Animal only
This animal study investigated the neuroprotective effects of hexarelin, a growth hormone secretagogue receptor type 1a (GHS-R1a) agonist, on retinal ganglion cell (RGC) survival following optic nerve transection (ONT) in golden hamsters. Researchers administered hexarelin at varying doses either once or twice daily for five days post-ONT and quantified RGC survival at seven days using Tuj1 immunostaining on retinal whole mounts. Single daily doses (25, 50, and 100 µg/kg) produced a dose-dependent increase in RGC survival compared to saline controls (62.4%, 68.5%, and 74.6% vs. 51.2%, respectively). Twice-daily dosing yielded further improvements, with the highest tested regimen (150 µg/kg twice daily) associated with a survival rate exceeding baseline (109.2% vs. 72.9% for twice-daily saline). The study suggests hexarelin may exert anti-apoptotic neuroprotective effects in the retina, attributed to its GHS-R1a agonism. Key limitations include the use of a single animal species (golden hamster), absence of mechanistic pathway data, and no translation to human subjects or disease models such as glaucoma.
Indian journal of pharmacology · Mar 2026DOI ↗ In vitro
This study investigated the metabolic fate of alexamorelin — a synthetic peptide growth hormone secretagogue (GHS) with potential performance-enhancing properties — to identify biomarkers useful for doping control. Researchers used in silico metabolite prediction software (GLORYx) alongside in vitro incubations with pooled human hepatocytes from 10 donors, analyzing samples via liquid chromatography–high-resolution tandem mass spectrometry (LC-HRMS/MS). GLORYx predicted 21 possible single-reaction metabolites, with N-acetylation ranked highest in probability (98%), and other transformations such as hydroxylation, N-oxidation, and glucuronidation predicted at lower probabilities. However, after 3 hours of hepatocyte incubation, only one metabolite was experimentally detected: examorelin (hexarelin), produced by carboxypeptidase-mediated cleavage of the C-terminal alanine residue. The parent compound decreased approximately 150-fold over the incubation period, indicating rapid and extensive hepatic metabolism. A key limitation is that examorelin is itself a commercially available GHS compound, meaning it cannot serve as a specific biomarker for alexamorelin use. The authors conclude that direct detection of alexamorelin itself remains the most reliable strategy for confirming its consumption in anti-doping contexts. This study was conducted entirely in vitro and does not involve human subjects or animal models.
Journal of analytical toxicology · Jul 2025DOI ↗ Animal only
This study investigated whether hexarelin — a synthetic peptide ligand targeting the CD36 receptor — could reduce the hyper-inflammatory response associated with severe SARS-CoV-2 infection. Using the K18-hACE2 transgenic mouse model, which expresses the human ACE2 receptor and is widely used to study COVID-19 pathology, the researchers examined how SARS-CoV-2 infection drives alveolar macrophages toward a pro-inflammatory phenotype and whether CD36 modulation could interrupt this process. The study found that CD36 signaling appears to play a regulatory role in macrophage-driven cytokine overproduction — the so-called "cytokine storm" — and that hexarelin treatment showed potential for blunting this response, thereby potentially limiting progression to acute respiratory distress syndrome (ARDS). The study is limited by its reliance on an animal model, meaning results may not translate directly to human patients. The transgenic mouse system, while a useful proxy for human COVID-19, does not fully recapitulate human immunological complexity. No clinical data in humans were presented. The authors acknowledge that ARDS from SARS-CoV-2 remains an unmet therapeutic need and position hexarelin as a candidate for further investigation.
Frontiers in pharmacology · Feb 2024DOI ↗ In vitro
This study used all-atom molecular dynamics (MD) simulations, complemented by Fourier transform infrared (FTIR) spectroscopy, to investigate how two permeability enhancers (PEs) — sodium caprate and SNAC (sodium N-[8-(2-hydroxybenzoyl)amino]caprylate) — interact with four peptide drugs (octreotide, hexarelin, degarelix, and insulin) in the presence of taurocholate, an intestinal bile salt. The simulations revealed that the two PEs had distinct, peptide-dependent effects: they tended to promote release of more hydrophobic peptides while inhibiting release of more water-soluble ones. At lower peptide concentrations, peptide–peptide interactions decreased while interactions with PEs and taurocholate increased. Introducing all components together produced dynamic mixed aggregates with reduced peptide–peptide hydrogen bonding compared to peptide-only systems. FTIR analysis of insulin showed that SNAC increased β-sheet formation, while sodium caprate favored α-helical and random-coil structures. The authors suggest these molecular-level insights could guide the rational design of PE-based oral peptide formulations. Key limitations include the exclusive use of computational and in vitro/spectroscopic methods, with no cell-based, animal, or human data reported.
