GHRP-6 (5mg)

GHRP-6 Peptide

GHRP-6 peptideis a hexapeptide made of six amino acids and is classified amongst researchers as a growth hormone secretagogue (GHS), the classification of which is speculated to facilitate growth hormone (GH) release from the anterior pituitary gland cells. It may achieve this action by potentially acting as a ghrelin receptor agonist and is amongst the ghrelin analogs developed in recent decades. Researchers have suggested that the ghrelin receptor is found in anterior pituitary gland cells. Since their activation appears to result in the synthesis of growth hormone, the receptors are also termed “growth hormone secretagogue receptors” (GHS-Rs). Since ghrelin is posited to impact hunger hormone stimulation, GHRP-6 is also posited to exert similar actions and stimulate food intake. In addition, it has been suggested that it positively influences cardiac muscle cells even in fibrosis cases, and may deliver possible positive neurological impacts in experimental settings.

Specifications

Molecular Formula: C₄₆H₅₆N₁₂O₆

Molecular Weight: 873.032 g/mol

Sequence: His-D-Trp-Ala-Trp-D-Phe-Lys

GHRP-6 Peptide Research

GHRP-6 and the GHS Receptors

Upon binding to GHS receptors, GHRP-6 is understood to trigger a cascade of intracellular signaling processes considered essential for GH secretion.[1] One of the primary pathways activated may involve stimulation of Gq protein subtypes, theorized to lead to the activation of phospholipase C (PLC). Upon activation, PLC facilitates the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) into two secondary messengers: inositol triphosphate (IP3) and diacylglycerol (DAG). The release of IP3 into the cytoplasm may play a pivotal role in elevating intracellular calcium levels, achieved through binding to receptors on the endoplasmic reticulum (ER) and prompting the release of calcium ions (Ca2+) from these intracellular stores. The resulting surge in cytosolic calcium is considered a critical signal promoting the fusion of GH-containing vesicles with the plasma membrane, leading to growth hormone secretion via exocytosis. Simultaneously, DAG appears to activate protein kinase C (PKC) — a key signaling molecule in numerous cellular processes including hormone secretion — further supporting vesicle fusion and GH release.

Researchers have observed a potential rise in growth hormone (GH) concentrations following GHRP-6 exposure, with data indicating an average peak GH level of approximately 15.7 nanograms per milliliter (ng/ml). The cumulative average quantity of GH secreted over the initial 90-minute period of the study was recorded at 674 ng/ml.[2] In a separate study evaluating GHRP-6 against a control compound, GHRP-6 exposure was tentatively associated with a GH release of 15.4 ng/ml, compared to 5.5 ng/ml in the control group — implying a potential link between GHRP-6 exposure and elevated GH levels.[3]

GHRP-6 and the CD36 Receptors

GHRP-6 has been proposed to potentially interact with receptor sites beyond those specifically associated with ghrelin, known as GHS-Rs, with the possibility that these additional receptor sites may include CD36 receptors.[4] CD36 receptors, involved in a broad array of biological processes, are hypothesized to contribute to lipid metabolism through their role as scavenger receptors, facilitating the absorption and transport of lipids throughout the organism. CD36 receptors may also influence immune responses, particularly in activities such as phagocytosis — in which cells ingest harmful particles — and inflammation, a critical immune response to infection and injury. Additionally, CD36 receptors have been associated with angiogenesis, the process by which new blood vessels develop from pre-existing ones, considered essential for tissue recovery and development.

GHRP-6 and Neurological Dysfunction

A 2018 study highlighted the presence of ghrelin receptors in the substantia nigra — a brain region understood to be adversely affected by Parkinson’s disease pathology.[1] Scientists noted that they “found a dramatic decrease in the expression of GHSR in PD-specific induced pluripotent stem cell (iPSC)-derived dopaminergic (DAnergic) neurons generated from [research models] carrying parkin gene (PARK2) mutations.” Genetically predisposed cases are proposed to exhibit a significant reduction in ghrelin receptors within the substantia nigra. Genetically modified rats also appeared to develop Parkinson’s-like symptoms upon introduction of a receptor antagonist. Researchers hypothesize that peptides interacting with receptors in the substantia nigra may potentially reduce neuronal apoptosis and thereby attenuate or delay the onset of this condition.

GHRP-6 Peptide and Brain Cell Death

The potential role of GHRP-6 in supporting recovery from stroke has been evaluated in animal model research. Exposure to the peptide may help mitigate reductions in blood supply to brain tissue following a stroke and may support memory recall functions, which can be compromised during such events.[2] At a molecular level, the peptide and its analogs may prevent apoptosis of central nervous system neurons, potentially inhibiting genetic reprogramming and inflammatory responses.

