Hexarelin

Mechanism (as reported)

Hexarelin has been reported to bind to and activate GHSR in the brain (PMID 25278975) and has been discussed as part of a broader GH secretagogue class whose GH release is subject to negative feedback (PMID 28400207). Separate cardiovascular evidence in the provided sources also reports a non-GHSR receptor (CD36) involvement in cardiac effects (PMID 25278975). In an ischemia/reperfusion acute kidney injury study, a mechanism was investigated involving apoptosis-pathway modulation and molecular docking suggesting interaction with MDM2 and associated suppression of MDM2/p53 signaling (PMID 37710348).

Key findings (each cites a source)

• A review of GH secretagogues reported that GH secretagogues promote pulsatile GH release subject to negative feedback. [PMID 28400207]
• The same review reported available studies indicate GH secretagogues are well tolerated, with some concern for increases in blood glucose because of decreases in insulin sensitivity. [PMID 28400207]
• The cardiovascular review reported that hexarelin can bind to and activate GHSR in the brain similar to ghrelin, and that peripheral distribution of GHSR suggests potential direct cardiovascular actions beyond growth hormone release. [PMID 25278975]
• The cardiovascular review reported that non-GHSR CD36 had been demonstrated as a specific cardiac receptor for hexarelin and to mediate its cardioprotective effects. [PMID 25278975]
• A study in an ischemia/reperfusion acute kidney injury model reported that hexarelin pretreatment was associated with reduced kidney pathological changes and improved renal function, along with reduced apoptosis markers and increased anti-apoptotic Bcl-2. [PMID 37710348]
• In the ischemia/reperfusion acute kidney injury study, molecular docking suggested strong binding affinity between hexarelin and MDM2, and the study reported suppression of MDM2 and p53 expression with hexarelin in vivo and in vitro. [PMID 37710348]
• A study of elastase-induced abdominal aortic aneurysm in mice reported that hexarelin attenuated aneurysm development, including improved elastin degradation and effects on smooth muscle cell phenotype markers (increased α-SMA and decreased MMP2). [PMID 34856183]
• The abdominal aortic aneurysm study reported that hexarelin inhibited inflammatory cell infiltration, NLRP3 inflammasome activation, IL-18 production, and suppressed NF-κB signaling. [PMID 34856183]
• A human physiology study reported that infusion of somatostatin (SS) reduced peak GH response to hexarelin, and that SS withdrawal at the time of hexarelin bolus increased peak serum GH concentration. [PMID 9425393]
• The human study reported that SS did not alter the prolactin and cortisol response to hexarelin. [PMID 9425393]
• A human repeated-administration study reported that hexarelin and GHRH-(1-29)-NH2 were synergistic in producing peak GH secretion rates after a first dose. [PMID 8762732]
• The same repeated-administration study reported that synergism between hexarelin and GHRH-(1-29)-NH2 was lost after repeated administration, and that the magnitude of the GH response to a second dose depended on dosing interval. [PMID 8762732]