Protective effects of agonists of growth hormone-releasing hormone (GHRH) in early experimental diabetic retinopathy

Menaka C. Thounaojam, Folami L. Powell, Sagar Patel, Diana R. Gutsaeva, Amany Tawfik, Sylvia B. Smith, Julian Nussbaum, Norman L Block, Pamela M. Martin, Andrew V Schally, Manuela Bartoli

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)13248-13253
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number50
DOIs
StatePublished - Dec 12 2017

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Growth Hormone-Releasing Hormone
Diabetic Retinopathy
Retina
Streptozocin
Hormone Antagonists
Hyperglycemia
Anti-Inflammatory Agents
Antioxidants
Retinal Ganglion Cells
Gene Expression Regulation
Capillary Permeability
Therapeutic Uses
Vascular Endothelial Growth Factor A
Up-Regulation
Down-Regulation
Western Blotting
Cytokines
N-Me-Tyr1,D-Ala2,Asn8,Arg29-NHCH3-JI-38
Wounds and Injuries

Keywords

  • Diabetic retinopathy
  • GH
  • GHRH
  • GHRH-R
  • Type 1 diabetes

ASJC Scopus subject areas

  • General

Cite this

Protective effects of agonists of growth hormone-releasing hormone (GHRH) in early experimental diabetic retinopathy. / Thounaojam, Menaka C.; Powell, Folami L.; Patel, Sagar; Gutsaeva, Diana R.; Tawfik, Amany; Smith, Sylvia B.; Nussbaum, Julian; Block, Norman L; Martin, Pamela M.; Schally, Andrew V; Bartoli, Manuela.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 50, 12.12.2017, p. 13248-13253.

Research output: Contribution to journalArticle

Thounaojam, MC, Powell, FL, Patel, S, Gutsaeva, DR, Tawfik, A, Smith, SB, Nussbaum, J, Block, NL, Martin, PM, Schally, AV & Bartoli, M 2017, 'Protective effects of agonists of growth hormone-releasing hormone (GHRH) in early experimental diabetic retinopathy', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 50, pp. 13248-13253. https://doi.org/10.1073/pnas.1718592114
Thounaojam, Menaka C. ; Powell, Folami L. ; Patel, Sagar ; Gutsaeva, Diana R. ; Tawfik, Amany ; Smith, Sylvia B. ; Nussbaum, Julian ; Block, Norman L ; Martin, Pamela M. ; Schally, Andrew V ; Bartoli, Manuela. / Protective effects of agonists of growth hormone-releasing hormone (GHRH) in early experimental diabetic retinopathy. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 50. pp. 13248-13253.
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AU - Tawfik, Amany

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