The antidiabetic drug glibenclamide exerts direct retinal neuroprotection

doi:10.1016/j.trsl.2020.10.003

Translational Research

Volume 229, March 2021, Pages 83-99

https://doi.org/10.1016/j.trsl.2020.10.003 Get rights and content

Sulfonylureas, widely used as hypoglycemic agents in adults with type 2 diabetes, have neuroprotective effects in preclinical models of central nervous system injury, and in children with neuropsychomotor impairments linked to neonatal diabetes secondary to ATP-sensitive potassium channel mutations. In the human and rodent retina, we show that the glibenclamide-activated channel sulfonylurea receptor 1 (SUR1) is expressed in the retina and enriched in the macula; we also show that it colocalizes with the potassium channel Kir6.2, and with the cation channel transporter TRPM4. Glibenclamide (glyburide), administered at doses that did not decrease the glycemia, or injected directly into the eye, protected the structure and the function of the retina in various models of retinal injury that recapitulate the pathogenic neurodegenerative events in the diabetic retina. The downregulation of SUR1 using a siRNA suppressed the neuroprotective effects of glibenclamide on excitotoxic stress-induced cell death. The glibenclamide effects include the transcriptional regulation of antioxidant and neuroprotective genes. Ocular glibenclamide could be repurposed for diabetic retinopathy.

Section snippets

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.

REFERENCES (59)

UH Panton et al.
Projected diabetes prevalence and related costs in three North American Urban Centres (2015-2040)
Public Health
(2018)
Q Li et al.
Early retinal damage in experimental diabetes: electroretinographical and morphological observations
Exp Eye Res
(2002)
R Tzekov et al.
The electroretinogram in diabetic retinopathy
Surv Ophthalmol
(1999)
S Omri et al.
Microglia/macrophages migrate through retinal epithelium barrier by a transcellular route in diabetic retinopathy: role of PKCzeta in the Goto Kakizaki rat model
Am J Pathol
(2011)
JM Simard et al.
Spinal cord injury with unilateral versus bilateral primary hemorrhage—effects of glibenclamide
Exp Neurol
(2012)
JM Simard et al.
Comparative effects of glibenclamide and riluzole in a rat model of severe cervical spinal cord injury
Exp Neurol
(2012)
MM Al-Gayyar et al.
Neurovascular protective effect of FeTPPs in N-methyl-D-aspartate model: similarities to diabetes [published correction appears in Am J Pathol 2015;185:1795-6]
Am J Pathol
(2010)
G Jerums et al.
Lack of effect of gliclazide on early diabetic nephropathy and retinopathy: a two-year controlled study
Diabetes Res Clin Pract
(1987)
BP Walcott et al.
Novel treatment targets for cerebral edema
Neurotherapeutics
(2012)
J Zhou et al.
Steap4 plays a critical role in osteoclastogenesis in vitro by regulating cellular iron/reactive oxygen species (ROS) levels and cAMP response element-binding protein (CREB) activation
J. Biol. Chem
(2013)

MD Robinson et al.

edgeR: a Bioconductor package for differential expression analysis of digital gene expression data

Bioinformatics

(2010)

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The antidiabetic drug glibenclamide exerts direct retinal neuroprotection

Section snippets

INTRODUCTION

RESEARCH DESIGN AND METHODS

SUR1, expressed in human and nonhuman primate retina, is enriched in the macula and colocalizes with TRPM4 and with Kir6.2

DISCUSSION

ACKNOWLEDGMENTS

Public Health

Exp Eye Res

Surv Ophthalmol

Am J Pathol

Exp Neurol

Exp Neurol

Am J Pathol

Diabetes Res Clin Pract

Neurotherapeutics

J. Biol. Chem

Free Radic Biol Med

Prog Retin Eye Res

Epidemiological perspectives of diabetes

Cell Biochem Biophys

Diabetic retinopathy – ocular complications of diabetes mellitus

World J Diabetes

Neurodegeneration in the pathogenesis of diabetic retinopathy: molecular mechanisms and therapeutic implications

Curr Med Chem

Trends in incidence, prevalence and prescribing in type 2 diabetes mellitus between 2000 and 2013 in primary care: a retrospective cohort study

BMJ Open

Glibenclamide for the treatment of acute CNS injury

Pharmaceuticals (Basel)

Hemorrhagic transformation of ischemic stroke in diabetics on sulfonylureas

Ann Neurol

Sulfonylureas improve outcome in patients with type 2 diabetes and acute ischemic stroke

Stroke

Glibenclamide for the treatment of ischemic and hemorrhagic stroke

Int J Mol Sci

Sulfonylurea therapy benefits neurological and psychomotor functions in patients with neonatal diabetes owing to potassium channel mutations

Diabetes Care

Glial cells of the human fovea

Mol Vis

The role of PKCzeta in NMDA-induced retinal ganglion cell death: prevention by aspirin

Apoptosis

Spontaneous diabetes produced by selective breeding of normal Wistar rats

Proc. Jpn. Acad

PKCzeta mediates breakdown of outer blood-retinal barriers in diabetic retinopathy

PLoS One

Neonatal hyperglycemia inhibits angiogenesis and induces inflammation and neuronal degeneration in the retina

PLoS One

STAR: ultrafast universal RNA-seq aligner

Bioinformatics

RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome

BMC Bioinformatics

edgeR: a Bioconductor package for differential expression analysis of digital gene expression data

Bioinformatics