title: Effect of glucocorticoids on neuronal and vascular pathology in a transgenic model of selective Müller cell ablation.
abstract: Retinal diseases such as macular telangiectasis type 2 (MacTel), age-related macular degeneration (AMD) and diabetic retinopathy (DR) affect both neurons and blood vessels. Treatments addressing both at the same time might have advantages over more specific approaches, such as vascular endothelial growth factor (VEGF) inhibitors, which are used to treat vascular leak but are suspected to have a neurotoxic effect. Here, we studied the effects of an intravitreal injection of triamcinolone acetonide (TA) in a transgenic model in which patchy Müller cell ablation leads to photoreceptor degeneration, vascular leak, and intraretinal neovascularization. TA was injected 4 days before Müller cell ablation. Changes in photoreceptors, microglia and Müller cells, retinal vasculature, differential expression of p75 neurotrophin receptor (p75(NTR) ), tumor necrosis factor-α (TNFα), the precursor and mature forms of neurotrophin 3 (pro-NT3 and mature NT3) and activation of the p53 and p38 stress-activated protein kinase (p38/SAPK) signaling pathways were examined. We found that TA prevented photoreceptor degeneration and inhibited activation of microglial and Müller cells. TA attenuated Müller cell loss and inhibited overexpression of p75(NTR) , TNFα, pro-NT, and the activation of p53 and p38/SAPK signaling pathways. TA not only prevented the development of retinal vascular lesions but also inhibited fluorescein leakage from established vascular lesions. TA inhibited overexpression of VEGF in transgenic mice but without affecting its basal level expression in the normal retina. Our data suggest that glucocorticoid treatment may be beneficial for treatment of retinal diseases such as MacTel, AMD, and DR that affect both neurons and the vasculature.
authors.affiliation: Macular Research Group. Save Sight Institute, The University of Sydney, Australia.
authors.forename: Weiyong
authors.initials: W
authors.lastname: Shen
authors.forename: So-Ra
authors.initials: SR
authors.lastname: Lee
authors.forename: Joana
authors.initials: J
authors.lastname: Araujo
authors.forename: Sook H
authors.initials: SH
authors.lastname: Chung
authors.forename: Ling
authors.initials: L
authors.lastname: Zhu
authors.forename: Mark C
authors.initials: MC
authors.lastname: Gillies
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D063928:Ependymoglial Cells / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D005911:Gliosis / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D005938:Glucocorticoids / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020933:Neurotrophin 3 / Q000378:metabolism; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D012164:Retinal Diseases / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D012171:Retinal Vessels / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D013629:Tamoxifen; D014222:Triamcinolone Acetonide / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D005938:Glucocorticoids; D018696:Neuroprotective Agents; D020933:Neurotrophin 3; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D013629:Tamoxifen; D048055:Mitogen-Activated Protein Kinase 8; D048051:p38 Mitogen-Activated Protein Kinases; D014222:Triamcinolone Acetonide
keywords: Müller cell; blood retinal barrier; glucocorticoids; microglia; neuroprotection; photoreceptor; retina