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      Topical Administration of Somatostatin Prevents Retinal Neurodegeneration in Experimental Diabetes

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          Abstract

          Retinal neurodegeneration is an early event in the pathogenesis of diabetic retinopathy (DR). Somatostatin (SST) is an endogenous neuroprotective peptide that is downregulated in the diabetic eye. The aim of the study was to test the usefulness of topical administration of SST in preventing retinal neurodegeneration. For this purpose, rats with streptozotocin-induced diabetes mellitus (STZ-DM) were treated with either SST eye drops or vehicle for 15 days. Nondiabetic rats treated with vehicle served as a control group. Functional abnormalities were assessed by electroretinography (ERG), and neurodegeneration was assessed by measuring glial activation and the apoptotic rate. In addition, proapoptotic (FasL, Bid, and activation of caspase-8 and caspase-3) and survival signaling pathways (BclxL) were examined. Intraretinal concentrations of glutamate and its main transporter glutamate/aspartate transporter (GLAST) were also determined. Treatment with SST eye drops prevented ERG abnormalities, glial activation, apoptosis, and the misbalance between proapoptotic and survival signaling detected in STZ-DM rats. In addition, SST eye drops inhibited glutamate accumulation in the retina and GLAST downregulation induced by diabetes mellitus. We conclude that topical administration of SST has a potent effect in preventing retinal neurodegeneration induced by diabetes mellitus. In addition, our findings open up a new preventive pharmacological strategy targeted to early stages of DR.

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          Most cited references40

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          Diabetic retinopathy: seeing beyond glucose-induced microvascular disease.

          Diabetic retinopathy remains a frightening prospect to patients and frustrates physicians. Destruction of damaged retina by photocoagulation remains the primary treatment nearly 50 years after its introduction. The diabetes pandemic requires new approaches to understand the pathophysiology and improve the detection, prevention, and treatment of retinopathy. This perspective considers how the unique anatomy and physiology of the retina may predispose it to the metabolic stresses of diabetes. The roles of neural retinal alterations and impaired retinal insulin action in the pathogenesis of early retinopathy and the mechanisms of vision loss are emphasized. Potential means to overcome limitations of current animal models and diagnostic testing are also presented with the goal of accelerating therapies to manage retinopathy in the face of ongoing diabetes.
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            Müller Cell-Derived VEGF Is Essential for Diabetes-Induced Retinal Inflammation and Vascular Leakage

            OBJECTIVE Vascular endothelial growth factor (VEGF-A or VEGF) is a major pathogenic factor and therapeutic target for diabetic retinopathy (DR). Since VEGF has been proposed as a survival factor for retinal neurons, defining the cellular origin of pathogenic VEGF is necessary for the effectiveness and safety of long-term anti-VEGF therapies for DR. To determine the significance of Müller cell-derived VEGF in DR, we disrupted VEGF in Müller cells with an inducible Cre/lox system and examined diabetes-induced retinal inflammation and vascular leakage in these conditional VEGF knockout (KO) mice. RESEARCH DESIGN AND METHODS Leukostasis was determined by counting the number of fluorescently labeled leukocytes inside retinal vasculature. Expression of biomarkers for retinal inflammation was assessed by immunoblotting of TNF-α, ICAM-1, and NF-κB. Vascular leakage was measured by immunoblotting of retinal albumin and fluorescent microscopic analysis of extravascular albumin. Diabetes-induced vascular alterations were examined by immunoblotting and immunohistochemistry for tight junctions, and by trypsin digestion assays for acellular capillaries. Retinal integrity was analyzed with morphologic and morphometric analyses. RESULTS Diabetic conditional VEGF KO mice exhibited significantly reduced leukostasis, expression of inflammatory biomarkers, depletion of tight junction proteins, numbers of acellular capillaries, and vascular leakage compared to diabetic control mice. CONCLUSIONS Müller cell-derived VEGF plays an essential and causative role in retinal inflammation, vascular lesions, and vascular leakage in DR. Therefore, Müller cells are a primary cellular target for proinflammatory signals that mediates retinal inflammation and vascular leakage in DR.
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              The significance of vascular and neural apoptosis to the pathology of diabetic retinopathy.

              The most striking features of diabetic retinopathy are the vascular abnormalities that are apparent by fundus examination. There is also strong evidence that diabetes causes apoptosis of neural and vascular cells in the retina. Thus, there is good reason to define diabetic retinopathy as a form of chronic neurovascular degeneration. In keeping with the gradual onset of retinopathy in humans, the rate of cell loss in the animal models is insidious, even in uncontrolled diabetes. This is not surprising given that a sustained high rate of cell loss without regeneration would soon lead to catastrophic tissue destruction. The consequences of ongoing cell death are difficult to detect, and even the quantification of cumulative cell loss requires painstaking histology and microscopy. This subtle cell loss raises the issue of the relevance of the phenomenon to the progression of diabetic retinopathy and the ultimate loss of vision. Neuronal function may be compromised in advance of apoptosis, contributing to an early deterioration of vision. Here we review some of the evidence supporting apoptotic cell death as a contributing mechanism of diabetic retinopathy, explore some of the potential causes, and discuss the potential links between apoptosis and loss of visual function in diabetic retinopathy.
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                Author and article information

                Journal
                Diabetes
                Diabetes
                diabetes
                diabetes
                Diabetes
                Diabetes
                American Diabetes Association
                0012-1797
                1939-327X
                July 2013
                14 June 2013
                : 62
                : 7
                : 2569-2578
                Affiliations
                [1] 1Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
                [2] 2CIBERDEM, Ministerio de Ciencia e Innovación, Madrid, Spain
                [3] 3BCN Peptides, Barcelona, Spain
                [4] 4Instituto de Investigaciones Biomédicas Alberto Sols, Madrid, Spain
                Author notes
                Corresponding author: Cristina Hernández, cristina.hernandez@ 123456vhir.org .
                Article
                0926
                10.2337/db12-0926
                3712066
                23474487
                bd029564-98e7-4e42-81a6-ec9bd95da146
                © 2013 by the American Diabetes Association.

                Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

                History
                : 12 July 2012
                : 02 March 2013
                Page count
                Pages: 10
                Categories
                Original Research
                Complications

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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