and Preventive Medicine, Second University of Naples, 80138 Naples, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Ferraraccio
authors.affiliation: The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: M K
authors.initials: MK
authors.lastname: Kaneva
authors.affiliation: Faculty of Science and Technology, Department of Life Sciences, University of Westminster, London W1W 6UW, UK.
authors.forename: S J
authors.initials: SJ
authors.lastname: Getting
authors.affiliation: Department of Translational Medicine, University of Naples Federico II, 80131 Naples, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Surace
authors.affiliation: Multidisciplinary Department of Medical-Surgical and Dental Specialties, Second University of Naples, 80138 Naples, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Testa
authors.affiliation: Multidisciplinary Department of Medical-Surgical and Dental Specialties, Second University of Naples, 80138 Naples, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Simonelli
authors.affiliation: Pharmacy Department, University of Naples Federico II, 80131 Naples, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Grieco
authors.affiliation: Pharmacy Department, University of Naples Federico II, 80131 Naples, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Merlino
authors.affiliation: The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: M
authors.initials: M
authors.lastname: Perretti
authors.affiliation: Department of Experimental Medicine, Second University of Naples, 80138 Naples, Italy.
authors.forename: M
authors.initials: M
authors.lastname: D'Amico
authors.affiliation: Department of Experimental Medicine, Second University of Naples, 80138 Naples, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Di Filippo
mesh_terms: D000818:Animals; D054418:Chemokine CCL20 / Q000378:metabolism; D054405:Chemokine CCL3 / Q000378:metabolism; D054426:Chemokine CXCL2 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism*; D003930:Diabetic Retinopathy / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D007093:Imidazoles / Q000494:pharmacology; D053582:Interleukin-1alpha / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D010456:Peptides, Cyclic / Q000494:pharmacology; D044102:Receptor, Melanocortin, Type 1 / Q000378:metabolism*; D044101:Receptors, Melanocortin / Q000378:metabolism*; D012160:Retina / Q000187:drug effects* / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C523069:BMS-470539; D054418:Chemokine CCL20; D054405:Chemokine CCL3; D054426:Chemokine CXCL2; D007093:Imidazoles; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D015850:Interleukin-6; C454109:PG 901; D010456:Peptides, Cyclic; D044102:Receptor, Melanocortin, Type 1; D044101:Receptors, Melanocortin; D042461:Vascular Endothelial Growth Factor A