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      Long-Term Oral Treatment with Non-Hypoglycemic Dose of Glibenclamide Reduces Diabetic Retinopathy Damage in the Goto-KakizakiRat Model

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          Abstract

          Diabetic retinopathy (DR) remains a major cause of vision loss, due to macular edema, retinal ischemia and death of retinal neurons. We previously demonstrated that acute administration of glibenclamide into the vitreous, or given orally at a non-hypoglycemic dose, protected the structure and the function of the retina in three animal models that each mimic aspects of diabetic retinopathy in humans. In this pilot study, we investigated whether one year of chronic oral glibenclamide, in a non-hypoglycemic regimen (Amglidia ®, 0.4 mg/kg, Ammtek/Nordic Pharma, 5 d/week), could alleviate the retinopathy that develops in the Goto-Kakizaki (GK) rat. In vivo, retinal function was assessed by electroretinography (ERG), retinal thickness by optical coherence tomography (OCT) and retinal perfusion by fluorescein and indocyanin green angiographies. The integrity of the retinal pigment epithelium (RPE) that constitutes the outer retinal barrier was evaluated by quantitative analysis of the RPE morphology on flat-mounted fundus ex vivo. Oral glibenclamide did not significantly reduce the Hb1Ac levels but still improved retinal function, as witnessed by the reduction in scotopic implicit times, limited diabetes-induced neuroretinal thickening and the extension of ischemic areas, and it improved the capillary coverage. These results indicate that low doses of oral glibenclamide could still be beneficial for the prevention of type 2 diabetic retinopathy. Whether the retinas ofpatients treated specifically with glibenclamideare less at risk of developing diabetic complications remains to be demonstrated.

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          Mechanisms of macular edema: Beyond the surface.

          Macular edema consists of intra- or subretinal fluid accumulation in the macular region. It occurs during the course of numerous retinal disorders and can cause severe impairment of central vision. Major causes of macular edema include diabetes, branch and central retinal vein occlusion, choroidal neovascularization, posterior uveitis, postoperative inflammation and central serous chorioretinopathy. The healthy retina is maintained in a relatively dehydrated, transparent state compatible with optimal light transmission by multiple active and passive systems. Fluid accumulation results from an imbalance between processes governing fluid entry and exit, and is driven by Starling equation when inner or outer blood-retinal barriers are disrupted. The multiple and intricate mechanisms involved in retinal hydro-ionic homeostasis, their molecular and cellular basis, and how their deregulation lead to retinal edema, are addressed in this review. Analyzing the distribution of junction proteins and water channels in the human macula, several hypotheses are raised to explain why edema forms specifically in the macular region. "Pure" clinical phenotypes of macular edema, that result presumably from a single causative mechanism, are detailed. Finally, diabetic macular edema is investigated, as a complex multifactorial pathogenic example. This comprehensive review on the current understanding of macular edema and its mechanisms opens perspectives to identify new preventive and therapeutic strategies for this sight-threatening condition.
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            Newly expressed SUR1-regulated NC(Ca-ATP) channel mediates cerebral edema after ischemic stroke.

            Pathological conditions in the central nervous system, including stroke and trauma, are often exacerbated by cerebral edema. We recently identified a nonselective cation channel, the NC(Ca-ATP) channel, in ischemic astrocytes that is regulated by sulfonylurea receptor 1 (SUR1), is opened by depletion of ATP and, when opened, causes cytotoxic edema. Here, we evaluated involvement of this channel in rodent models of stroke. SUR1 protein and mRNA were newly expressed in ischemic neurons, astrocytes and capillaries. Upregulation of SUR1 was linked to activation of the transcription factor Sp1 and was associated with expression of functional NC(Ca-ATP) but not K(ATP) channels. Block of SUR1 with low-dose glibenclamide reduced cerebral edema, infarct volume and mortality by 50%, with the reduction in infarct volume being associated with cortical sparing. Our findings indicate that the NC(Ca-ATP) channel is crucially involved in development of cerebral edema, and that targeting SUR1 may provide a new therapeutic approach to stroke.
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              Diabetic retinopathy - ocular complications of diabetes mellitus.

              In industrialized nations diabetic retinopathy is the most frequent microvascular complication of diabetes mellitus and the most common cause of blindness in the working-age population. In the next 15 years, the number of patients suffering from diabetes mellitus is expected to increase significantly. By the year 2030, about 440 million people in the age-group 20-79 years are estimated to be suffering from diabetes mellitus worldwide (prevalence 7.7%), while in 2010 there were 285 million people with diabetes mellitus (prevalence 6.4%). This accounts for an increase in patients with diabetes in industrialized nations by 20% and in developing countries by 69% until the year 2030. Due to the expected rise in diabetic patients, the need for ophthalmic care of patients (i.e., exams and treatments) will also increase and represents a challenge for eye-care providers. Development of optimized screening programs, which respect available resources of the ophthalmic infrastructure, will become even more important. Main reasons for loss of vision in patients with diabetes mellitus are diabetic macular edema and proliferative diabetic retinopathy. Incidence or progression of these potentially blinding complications can be greatly reduced by adequate control of blood glucose and blood pressure levels. Additionally, regular ophthalmic exams are mandatory for detecting ocular complications and initiating treatments such as laser photocoagulation in case of clinical significant diabetic macular edema or early proliferative diabetic retinopathy. In this way, the risk of blindness can considerably be reduced. In advanced stages of diabetic retinopathy, pars-plana vitrectomy is performed to treat vitreous hemorrhage and tractional retinal detachment. In recent years, the advent of intravitreal medication has improved therapeutic options for patients with advanced diabetic macular edema.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Pharmaceutics
                Pharmaceutics
                pharmaceutics
                Pharmaceutics
                MDPI
                1999-4923
                17 July 2021
                July 2021
                : 13
                : 7
                : 1095
                Affiliations
                [1 ]Physiopathology of Ocular Diseases: Therapeutic Innovations, Sorbonne University and Universityof Paris, Inserm UMRS 1138, F-75006 Paris, France; marianne.berdugo@ 123456gmail.com (M.B.); kimberley.delaunay@ 123456live.fr (K.D.); cecile.lebon@ 123456sorbonne-universite.fr (C.L.); marie-christine.naud@ 123456crc.jussieu.fr (M.-C.N.); lolitaradet@ 123456gmail.com (L.R.); lea.zennaro@ 123456inovarion.com (L.Z.); emilie.picard@ 123456crc.jussieu.fr (E.P.); adaruich.matet@ 123456gmail.com (A.D.); elsa.kermorvant@ 123456aphp.fr (E.K.-D.); patricia.lassiaz@ 123456crc.jussieu.fr (P.C.)
                [2 ]Department of Ophthalmology, AP-HP Hospital University Necker-Sick Children, F-75015 Paris, France
                [3 ]Department of Paediatric Endocrinology, Gynecology and Diabetology, AP-HP Hospital University Necker-Sick Children, F-75015 Paris, France; jacques.beltrand@ 123456aphp.fr (J.B.); michel.polak@ 123456aphp.fr (M.P.)
                [4 ]Faculté de Santé, University of Paris, F-75006 Paris, France
                [5 ]Institut Cochin, InsermU1016, F-75005 Paris, France
                [6 ]Neonatal and Intensive Care Unit, AP-HP Hospital University Necker-Sick Children, F-75015 Paris, France
                [7 ]Institute Imagine, InsermU1163, F-75015 Paris, France
                [8 ]Ophthalmology, AP-HP Hospital Cochin, F-75005 Paris, France
                Author notes
                Author information
                https://orcid.org/0000-0001-8571-9513
                Article
                pharmaceutics-13-01095
                10.3390/pharmaceutics13071095
                8308933
                34371786
                59fd0808-5782-4019-9735-466e0582d50e
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

                History
                : 31 May 2021
                : 15 July 2021
                Categories
                Article

                diabetic retinopathy,retinal neuroprotection,glibenclamide,glyburide,sulfonylureas,diabetes complications,retinal edema

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