Nanoscale · Dec 2023DOI ↗ Animal only
This study investigated whether the growth hormone-releasing peptide Hexarelin could protect against ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) and explored its molecular mechanisms. Using a rat I/R model, animals were pretreated with Hexarelin for seven days before injury induction. Researchers assessed kidney function (serum creatinine), histology (tubular necrosis and dilation), and apoptosis markers. In vitro, a hypoxia/reoxygenation (H/R) model in human kidney tubular (HK-2) cells was used to complement findings. The study reports that Hexarelin pretreatment reduced pathological kidney changes, improved renal function, and suppressed apoptosis, as evidenced by downregulation of pro-apoptotic proteins (Caspase-3, Bax, Bad) and upregulation of anti-apoptotic Bcl-2. Gene Set Enrichment Analysis (GSEA) highlighted the apoptosis pathway's role in I/R-AKI. Molecular docking suggested Hexarelin binds MDM2, a negative regulator of p53, and both MDM2 and p53 expression were suppressed by Hexarelin in vivo and in vitro. Key limitations include exclusive use of animal and cell models with no human data, a relatively narrow mechanistic focus, and reliance on computational docking without direct protein-interaction validation.
European journal of medical research · Sep 2023DOI ↗ In vitro
This study investigated whether two growth hormone secretagogues (GHSs) — hexarelin and JMV2894 — could protect neural cells from oxidative stress in the context of amyotrophic lateral sclerosis (ALS). The researchers used human neuroblastoma cells (SH-SY5Y) engineered to express the SOD1-G93A mutant protein, a model relevant to familial ALS. Cells were exposed to hydrogen peroxide (H₂O₂) to simulate oxidative stress, with or without GHS co-treatment. The study found that both hexarelin and JMV2894 appeared to protect cells from H₂O₂-induced cytotoxicity by activating molecular pathways associated with the regulation of apoptosis and cell survival. The authors suggest these compounds may have antioxidant and neuroprotective properties worth exploring for ALS therapy. Key limitations include that this is a cell-based (in vitro) study only, using a cancer-derived cell line rather than primary motor neurons, and no animal or human data were generated. The authors themselves acknowledge the need for further work to clarify mechanisms and develop improved GHS candidates before any translational conclusions can be drawn.
International journal of molecular sciences · Jan 2023DOI ↗ Animal only
This study investigated whether hexarelin, a synthetic growth hormone-releasing peptide, could reduce the development of abdominal aortic aneurysm (AAA) using an elastase-induced mouse model. Mice received hexarelin injections twice daily, and outcomes were assessed via echocardiography, in situ imaging, histology, and molecular analyses. The study found that hexarelin-treated mice showed reduced infrarenal aortic diameter and improved elastin integrity compared to untreated controls. At the cellular level, hexarelin appeared to preserve smooth muscle cell (SMC) contractile phenotype, evidenced by increased α-SMA expression and decreased MMP2. Additionally, hexarelin was associated with reduced inflammatory cell infiltration, suppression of NLRP3 inflammasome activation, lower IL-18 production, and inhibition of the NF-κB signaling pathway. The authors concluded that hexarelin attenuates AAA development by targeting SMC phenotype switching and NF-κB-mediated inflammation. Key limitations include the exclusive use of an animal model, meaning findings have not been validated in humans, and the mechanistic conclusions are based on a single preclinical model that may not fully replicate human AAA pathophysiology.
Microvascular research · Nov 2021DOI ↗ Review
This review paper examines the biological pathway linking growth hormone releasing peptides (GHRPs) — with a focus on the peptide hexarelin — to metabolic regulation via the scavenger receptor CD36 and the nuclear receptor PPARγ. The authors summarize evidence showing that GHRPs can activate PPARγ through CD36, and discuss how this pathway may influence key metabolic processes including atherosclerosis, hepatic cholesterol biosynthesis, and mitochondrial biogenesis in fat tissue. The paper also discusses the role of the PPARγ coactivator PGC-1 in mediating these downstream effects. The authors contextualize this pathway alongside established pharmacological approaches, such as thiazolidinediones, which also target PPARγ to improve insulin resistance in diabetic patients. The paper proposes that the GHRP-CD36-PPARγ axis represents a novel potential target for addressing metabolic disorders. As a review, the paper synthesizes existing preclinical and some clinical research but does not present original experimental data. Key limitations include the absence of new human trial data and the largely preclinical nature of much of the underlying evidence for hexarelin specifically.
International journal of molecular sciences · May 2018DOI ↗ Limited · human
This study developed and validated an analytical method for detecting a broad panel of 18 performance-enhancing peptides (molecular weight <2 kDa) in human urine, as defined by the World Anti-Doping Agency (WADA) prohibited list. The method uses direct urine injection—bypassing complex sample preparation—coupled with liquid chromatography and ion mobility time-of-flight mass spectrometry (IM-TOFMS). The researchers reported limits of detection (LOD) ranging from 50 to 500 pg/mL, well below WADA's minimum required performance level of 2 ng/mL. The method demonstrated acceptable precision (imprecision <20%) and linearity across a 0–10 ng/mL working range. Stability testing identified –20°C as the appropriate storage temperature for urine samples. As a proof-of-concept, the method was applied to real elimination study urine samples from individuals who had administered GHRP-2, GHRP-6, or LHRH, successfully detecting these compounds. Key limitations include the small number of human subjects used in the elimination studies, which were primarily intended to demonstrate analytical feasibility rather than investigate pharmacokinetics or clinical effects. The study is a methodological/analytical validation paper focused on anti-doping screening, not a clinical or therapeutic investigation.
Journal of separation science · Dec 2015DOI ↗