Synthetic Growth Hormone-Releasing Peptides (GHRPs): A Historical Appraisal of the Evidences Supporting Their Cytoprotective Effects

Background: Growth hormone-releasing peptides (GHRPs) constitute a group of small synthetic peptides that stimulate the growth hormone secretion and the downstream axis activity. Mounting evidences since the early 1980s delineated unexpected pharmacological cardioprotective and cytoprotective properties for the GHRPs. However, despite intense basic pharmacological research, alternatives to prevent cell and tissue demise before lethal insults have remained as an empty niche in the clinical armamentarium. Here, we have rigorously reviewed the investigational development of GHRPs and their clinical niching perspectives. Methodology: PubMed/MEDLINE databases, including original research and review articles, were explored. The search design was date escalated from 1980 and included articles in English only. Results and Conclusions: GHRPs bind to two different receptors (GHS-R1a and CD36), which redundantly or independently exert relevant biological effects. GHRPs’ binding to CD36 activates prosurvival pathways such as PI-3K/AKT1, thus reducing cellular death. Furthermore, GHRPs decrease reactive oxygen species (ROS) spillover, enhance the antioxidant defenses, and reduce inflammation. These cytoprotective abilities have been revealed in cardiac, neuronal, gastrointestinal, and hepatic cells, representing a comprehensive spectrum of protection of parenchymal organs. Antifibrotic effects have been attributed to some of the GHRPs by counteracting fibrogenic cytokines. In addition, GHRP family members have shown a potent myotropic effect by promoting anabolia and inhibiting catabolia. Finally, GHRPs exhibit a broad safety profile in preclinical and clinical settings. Despite these fragmented lines incite to envision multiple pharmacological uses for GHRPs, especially as a myocardial reperfusion damage-attenuating candidate, this family of “drugable” peptides awaits for a definitive clinical niche.

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Effects of Growth Hormone Releasing Peptides on Stimulated Growth Hormone Secretion in Old Rats

Growth Hormone II ◽

10.1007/978-1-4613-8372-7_13 ◽

1994 ◽

pp. 167-192 ◽

Cited By ~ 4

Author(s):

Richard F. Walker ◽

Sei-Won Yang ◽

Ryuji Masuda ◽

Cheng-Shih Hu ◽

Barry B. Bercu

Keyword(s):

Growth Hormone ◽

Hormone Secretion ◽

Growth Hormone Secretion ◽

Old Rats ◽

Growth Hormone Releasing Peptides

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Desensitization from long-term intranasal treatment with hexarelin does not interfere with the biological effects of this growth hormone-releasing peptide in short children

Acta Endocrinologica ◽

10.1530/eje.0.1340716 ◽

1996 ◽

Vol 134 (6) ◽

pp. 716-719 ◽

Cited By ~ 27

Author(s):

Beatrice Klinger ◽

Aviva Silbergeld ◽

Romano Deghenghi ◽

Jenny Frenkel ◽

Zvi Laron

Keyword(s):

Growth Hormone ◽

Growth Velocity ◽

Biological Effects ◽

Hormone Secretion ◽

Growth Hormone Secretion ◽

Human Growth ◽

Pediatric Endocrinology ◽

Short Children ◽

The Mean

Klinger B, Silbergeld A, Deghenghi R, Frenkel J, Laron Z. Desensitization from long-term intranasal treatment with hexarelin does not interfere with the biological effects of this growth hormonereleasing peptide in short children. Eur J Endocrinol 1996;134:716–9. ISSN 0804–4643 A clinical, prospective experiment was carried out to determine whether long-term intranasal administration of the growth hormone-releasing peptide hexarelin (His-d-2-methyl-Trp-Ala-Trp-d-Phe-Lys-NH2) affects pituitary growth hormone secretion. Hexarelin (60 μg/kg t.i.d.) was administered to seven prepubertal constitutionally short children (mean age ±sd = 7.6 ± 2.4 years). Serum human growth hormone (hGH) response to an intranasal (20 μg/kg) and intravenous (1 μg/kg) bolus of hexarelin before, during and after 6–10 months of treatment was measured. The mean (±sd) peak rise of hGH to the intranasal bolus before treatment was 70.6 ± mU/I. After 7 days of hexarelin treatment, mean peak values dropped to 34.1 ±15.7 mU/l (p < 0.002) and thereafter remained constant for 6 months of treatment at 37.5 10.3 ±mU/l (p < 0.03). The pretreatment peak to the iv hexarelin bolus was 84.8 52.5 ±mU/l, and at the end of the treatment period it was 19.8 10.9 ±mU/l (p < 0.05). Three months after stopping treatment the mean (±sd) hGH response rose to 42.1 ±4.7 mU/l (p < 0.005). Growth velocity increased from 5.3±0.9 cm/year (before treatment) to 7.4 1.6 cm/year at ±6–10 months of treatment (p < 0.005). In conclusion, the partial suppression of pituitary hGH responsiveness to long-term intranasal hexarelin treatment, probably due to desensitization, does not affect the observed increase in growth velocity. Z Laron, Pediatric Endocrinology, 11 El Al Street, Ramat Efal, 52960, Israel

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Recent Advances in Potential Clinical Application of Ghrelin in Obesity

