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 America2017PMID: 29180438

View on PubMed DOI: 10.1073/pnas.1718592114

Plain Language Summary

Researchers investigated whether GHRH-related compounds could protect against diabetic retinopathy, a common complication of diabetes that damages the eyes. The GHRH agonist MR-409 preserved retinal structure in diabetic rats by reducing inflammation and oxidative stress, while also balancing factors that control blood vessel growth and leakage. In contrast, the GHRH blocker MIA-602 actually worsened retinal damage, indicating that activating (rather than blocking) the GHRH pathway may be protective for diabetic eye disease.

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.

Authors

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

Keywords

GHGHRHGHRH-Rdiabetic retinopathytype 1 diabetes