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

Thounaojam, Menaka C.; Powell, Folami Lamoke; Patel, S. J.; Gutsaeva, Diana; Tawfik, Amany; Smith, Sylvia B.; Nussbaum, Julian J.; Block, Norman L.; Martin, Pamela M.; Bartoli, Manuela

doi:10.1073/pnas.1718592114

Cited by 39 publications

(43 citation statements)

References 44 publications

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“…We finally evaluated the effects of MIA-690 ( www.nature.com/scientificreports www.nature.com/scientificreports/ Discussion GHRH and mRNAs for GHRH-R have been found in rat cortex and brain stem 22,23 , and various reports suggested that GHRH might play a key role in cognitive and mood disorders 20,[24][25][26][27][28] . GHRH-antagonists compounds can exert powerful antitumor effects, possibly related in part to their antinflammatory and antioxidant properties 17,[29][30][31][32][33] . In the present study we show that MIA-690, a GHRH antagonist, and MR-409, a GHRH analog, exhibit antinflammatory and antioxidant effects on prefrontal cortex specimens, ex vivo (Figs.…”

Section: Mr-409 Induced Down Regulation Of P Ghrh-r Gene and Protein mentioning

confidence: 99%

“…Accordingly, various studies showed that GHRH and GHRH antagonists can influence the inflammatory and reduction/oxidation (redox) status in cancer and other tissues 29,33 . www.nature.com/scientificreports www.nature.com/scientificreports/ In particular, MIA 690 decreased inflammation by reducing the infiltration of macrophages and leucocytes, the production of TNF-α, IL-1β, and monocyte chemotactic protein-1 (MCP-1) in tissue after insult with lipopolisaccaride (LPS) and the production of the pro-inflammatory markers in carrageenan-induced chronic prostatis 31,32 . In addition, MIA-690 showed antioxidant and neuroprotective properties 28 .…”

Section: Mr-409 Induced Down Regulation Of P Ghrh-r Gene and Protein mentioning

confidence: 99%

“…In addition, MIA-690 showed antioxidant and neuroprotective properties 28 . In a model of Alzheimer's disease as well as in cancer and other tissues, MR-409 has been described to exert antinflammatory and antioxidant effects, as well as in early experimental diabetic retinopathy 31 . In this context, the authors suggested that the protective effects of the MR-409 could be mediated by its direct and/or GH-mediated action.…”

Section: Mr-409 Induced Down Regulation Of P Ghrh-r Gene and Protein mentioning

confidence: 99%

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Antinflammatory, antioxidant, and behavioral effects induced by administration of growth hormone-releasing hormone analogs in mice

Recinella

Chiavaroli

Orlando

et al. 2020

Sci Rep

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Growth hormone-releasing hormone (GHRH) antagonist MIA-690 and GHRH agonist MR-409, previously synthesized and developed by us have demonstrated potent antitumor effects. However, little is known about the effects of these analogs on brain functions. We investigated the potential antinflammatory and antioxidant effects of GHRH antagonist MIA-690 and GHRH agonist MR-409, on isolated mouse prefrontal cortex specimens treated with lipopolysaccharide (LPS). Additionally, we studied their effects on emotional behavior after chronic in vivo treatment. Ex vivo, MIA-690 and MR-409 inhibited LPS-induced inflammatory and pro-oxidative markers. In vivo, both MIA-690 and MR-409 induced anxiolytic and antidepressant-like effects, increased norepinephrine and serotonin levels and decreased nuclear factor-kB, tumor necrosis factor-α and interleukin-6 gene expression in prefrontal cortex. Increased nuclear factor erythroid 2-related factor 2 expression was also found in mice treated with MIA-690 and MR-409. MIA-690 showed higher efficacy in inhibiting all tested inflammatory and oxidative markers. In addition, MR-409 induced a down regulation of the gene and protein expression of pituitary-type GHRH-receptor in prefrontal cortex of mice after 4 weeks of treatment at 5 µg/day. In conclusion, our results demonstrate anxiolytic and antidepressant-like effects of GHRH analogs that could involve modulatory effects on monoaminergic signaling, inflammatory and oxidative status. Growth hormone (GH)-releasing hormone (GHRH) is a neurosecretory peptide produced by hypothalamic neurons which stimulates synthesis and release of GH in the anterior pituitary gland 1,2. In addition to its recognized metabolic and endocrine effects, GHRH exerts also various effects on central and peripheral tissues such as brain, gastrointestinal tract, heart, kidney and retina 3-5. In the pituitary, as well as in peripheral tissues, GHRH binds to pituitary-type GHRH-receptor (P GHRH-R), a G protein-coupled receptor which stimulates the adenylyl cyclase, cAMP and protein kinase A (PKA) cascade 6 , and to its splice variant (SV1) 1,7-9. Various GHRH receptor agonist and antagonist peptides have been synthesized by us and other groups and studied for their biological activity 1,10-16. In particular, the novel GHRH antagonists of the Miami (MIA) series, MIA-690 and MIA-602, were found to inhibit growth of different human cancer lines and xenografted into nude mice in microgram doses after subcutaneous administration 15,17,18. The most potent antitumor analogs, MIA-690 and MIA-602 also showed antinflammatory activities 15. However the MIA-series of GHRH analogs with increased GHRH-R binding affinity have a weak GH inhibitory activity on pituitary somatotrophs 15. GHRH agonists of MR series, such as MR-409, exhibit higher potency upon subcutaneous administration and binding activity than the parent hormone 14,17. Recently, MR-409, a GHRH agonist, was found to inhibit in vivo growth of lung cancer xenografted into nude mice 14,16. The antinflammatory and antioxidant ...

