Growth hormone‐releasing hormone antagonists reduce prostatic enlargement and inflammation in carrageenan‐induced chronic prostatitis

Popovics, Petra; Cai, Renzhi; Sha, Wei; Rick, Ferenc G.; Schally, Andrew V.

doi:10.1002/pros.23655

Cited by 32 publications

(29 citation statements)

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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%

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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%

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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“…In other studies, GHRH stimulated multiple pathways involved in inflammation and growth in both BPH-1 and PrEp cells including NFκB p65, AKT, ERK1/2, EGFR, and STAT3. 24 The current study investigated the effects of GHRH antagonist MIA 602, GHRH and GHRH agonist MR 409 in the regulation of inflammatory processes; which strongly affect the endothelial permeability of BPAECs. We decided to focus on the effects of those compounds toward the expression of P53, since P53 has been recently shown to be a major regulator of the endothelium permeability.…”

Section: Discussionmentioning

confidence: 99%

GHRH antagonists support lung endothelial barrier function

et al. 2019

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Growth Hormone-Releasing Hormone (GHRH) regulates the release of growth hormone from the anterior pituitary gland. GHRH also acts as a growth and inflammatory factor in a variety of experimental models in oncology. In the current study, we used bovine pulmonary arterial cells in order to investigate the effects of GHRH and its antagonistic and agonistic analogs in key intracellular pathways that regulate endothelial permeability. GHRH antagonists suppressed the activation of MLC2, ERK1/2, JAK2/STAT3 pathway and increased the intracellular P53 and pAMPK levels. In contrast, both GHRH and GHRH agonist MR409 exerted the opposite effects. Furthermore, GHRH antagonists supported the integrity of endothelial barrier, while GHRH and GHRH agonists had the contrary effects, as reflected in measurements of transendothelial resistance. Our observations support the evidence for the antiinflammatory role of GHRH antagonists in the vasculature. Moreover, our results suggest that GHRH antagonists should be considered as promising therapeutic agents for treating severe respiratory abnormalities, such as the lethal Acute Respiratory Distress Syndrome (ARDS).

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“…We previously showed that carrageenan induces chronic prostatic inflammation in rats and increases mRNA expression of Spp1, which encodes osteopontin (OPN) 16 . OPN is a secreted phosphoglycoprotein and an extracellular matrix constituent 17 .…”

Section: Introductionmentioning

confidence: 99%

Prostatic osteopontin expression is associated with symptomatic benign prostatic hyperplasia

Popovics

Awadallah

Kohrt

et al. 2019

Preprint

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AbstractBackgroundMale lower urinary tract symptoms (LUTS) occur in more than half of men above 50 years of age. LUTS were traditionally attributed to benign prostatic hyperplasia (BPH) and therefore the clinical terminology often use LUTS and BPH interchangeably. More recently, LUTS were also linked to fibrogenic and inflammatory processes. We tested whether osteopontin (OPN), a pro-inflammatory and pro-fibrotic molecule, is increased in symptomatic BPH. We also tested whether prostate epithelial and stromal cells secrete OPN in response to pro-inflammatory stimuli and identified downstream targets of OPN in prostate stromal cells.MethodsImmunohistochemistry was performed on prostate sections obtained from the transition zone (TZ) of patients who underwent surgery (Holmium laser enucleation of the prostate) to relieve LUTS i.e. surgical BPH (S-BPH) or patients who underwent radical prostatectomy to remove low-grade prostate cancer (incidental BPH, I-BPH). Images of stained tissue sections were captured with a Nuance Multispectral Imaging system and histoscore, as a measure of OPN staining intensity, was determined with inForm software. OPN protein abundance was determined by Western blot. The ability of prostate cells to secrete osteopontin in response to IL-1β and TGF-β1 was determined in stromal (BHPrS-1) and epithelial (NHPrE-1 and BHPrE-1) cells by ELISA. qPCR was used to measure gene expression changes in these cells in response to OPN.ResultsOPN immunostaining (p=0.0107) and protein levels were more abundant in S-BPH than I-BPH. Staining was distributed across all cell types with highest levels in epithelial cells. Multiple OPN protein variants were identified in immortalized prostate stromal and epithelial cells. TGF-β1 stimulated OPN secretion by NHPrE-1 cells and both IL-1β and TGF-β1 stimulated OPN secretion by BHPrS-1 cells. Interestingly, recombinant OPN increased the mRNA expression of CXCL1, CXCL2, CXCL8, PTGS2 and IL6 in BHPrS-1, but not in epithelial cell lines.ConclusionsOPN is more abundant in prostates of men with S-BPH compared to men with I-BPH. OPN secretion is stimulated by pro-inflammatory cytokines, and OPN acts directly on stromal cells to drive the synthesis of pro-inflammatory mRNAs. Pharmacological manipulation of prostatic OPN may have the potential to reduce LUTS by inhibiting both inflammatory and fibrotic pathways.

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Growth hormone‐releasing hormone antagonists reduce prostatic enlargement and inflammation in carrageenan‐induced chronic prostatitis

Abstract: The study demonstrates that GHRH antagonists could be beneficial for the treatment of prostatic inflammation and BPH in part by inhibiting the growth-promoting and inflammatory effects of locally produced GHRH.

Cited by 32 publications

References 54 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

GHRH antagonists support lung endothelial barrier function

Prostatic osteopontin expression is associated with symptomatic benign prostatic hyperplasia

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