@article{4d8b728d9c354617bbba84b4c7c61415,
title = "Protective effects of agonists of growth hormone-releasing hormone (GHRH) in early experimental diabetic retinopathy",
abstract = "The potential therapeutic effects of agonistic analogs of growth hormone-releasing hormone (GHRH) and their mechanism of action were investigated in diabetic retinopathy (DR). Streptozotocin-induced diabetic rats (STZ-rats) were treated with 15 μg/kg GHRH agonist, MR-409, or GHRH antagonist, MIA-602. At the end of treatment, morphological and biochemical analyses assessed the effects of these compounds on retinal neurovascular injury induced by hyperglycemia. The expression levels of GHRH and its receptor (GHRH-R) measured by qPCR and Western blotting were significantly down-regulated in retinas of STZ-rats and in human diabetic retinas (postmortem) compared with their respective controls. Treatment of STZ-rats with the GHRH agonist, MR-409, prevented retinal morphological alteration induced by hyperglycemia, particularly preserving survival of retinal ganglion cells. The reverse, using the GHRH antagonist, MIA-602, resulted in worsening of retinal morphology and a significant alteration of the outer retinal layer. Explaining these results, we have found that MR-409 exerted antioxidant and anti-inflammatory effects in retinas of the treated rats, as shown by up-regulation of NRF-2-dependent gene expression and down-regulation of proinflammatory cytokines and adhesion molecules. MR-409 also significantly down-regulated the expression of vascular endothelial growth factor while increasing that of pigment epithelium-derived factor in diabetic retinas. These effects correlated with decreased vascular permeability. In summary, our findings suggest a neurovascular protective effect of GHRH analogs during the early stage of diabetic retinopathy through their antioxidant and anti-inflammatory properties.",
keywords = "Diabetic retinopathy, GH, GHRH, GHRH-R, Type 1 diabetes",
author = "Thounaojam, {Menaka C.} and Powell, {Folami L.} and Sagar Patel and Gutsaeva, {Diana R.} and Amany Tawfik and Smith, {Sylvia B.} and Julian Nussbaum and Block, {Norman L.} and Martin, {Pamela M.} and Schally, {Andrew V.} and Manuela Bartoli",
note = "Funding Information: ACKNOWLEDGMENTS. We thank Dr. Sean Shaw and Dr. Jianghe Yuan for their excellent technical assistance. The work on GHRH agonists and antagonists in the laboratory of A.V.S. was supported by the Medical Research Service of the Department of Veterans Affairs and the University of Miami School of Medicine. We acknowledge the financial support of the National Eye Institute [EY022416 (to M.B.) and EY022704 (to P.M.M.)] and of the Jon Simowitz philanthropic gift, a gift to the Department of Ophthalmology and the Culver-Vision Discovery Institute at Augusta University. Funding Information: 21. Martinez-Moreno CG, Trudeau VL, Harvey S (2015) Co-storage and secretion of growth hormone and secretoneurin in retinal ganglion cells. Gen Comp Endocrinol 220:124–132. Materials and Methods Human Samples. Deidentified, postmortem human retina samples were obtained from the Georgia Eye Bank through their approved research program and used in the present study per protocol approved by the institutional biosafety committee at Augusta University. All tissue samples were dei-dentified prior to receipt; therefore, IRB approval was not required. Animals and Treatments. All the animal procedures were performed in compliance with the Association for Research in Vision and Ophthalmology Statement for the humane use of laboratory animals. All experiments involving animals adhered to the Public Health Service Policy on Humane Care and Use of Laboratory Animals (revised July 2017) and were approved by the Augusta University institutional animal care and use committee. Adult male Sprague-Dawley rats (250–300 g) obtained from Evigo Laboratories were made diabetic by a single intravenous injection of STZ (Sigma-Aldrich). 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We acknowledge the financial support of the National Eye Institute [EY022416 (to M.B.) and EY022704 (to P.M.M.)] and of the Jon Simowitz philanthropic gift, a gift to the Department of Ophthalmology and the Culver-Vision Discovery Institute at Augusta University.",
year = "2017",
month = dec,
day = "12",
doi = "10.1073/pnas.1718592114",
language = "English (US)",
volume = "114",
pages = "13248--13253",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "50",
}
