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

View Article: PubMed Central - PubMed

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus

GHRP mechanism of action. GHRPs are endowed with the ability to bind two different receptors that seem to mediate its cytoprotective and other pharmacological properties (GHS-R1a and CD36). The main biological properties/pharmacological actions of GHRP-6 as cyto- and cardioprotective candidates are summarized as follows: Inotropic: mediated by an elevation of Ca2+ influx via PLC/DAG/PKC, through the voltage-gated calcium channel, triggering Ca2+ release from thapsigargin-sensitive intracellular stores, which translated in a positive inotropic response without a chronotropic effect. Anti-fibrotic: via upregulation of PPARγ, which is followed by a transforming growth factor-beta (TGF-β), CTGF, and platelet-derived growth factor (PDGF) downregulation. Anti-inflammatory: blunts NFκB expression and activation. Cell survival: it involves the phosphatidylinositol 3-kinase/RAC-alpha serine/threonine-protein kinase (PI-3K/AKT1) pathway, as the induction of the hypoxia-inducible factor-1 alpha (HIF-1α). Cardioprotective: as shown, it involves different biological actions that converge to enhance cardiomyocytes survival. Vasodilatory: it seems to involve e-NOS upregulation and endothelin activity reduction. Anabolic: it is mediated by the IGF-1/AKT1 and mTOR pathway activity.
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f4-10.1177_1179546817694558: GHRP mechanism of action. GHRPs are endowed with the ability to bind two different receptors that seem to mediate its cytoprotective and other pharmacological properties (GHS-R1a and CD36). The main biological properties/pharmacological actions of GHRP-6 as cyto- and cardioprotective candidates are summarized as follows: Inotropic: mediated by an elevation of Ca2+ influx via PLC/DAG/PKC, through the voltage-gated calcium channel, triggering Ca2+ release from thapsigargin-sensitive intracellular stores, which translated in a positive inotropic response without a chronotropic effect. Anti-fibrotic: via upregulation of PPARγ, which is followed by a transforming growth factor-beta (TGF-β), CTGF, and platelet-derived growth factor (PDGF) downregulation. Anti-inflammatory: blunts NFκB expression and activation. Cell survival: it involves the phosphatidylinositol 3-kinase/RAC-alpha serine/threonine-protein kinase (PI-3K/AKT1) pathway, as the induction of the hypoxia-inducible factor-1 alpha (HIF-1α). Cardioprotective: as shown, it involves different biological actions that converge to enhance cardiomyocytes survival. Vasodilatory: it seems to involve e-NOS upregulation and endothelin activity reduction. Anabolic: it is mediated by the IGF-1/AKT1 and mTOR pathway activity.

Mentions: As judged by the PubMed outcomes, the cytoprotective effects of synthetic peptidyl GHRP appear far less studied in noncardiac, parenchymal epithelial organs or multiple organ systems than in the cardiovascular system. However, the results of the reviewed studies are consistent with a broad cytoprotective influence for various organs by reducing inflammation and preventing necrosis and/or apoptosis. The mechanism of GHRP-mediated pharmacological actions is shown in Figure 4.


Synthetic Growth Hormone-Releasing Peptides (GHRPs): A Historical Appraisal of the Evidences Supporting Their Cytoprotective Effects
GHRP mechanism of action. GHRPs are endowed with the ability to bind two different receptors that seem to mediate its cytoprotective and other pharmacological properties (GHS-R1a and CD36). The main biological properties/pharmacological actions of GHRP-6 as cyto- and cardioprotective candidates are summarized as follows: Inotropic: mediated by an elevation of Ca2+ influx via PLC/DAG/PKC, through the voltage-gated calcium channel, triggering Ca2+ release from thapsigargin-sensitive intracellular stores, which translated in a positive inotropic response without a chronotropic effect. Anti-fibrotic: via upregulation of PPARγ, which is followed by a transforming growth factor-beta (TGF-β), CTGF, and platelet-derived growth factor (PDGF) downregulation. Anti-inflammatory: blunts NFκB expression and activation. Cell survival: it involves the phosphatidylinositol 3-kinase/RAC-alpha serine/threonine-protein kinase (PI-3K/AKT1) pathway, as the induction of the hypoxia-inducible factor-1 alpha (HIF-1α). Cardioprotective: as shown, it involves different biological actions that converge to enhance cardiomyocytes survival. Vasodilatory: it seems to involve e-NOS upregulation and endothelin activity reduction. Anabolic: it is mediated by the IGF-1/AKT1 and mTOR pathway activity.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5392015&req=5

f4-10.1177_1179546817694558: GHRP mechanism of action. GHRPs are endowed with the ability to bind two different receptors that seem to mediate its cytoprotective and other pharmacological properties (GHS-R1a and CD36). The main biological properties/pharmacological actions of GHRP-6 as cyto- and cardioprotective candidates are summarized as follows: Inotropic: mediated by an elevation of Ca2+ influx via PLC/DAG/PKC, through the voltage-gated calcium channel, triggering Ca2+ release from thapsigargin-sensitive intracellular stores, which translated in a positive inotropic response without a chronotropic effect. Anti-fibrotic: via upregulation of PPARγ, which is followed by a transforming growth factor-beta (TGF-β), CTGF, and platelet-derived growth factor (PDGF) downregulation. Anti-inflammatory: blunts NFκB expression and activation. Cell survival: it involves the phosphatidylinositol 3-kinase/RAC-alpha serine/threonine-protein kinase (PI-3K/AKT1) pathway, as the induction of the hypoxia-inducible factor-1 alpha (HIF-1α). Cardioprotective: as shown, it involves different biological actions that converge to enhance cardiomyocytes survival. Vasodilatory: it seems to involve e-NOS upregulation and endothelin activity reduction. Anabolic: it is mediated by the IGF-1/AKT1 and mTOR pathway activity.
Mentions: As judged by the PubMed outcomes, the cytoprotective effects of synthetic peptidyl GHRP appear far less studied in noncardiac, parenchymal epithelial organs or multiple organ systems than in the cardiovascular system. However, the results of the reviewed studies are consistent with a broad cytoprotective influence for various organs by reducing inflammation and preventing necrosis and/or apoptosis. The mechanism of GHRP-mediated pharmacological actions is shown in Figure 4.

View Article: PubMed Central - PubMed

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus