The antidiabetic drug glibenclamide exerts direct retinal neuroprotection
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INTRODUCTION
The prevalence of diabetes worldwide is expected to reach 7.7% by 20301 and could reach about 12% in large cities in the United States.2 Diabetic retinopathy is the major cause of vision loss in the working-age population of western countries, and a growing health concern in emerging countries. After 10 years, 50% of types 1 and 30% of type 2 diabetic patients have retinal microvascular complications.3 In diabetes, vision loss results from 2 major complications, macular edema and retinal cell
RESEARCH DESIGN AND METHODS
Primate human and nonhuman ocular tissues. The use of human tissues adhered to the tenets of the Declaration of Helsinki and was approved by the local ethics committee of the Swiss Department of Health on research involving human subjects (CER-VD No. 340/15 and CER-VD No. 19/15), and patients signed informed consent.
One retina was obtained from an enucleated eye from a nondiabetic patient (female, 56 years old) with a tumor and intact posterior retina (untreated anterior uveal melanoma). The
SUR1, expressed in human and nonhuman primate retina, is enriched in the macula and colocalizes with TRPM4 and with Kir6.2
In the normal human macula (Figs. 1 and 2), SUR1 is expressed in all retinal layers, including the GCL, the outer plexiform layer (OPL, ie, synapses), the outer nuclear layer (ONL, ie, photoreceptor nuclei layer), and at the outer limiting membrane (OLM) formed by junctions between photoreceptors and glial Müller cells, which is part of the outer retinal barrier; it is also expressed in retinal vessels (Fig 1 A inset). Colocalization with glutamine synthetase (GS), which is a marker of retinal
DISCUSSION
We have shown herein that the glibenclamide receptor SUR1 is expressed in the retina in rodents and in humans, and that glibenclamide (glyburide) exerts neuroprotective effects on the retina, avoiding cell death and preserving visual function through direct binding to its receptor SUR1. These data are consistent with reports showing that glibenclamide exerts neuroprotection in various models of cerebral and medullar injury.8,11,26, 27, 28, 29, 30, 31, 32, 33, 34 Indeed, SUR1 blockade with
ACKNOWLEDGMENTS
Conflicts of Interest: M.P. is scientific adviser for AMMTeK. All authors have read the journal's policy on disclosure of potential conflicts of interest.
This study was supported by the French Fondation de France, the association Centre de Recherche en Ophtalmologie (CRO)-Tous unis pour la Vision, the Aide aux Jeunes Diabétiques, the Société Francophone du Diabète and the French Agence Nationale de la Recherche (ANR-15-CE18-0032), which had no involvement in the studies. The guarantor is F.B.-C.
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2022, iScienceCitation Excerpt :DC treatment could retain the ERG response better than CT and Glb, which is likely owing to its potent antimicrobial and anti-inflammatory properties. Recently, Glb has been shown to protect mice retinal neurons in diabetic retinopathy and excitotoxicity models (Berdugo et al., 2021), which can be related to its anti-inflammatory effects. The reduced number of apoptotic retinal cells corroborated with a decreased expression of protein involved in cell death and apoptosis in the drug-treated eyes, especially with DC.
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2022, Progress in Retinal and Eye ResearchCitation Excerpt :For example, the mineralocorticoid receptor (Behar-Cohen and Zhao, 2021) is upregulated in photoreceptor, inner nuclear layer, ganglion cells of Goto-Kakizaki diabetic rats and human diabetic retinas, and the mineralocorticoid receptor inhibitor, spironolactone, reduces retinal inflammation and restores the blood-retinal barrier (Zhao et al., 2021). Also, the sulfonylurea receptor 1 (SUR1) is expressed in human retina axons colocalizes with the Kir6.2 channel, and the SUR1 inhibitor, glyburide, a common anti-diabetic drug, mitigates retinal gliosis in Goto-Kakizaki diabetic rats (Berdugo et al., 2021). Several investigators have suggested that choroidal vascular lesions are correlated with photoreceptor defects in persons with no visible DR and non-proliferative retinopathy (Choi et al., 2017; Parravano et al., 2021).
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