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Section: Mr-409 Induced Down Regulation Of P Ghrh-r Gene and Protein mentioning

confidence: 99%

Section: Mr-409 Induced Down Regulation Of P Ghrh-r Gene and Protein mentioning

confidence: 99%

Section: Mr-409 Induced Down Regulation Of P Ghrh-r Gene and Protein mentioning

confidence: 99%

See 1 more Smart Citation

Antinflammatory, antioxidant, and behavioral effects induced by administration of growth hormone-releasing hormone analogs in mice

Recinella

Chiavaroli

Orlando

et al. 2020

Sci Rep

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“…On the other hand, GHRH antagonist treatment has been shown to result in a significant alteration of the outer retinal layer and worsened retinal morphology. 17 Therefore, preserving cell survival may prevent NPDR progression. In this study, we report that cell apoptosis was decreased after the knockdown of Egr1, which suggests that the down-regulation of Egr1 may be an effective method to sustain HRVECs viability.…”

Section: Discussionmentioning

confidence: 99%

Egr1 mediates retinal vascular dysfunction in diabetes mellitus via promoting p53 transcription

Liu

et al. 2019

J Cellular Molecular Medi

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Objectives This study focused on investigating the expression and underlying molecular mechanism of early growth response 1 ( Egr1 ) in diabetic retinopathy. Methods A microarray assay was applied to examine differentially expressed genes in the retina tissues of normal rats, as well as in those of streptozotocin‐induced diabetic rats. Human retinal vascular endothelial cells (HRVECs) transfected with sh‐NC, sh‐ Egr1 or sh‐ Egr1 + pVax1‐p53 were cultured under high‐glucose conditions and then used to explore the role of Egr1 in vitro. The effect of Egr1 on retinal vascular dysfunction caused by diabetes was examined by sh‐ Egr1 administration in vivo Results Early growth response 1 was found to be up‐regulated in the retinas of diabetic rats compared to those of normal rats. Down‐regulation of Egr1 in HRVECs under high‐glucose conditions inhibited the apoptosis, migration and tube formation in vitro. Moreover, sh‐ Egr1 partially reduced the injurious effects of hyperglycaemia on retinal vascular function by decreasing apoptotic cells and microvascular formation in vivo. The reduction of Egr1 evidently down‐regulated the p53 expression. Overexpression of p53 rescued the inhibition of sh‐ Egr1 in HRVECs under high‐glucose concentration on apoptosis, migration and tube formation in vitro. Conclusion Down‐regulation of Egr1 partially reduced the injurious effects of hyperglycaemia on retinal vascular function via inhibiting p53 expression.

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“…Fluorescent images were taken at constant interval for every mouse studied in each experimental group. In addition, we assessed vascular permeability quantitatively by measuring albumin extravasation to the retinal tissue as described before [37]. Briefly, the mice were deeply anesthetized with ketamine/xylazine (80/12 mg/kg of body weight, respectively).…”

Section: Assessment Of Retinal Vascular Permeabilitymentioning

confidence: 99%

Role of Endothelial ADAM17 in Early Vascular Changes Associated with Diabetic Retinopathy

Shalaby

Thounaojam

Tawfik

et al. 2020

JCM

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ADAM17, a disintegrin and metalloproteinase 17, is a transmembrane metalloproteinase that regulates bioavailability of multiple membrane-bound proteins via ectodomain shedding. ADAM17 activity was shown to contribute to a number of vascular pathologies, but its role in the context of diabetic retinopathy (DR) is not determined. We found that expression and enzymatic activity of ADAM17 are upregulated in human diabetic postmortem retinas and a mouse model of streptozotocin-induced diabetes. To further investigate the contribution of ADAM17 to vascular alterations associated with DR, we used human retinal endothelial cells (HREC) treated with ADAM17 neutralizing antibodies and exposed to glucidic stress and streptozotocin-induced endothelial ADAM17 knockout mice. Evaluation of vascular permeability, vascular inflammation, and oxidative stress was performed. Loss of ADAM17 in endothelial cells markedly reduced oxidative stress evidenced by decreased levels of superoxide, 3-nitrotyrosine, and 4-hydroxynonenal and decreased leukocyte-endothelium adhesive interactions in vivo and in vitro. Reduced leukostasis was associated with decreased vascular permeability and was accompanied by downregulation of intercellular adhesion molecule-1 expression. Reduction in oxidative stress in HREC was associated with downregulation of NAD(P)H oxidase 4 (Nox4) expression. Our data suggest a role for endothelial ADAM17 in DR pathogenesis and identify ADAM17 as a potential new therapeutic target for DR.

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

Cited by 39 publications

References 44 publications

Antinflammatory, antioxidant, and behavioral effects induced by administration of growth hormone-releasing hormone analogs in mice

Antinflammatory, antioxidant, and behavioral effects induced by administration of growth hormone-releasing hormone analogs in mice

Egr1 mediates retinal vascular dysfunction in diabetes mellitus via promoting p53 transcription

Role of Endothelial ADAM17 in Early Vascular Changes Associated with Diabetic Retinopathy

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