title: Retinal pathology is associated with increased blood-retina barrier permeability in a diabetic and hypercholesterolaemic pig model: Beneficial effects of the LpPLA2inhibitor Darapladib.
abstract: Using a porcine model of diabetes mellitus and hypercholesterolaemia, we previously showed that diabetes mellitus and hypercholesterolaemia is associated with a chronic increase in blood-brain barrier permeability in the cerebral cortex, leading to selective binding of immunoglobulin G and deposition of amyloid-beta1-42peptide in pyramidal neurons. Treatment with Darapladib (GlaxoSmithKline, SB480848), an inhibitor of lipoprotein-associated phospholipase-A2, alleviated these effects. Here, investigation of the effects of chronic diabetes mellitus and hypercholesterolaemia on the pig retina revealed a corresponding increased permeability of the blood-retina barrier coupled with a leak of plasma components into the retina, alterations in retinal architecture, selective IgG binding to neurons in the ganglion cell layer, thinning of retinal layers due to cell loss and increased glial fibrillary acidic protein expression in Müller cells, all of which were curtailed by treatment with Darapladib. These findings suggest that chronic diabetes mellitus and hypercholesterolaemia induces increased blood-retina barrier permeability that may be linked to altered expression of blood-retina barrier-associated tight junction proteins, claudin and occludin, leading to structural changes in the retina consistent with diabetic retinopathy. Additionally, results suggest that drugs with vascular anti-inflammatory properties, such as Darapladib, may have beneficial effects on eye diseases strongly linked to vascular abnormalities such as diabetic retinopathy and age-related macular degeneration.
authors.affiliation: 1 Biomarker Discovery Center, New Jersey Institute for Successful Aging, School of Osteopathic Medicine, Rowan University, Stratford, NJ, USA.|2 Department of Geriatrics and Gerontology, School of Osteopathic Medicine, Rowan University, Stratford, NJ, USA.|3 Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Nimish K
authors.initials: NK
authors.lastname: Acharya
authors.affiliation: 4 Thomas Jefferson University, Philadelphia, PA, USA.|5 Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Qi
authors.affiliation: 1 Biomarker Discovery Center, New Jersey Institute for Successful Aging, School of Osteopathic Medicine, Rowan University, Stratford, NJ, USA.|2 Department of Geriatrics and Gerontology, School of Osteopathic Medicine, Rowan University, Stratford, NJ, USA.|6 Graduate School of Biomedical Sciences, Rowan University, Stratford, NJ, USA.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Goldwaser
authors.affiliation: 2 Department of Geriatrics and Gerontology, School of Osteopathic Medicine, Rowan University, Stratford, NJ, USA.|6 Graduate School of Biomedical Sciences, Rowan University, Stratford, NJ, USA.
authors.forename: George A
authors.initials: GA
authors.lastname: Godsey
authors.affiliation: 6 Graduate School of Biomedical Sciences, Rowan University, Stratford, NJ, USA.|7 Department of Cell Biology, School of Osteopathic Medicine, Rowan University, Stratford, NJ, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: 1 Biomarker Discovery Center, New Jersey Institute for Successful Aging, School of Osteopathic Medicine, Rowan University, Stratford, NJ, USA.|2 Department of Geriatrics and Gerontology, School of Osteopathic Medicine, Rowan University, Stratford, NJ, USA.
authors.forename: Mary C
authors.initials: MC
authors.lastname: Kosciuk
authors.affiliation: 8 Department of Orthopaedic Surgery, Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University.
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Freeman
authors.affiliation: 9 GlaxoSmithKline, Philadelphia, PA, USA.
authors.forename: Colin H
authors.initials: CH
authors.lastname: Macphee
authors.affiliation: 10 Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Wilensky
authors.affiliation: 7 Department of Cell Biology, School of Osteopathic Medicine, Rowan University, Stratford, NJ, USA.
authors.forename: Venkat
authors.initials: V
authors.lastname: Venkataraman
authors.affiliation: 1 Biomarker Discovery Center, New Jersey Institute for Successful Aging, School of Osteopathic Medicine, Rowan University, Stratford, NJ, USA.|2 Department of Geriatrics and Gerontology, School of Osteopathic Medicine, Rowan University, Stratford, NJ, USA.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Nagele
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001547:Benzaldehydes / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D001813:Blood-Retinal Barrier / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D002199:Capillary Permeability / Q000187:drug effects*; D062507:Claudin-5 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D003930:Diabetic Retinopathy / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D005911:Gliosis; D006937:Hypercholesterolemia / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D007074:Immunoglobulin G / Q000378:metabolism; D008297:Male; D062793:Occludin / Q000378:metabolism; D010091:Oximes / Q000494:pharmacology*; D064801:Phospholipase A2 Inhibitors / Q000494:pharmacology*; D011485:Protein Binding; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000201:enzymology; D034421:Sus scrofa; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides
chemical_list: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000893:Anti-Inflammatory Agents; D001547:Benzaldehydes; D062507:Claudin-5; D007074:Immunoglobulin G; D062793:Occludin; D010091:Oximes; D064801:Phospholipase A2 Inhibitors; C529040:darapladib; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides
keywords: Blood–retina barrier; blood vessels; blood–brain barrier; cholesterol; claudin-5; diabetes; endothelium; lipoprotein-associated phospholipase-A2; occludin; retina; tight junctions