1. GHRH and GHRH receptor levels are decreased in diabetic rats and humans.
2. Administration of GHRH agonists to diabetic rats reversed signs of diabetic retinopathy.
Evidence Rating Level: 2 (Good)
Study Rundown: Diabetic retinopathy is the main cause of blindness in the Western world. However, effective treatment for this condition remains limited, in part due to a lack of understanding as to how this condition develops. The growth hormone axis has been implied in retinal ganglion cell development and activity. Researchers at the Medical College of Georgia examined levels of growth hormone and growth hormone receptor in the retinas of diabetic rats and patients, and discovered that the growth hormone axis was downregulated relative to wild-type controls. Based on these findings, the authors hypothesized that treating these mice with growth hormone agonists might restore retinal integrity and function.
When diabetic and non-diabetic mice were treated with GHRH agonists, multiple structural and functional changes suggested reversal of pathologic features typically associated with diabetic retinopathy. For instance, retinal thickness decreased following treatment with the agonist. Furthermore, retinal cell death decreased following treatment, likely due to decreased production of reactive oxygen species. Gliosis and inflammation were also reduced in the presence of the GHRH agonist. Finally, the agonist appeared to have vasculoprotective effects as well, increasing the integrity of retinal blood vessels. Furthermore, GHRH antagonists resulted in worsening of retinal morphology.
These animal studies suggest GHRH agonists may protect against the development of diabetic retinopathy. Although the toxicity of this drug and optimal dose for administration still need to be determined, these studies highlight a new potential therapeutic for diabetic patients.
Relevant Reading: Diabetic retinopathy: research to clinical practice
In-Depth [animal study]: Retinas from streptozotocin-induced diabetic (STZ) rats and post-mortem human diabetic donors were obtained and qPCR performed to evaluate mRNA expression of GHRH and western blot performed to evaluate expression of its receptor (GHRH-R). A significant decrease in both GHRH and GHRH-R was noted in both diabetic mice and humans compared to normoglycemic controls (p< 0.01). STZ-rats were then treated with 15 ug/kg MR-409, a GHRH agonist, for 6 weeks and the retinas obtained for analysis. H&E staining of retinas from control rats along with treated and untreated STZ-rats revealed that whereas diabetes decreased the thickness of the retina, treatment with MR-409 normalized its structure. Because the decreased thickness of the retina in diabetes is typically due to increased retinal cell death, TUNEL staining was used to identify dying cells, revealing an increase in TUNEL-positive nuclei in STZ-rats and a reduction following treatment.
To assess retinal cell injury due to oxidation typically seen in diabetes, the reactive oxygen species 3-nitrotyrosine and 4-hydroxynonenal were evaluated using immunohistochemistry. These studies revealed a protective effect of MR-409 through the reduction of reactive oxygen species expression. Gliosis and inflammation in the retina were then evaluated due to these typical findings in retinas of diabetic patients and rats. To evaluate the induction of gliosis, immunohistochemistry was used to assess ICAM-1 and GFAP expression, molecules found to be upregulated with hyperglycemia. Treatment with MR-409, however, decreased these markers of gliosis. Additionally, using ELISA to evaluate cytokine production, a decrease of pro-inflammatory cytokines was noted following treatment along with an increase in anti-inflammatory cytokines (p< 0.05).
Finally, fundoscopy was performed on the rats to visualize the vascular integrity of the retinal blood vessels. Whereas the untreated STZ-rats demonstrated elevated dye extravasation due to hyperglycemia, this was significantly decreased following treatment (p<0.01) suggestive of improved vascular integrity.
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