Endothelin Receptor-A Antagonist Attenuates Retinal Vascular and Neuroretinal Pathology in Diabetic Mice

Chou, Jonathan; Rollins, Stuart D.; Ye, Minghao; Batlle, Daniel; Fawzi, Amani A.

doi:10.1167/iovs.13-13676

Cited by 39 publications

(38 citation statements)

References 47 publications

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“…Therefore, the neurodegeneration detected in homozygous db/db animals is related to hyperglycemia and cannot be attributed to a genetic nature. In addition, it should be emphasized that a similar high rate of TUNEL-positive cells have been reported previously, not only by our group (11,32) but also by other authors (33,34). We believe that this is not an impediment but is, on the contrary, a good model for testing the effectiveness of neuroprotective drugs such as GLP-1 agonists.…”

Section: Discussionsupporting

confidence: 90%

Topical Administration of GLP-1 Receptor Agonists Prevents Retinal Neurodegeneration in Experimental Diabetes

et al. 2015

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Retinal neurodegeneration is an early event in the pathogenesis of diabetic retinopathy (DR). Since glucagonlike peptide 1 (GLP-1) exerts neuroprotective effects in the central nervous system and the retina is ontogenically a brain-derived tissue, the aims of the current study were as follows: 1) to examine the expression and content of GLP-1 receptor (GLP-1R) in human and db/db mice retinas; 2) to determine the retinal neuroprotective effects of systemic and topical administration (eye drops) of GLP-1R agonists in db/db mice; and 3) to examine the underlying neuroprotective mechanisms. We have found abundant expression of GLP-1R in the human retina and retinas from db/db mice. Moreover, we have demonstrated that systemic administration of a GLP-1R agonist (liraglutide) prevents retinal neurodegeneration (glial activation, neural apoptosis, and electroretinographical abnormalities). This effect can be attributed to a significant reduction of extracellular glutamate and an increase of prosurvival signaling pathways. We have found a similar neuroprotective effect using topical administration of native GLP-1 and several GLP-1R agonists (liraglutide, lixisenatide, and exenatide). Notably, this neuroprotective action was observed without any reduction in blood glucose levels. These results suggest that GLP-1R activation itself prevents retinal neurodegeneration. Our results should open up a new approach in the treatment of the early stages of DR.

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Section: Discussionsupporting

confidence: 90%

Topical Administration of GLP-1 Receptor Agonists Prevents Retinal Neurodegeneration in Experimental Diabetes

et al. 2015

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“…44 Finally, it has been recently demonstrated that the blockade of ETA-R apart from ameliorating retinal vascular pathology by reducing pericyte loss and a cellular capillaries prevents retinal thinning in both the optic nerve and retinal periphery in db/db mice. 24 Therefore, ET-1 seems to be a key player involved in the cross-talk between neurodegeneration and vascular abnormalities in the setting of DR. The capacity of CaD to inhibit not only ET-1, but also ETA-R and ETB-R overexpression induced by diabetes, would seem to be a potent mechanism accounting for its effectiveness in preventing both neurodegeneration and early microvascular impairment.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the inhibition of ET-1 could lead not only to an improvement in microvascular hemodynamics in the retina, but also an amelioration of the retinal neurodegeneration associated with diabetes. In this regard, it should be noted that ET-1 has recently been shown to be involved in diabetesinduced neuroretinal degeneration, and, therefore, its inhibition would seem a promising therapeutic target in DR. 24 On this basis, the main aims of the present study were to examine whether CaD exerts beneficial effects on neurodegeneration and early microvascular abnormalities in an experimental model of DR. In addition, the putative mediators of both neurodegeneration (glutamate/GLAST, ET-1/ETB receptor) and early microvascular impairment (ET-1/ETA receptor, VEGF, and the PKC-delta-p38 MAPK pathway) have also been investigated.…”

Section: Introductionmentioning

confidence: 99%

Calcium Dobesilate Prevents Neurodegeneration and Vascular Leakage in Experimental Diabetes

Solà-Adell

Bogdanov

Hernández

et al. 2017

Current Eye Research

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Purpose: The mechanisms involved in the reported beneficial effects of Calcium dobesilate monohydrate (CaD) for the treatment of diabetic retinopathy (DR) remain to be elucidated. The main aim of the present study is to examine whether CaD prevents early events in the pathogenesis of DR such as neurodegeneration and vascular leakage. In addition, putative mediators of both neurodegeneration (glutamate/GLAST, ET-1/ETB receptor) and early microvascular impairment (ET-1/ETA receptor, oxidative stress, VEGF, and the PKC-delta-p38 MAPK pathway) have been examined. Methods: Diabetic (db/db) mice were randomly assigned to daily oral treatment with CaD (200 mg/Kg/ day) (n = 12) or vehicle (n = 12) for 14 days. In addition, 12 non-diabetic (db/+) mice matched by age were used as the control group. Functional abnormalities were assessed by electroretinography. Neurodegeneration and microvascular abnormalities were evaluated by immunohistochemistry and Western blot. Glutamate was determined by HPLC. Results: CaD significantly decreased glial activation and apoptosis and produced a significant improvement in the electroretinogram parameters. Mechanistically, CaD prevented the diabetes-induced upregulation of ET-1 and its cognate receptors (ETA-R and ETB-R), which are involved in microvascular impairment and neurodegeneration, respectively. In addition, treatment with CaD downregulated GLAST, the main glutamate transporter, and accordingly prevented the increase in glutamate. Finally, CaD prevented oxidative stress, and the upregulation of VEGF and PKC delta-p38 MAPK pathway induced by diabetes, thus resulting in a significant reduction in vascular leakage.Conclusions: Our findings demonstrate for the first time that CaD exerts neuroprotection in an experimental model of DR. In addition, we provide first evidence that CaD prevents the overexpression of ET-1 and its receptors in the diabetic retina. These beneficial effects on the neurovascular unit could pave the way for clinical trials addressed to confirm the effectiveness of CaD in very early stages of DR. ARTICLE HISTORY

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“…There are promising results of studies into somatostatins and brimonidine applied locally, which increased survival and limited apoptosis of photoreceptor cells in the retina [96]. Endothelin receptor antagonists decrease apoptosis of pericytes and reduce angiogenesis [97]. It has been confirmed that lixisenatide, a GLP-1 agonist, has a protective effect on the neurovascular unit in diabetic retinopathy [98].…”

Section: Treatment Of Diabetic Retinopathymentioning

confidence: 99%

Diagnosis and treatment of diabetic retinopathy — historical overview

Matuszewski

Bandurska-Stankiewicz

Modzelewski

et al. 2017

Clinical Diabetology

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Endothelin Receptor-A Antagonist Attenuates Retinal Vascular and Neuroretinal Pathology in Diabetic Mice

Abstract: Endothelin-A receptor blockade using atrasentan significantly reduces the vascular and neuroretinal complications in diabetic mice. Endothelin-A receptor blockade is a promising therapeutic target in diabetic retinopathy.

Cited by 39 publications

References 47 publications

Topical Administration of GLP-1 Receptor Agonists Prevents Retinal Neurodegeneration in Experimental Diabetes

Topical Administration of GLP-1 Receptor Agonists Prevents Retinal Neurodegeneration in Experimental Diabetes

Calcium Dobesilate Prevents Neurodegeneration and Vascular Leakage in Experimental Diabetes

Diagnosis and treatment of diabetic retinopathy — historical overview

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