Journal of Obesity ◽

10.1155/2012/535624 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 13

Author(s):

Christine Delporte

Keyword(s):

Growth Hormone ◽

Food Intake ◽

Biological Effects ◽

Hormone Secretion ◽

Growth Hormone Secretion ◽

Taste Receptor ◽

Molecular Targets ◽

Growth Hormone Secretagogue Receptor ◽

Growth Hormone Secretagogue ◽

Amino Acid Peptide

Ghrelin is the natural ligand of the growth hormone secretagogue receptor (GHS-R1a). Ghrelin is a 28 amino acid peptide possessing a unique acylation on the serine in position 3 catalyzed by ghrelinO-acyltransferase (GOAT). Ghrelin stimulates growth hormone secretion, but also appetite, food intake, weight gain, and gastric emptying. Ghrelin is involved in weight regulation, obesity, type 2 diabetes, and metabolic syndrome. Furthermore, a better understanding of ghrelin biology led to the identification of molecular targets modulating ghrelin levels and/or its biological effects: GOAT, ghrelin, and GHS-R1a. Furthermore, a recent discovery, showing the involvement of bitter taste receptor T2R in ghrelin secretion and/or synthesis and food intake, suggested that T2R could represent an additional interesting molecular target. Several classes of ghrelin-related pharmacological tools for the treatment of obesity have been or could be developed to modulate the identified molecular targets.

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Structure and Physiological Actions of Ghrelin

Scientifica ◽

10.1155/2013/518909 ◽

2013 ◽

Vol 2013 ◽

pp. 1-25 ◽

Cited By ~ 67

Author(s):

Christine Delporte

Keyword(s):

Growth Hormone ◽

Biological Effects ◽

Hormone Secretion ◽

Growth Hormone Secretion ◽

Peptide Hormone ◽

The Body ◽

Growth Hormone Secretagogue Receptor ◽

Growth Hormone Secretagogue ◽

Amino Acid Peptide ◽

Receptor Biology

Ghrelin is a gastric peptide hormone, discovered as being the endogenous ligand of growth hormone secretagogue receptor. Ghrelin is a 28 amino acid peptide presenting a uniquen-octanoylation modification on its serine in position 3, catalyzed by ghrelinO-acyl transferase. Ghrelin is mainly produced by a subset of stomach cells and also by the hypothalamus, the pituitary, and other tissues. Transcriptional, translational, and posttranslational processes generate ghrelin and ghrelin-related peptides. Homo- and heterodimers of growth hormone secretagogue receptor, and as yet unidentified receptors, are assumed to mediate the biological effects of acyl ghrelin and desacyl ghrelin, respectively. Ghrelin exerts wide physiological actions throughout the body, including growth hormone secretion, appetite and food intake, gastric secretion and gastrointestinal motility, glucose homeostasis, cardiovascular functions, anti-inflammatory functions, reproductive functions, and bone formation. This review focuses on presenting the current understanding of ghrelin and growth hormone secretagogue receptor biology, as well as the main physiological effects of ghrelin.

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Persistent diastolic dysfunction despite successful long-term octreotide treatment in acromegaly

Acta Endocrinologica ◽

10.1530/eje.1.01955 ◽

2005 ◽

Vol 153 (2) ◽

pp. 231-238 ◽

Cited By ~ 16

Author(s):

S W van Thiel ◽

J J Bax ◽

N R Biermasz ◽

E R Holman ◽

D Poldermans ◽

...

Keyword(s):

Growth Hormone ◽

Diastolic Function ◽

Biological Effects ◽

Hormone Secretion ◽

Growth Hormone Secretion ◽

Left Ventricular ◽

Doppler Imaging ◽

Diastolic Velocity ◽

Active Acromegaly

Introduction: This study was designed to evaluate potential reversibility of left-ventricular (LV) dysfunction in patients with acromegaly following long-term control of disease. It is unknown whether the cardiac changes induced by acromegaly can be reversed completely by long-term strict control of growth hormone excess by octreotide. Patients and methods: We compared LV systolic and diastolic function in inactive patients with acromegaly (n = 22), who were divided into patients with long-term control by octreotide (n = 14) and patients with long-term cure by surgery/radiotherapy (n = 8). We also assessed these parameters in patients with active acromegaly (n = 17). Results: In patients with active acromegaly, systolic function at rest was decreased by 18% (P < 0.01), LV mass index increased by 40% (P < 0.04) and isovolumetric relaxation time increased by 19% (P < 0.01), compared with patients with inactive acromegaly. These parameters were not different between well-controlled and cured patients. Using tissue Doppler imaging, the ratio between early and late diastolic velocity (E′/A′ ratio) was decreased in active, compared with inactive acromegaly (0.75±0.07 versus 1.24±0.15; P < 0.01). This E′/A′ ratio was considerably higher in cured, compared with octreotide-treated, patients (1.75±0.41 versus 1.05±0.1; P < 0.01). Conclusion: Diastolic function is persistently and significantly more impaired in acromegalic patients with long-term control by octreotide than in surgically cured patients, which points to biological effects of subtle abnormalities in growth hormone secretion. Criteria for strict biochemical control of acromegaly should thus be reconsidered.

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