GHRP-6 and Cognitive Function

Scientists have been investigating the relationship between mild muscular activity and cognitive functions encompassing learning and memory formation, with physical exertion hypothesized to support these processes. The precise underlying mechanism has nonetheless remained incompletely characterized. Researchers initially proposed that physical activity supported improved cerebral blood circulation, potentially increasing growth hormone production. Studies in rodent models have further suggested that GHRP-6 may support the conversion of short-term memories into long-term storage.[3] Additional scientific observations have proposed an active role for ghrelin and GHRP-6 in spatial learning tasks.

GHRP-6 and Cardiac Tissues

GHRP-6 has been proposed to potentially inhibit free radical-mediated cytotoxicity in cardiac cells in porcine models.[4] Researchers commented that “levels of oxidative stress markers suggested that GHRP6 prevented myocardial injury via a decrease in reactive oxygen species and by the preservation of antioxidant defense systems.” Investigation in this area is ongoing.

GHRP-6 and Reproduction

Studies in male rats have proposed a positive correlation between ghrelin receptor activity in the central nervous system and the modulation of arousal and mating impulses. GHRP-6 and its modified counterpart — suggested to antagonize the ghrelin receptor — may influence brain regions that facilitate reward-seeking behavior.[5] Data also suggests that ghrelin may exert an influence on mood, with the peptide and its analogs appearing to affect brain functions associated with mood regulation, stress hormone secretion, and reward behavior in murine models.[6]

GHRP-6 and Fibrosis

Researchers hypothesize that GHRP-6 may contribute to cell survival by reducing programmed cell death (apoptosis). The peptide has been associated with the CD36 receptor and may stimulate blood vessel growth, particularly within damaged tissue. Experiments in rat models suggest it may accelerate natural repair processes, supporting the formation of extracellular matrix proteins such as collagen and promoting appropriate tissue organization around wound sites — thereby potentially reducing fibrosis. Hypertrophic scars such as keloids are understood to arise from irregular matrix protein deposition, a process researchers suggest may be attenuated by GHRP-6.[7]

In a recent experimental study involving rodents, GHRP-6 exposure over a 60-day period appeared to potentially reduce the severity of liver fibrosis.[13] The study recorded a decline in levels of fibrogenic markers including transforming growth factor-beta (TGF-beta) and connective tissue growth factor (CTGF) — both recognized as critical contributors to fibrotic tissue development and progression. Fibrotic areas and hepatic nodularity were estimated to have decreased by approximately 75% and over 60% respectively, suggesting that GHRP-6 may help mitigate fibrosis and support healing processes under experimental conditions.

GHRP-6 and Cellular Apoptosis

Research has investigated the potential action of GHRP-6 on neuronal cells through its role in enhancing GH production and subsequently elevating insulin-like growth factor-1 (IGF-1) levels in targeted regions. IGF-1 — structurally similar to insulin — serves as GH’s principal anabolic mediator, supporting hypertrophy and potentially facilitating cell division and development. Initial observations suggest that GHRP-6 may elevate messenger RNA (mRNA) expression of IGF-1 within specific brain regions including the hypothalamus, cerebellum, and hippocampus, though this increase was notably absent in the cerebral cortex — indicating that GHRP-6, via GH, may encourage IGF-1 synthesis in a region-selective manner. The study also evaluated expression of the IGF-1 receptor and insulin-like growth factor-binding protein 2 (IGFBP-2), which regulates IGF-1 bioavailability through binding, though no significant changes in their expression were recorded following peptide exposure. Phosphorylation of protein kinase B (Akt) and the Bcl-2-associated death promoter (BAD) was observed in regions exhibiting elevated IGF-1 mRNA, potentially indicating that GH and GHRP-6 may activate cellular survival pathways in response to these growth factors. BAD, a member of the Bcl-2 protein family, is recognized as a key regulator of cellular survival and death, while Akt participates in a range of cellular processes including metabolism, apoptosis, growth, transcription, and cell migration. An increase in Bcl-2, an antiapoptotic protein, was also noted in the same regions — suggesting a possible inclination toward cell survival over programmed cell death — while levels of the proapoptotic protein Bax did not display a corresponding change. These findings tentatively propose that GHRP-6 may influence select neuroprotective mechanisms within the brain.

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References

1. Mousseaux D, Le Gallic L, Ryan J, Oiry C, Gagne D, Fehrentz JA, Galleyrand JC, Martinez J. Regulation of ERK1/2 activity by ghrelin-activated growth hormone secretagogue receptor 1A involves a PLC/PKCvarepsilon pathway. Br J Pharmacol. 2006 Jun;148(3):350-65. doi: 10.1038/sj.bjp.0706727. PMID: 16582936; PMCID: PMC1751558.
2. Cordido F, Peñalva A, Dieguez C, Casanueva FF. Massive growth hormone (GH) discharge in obese subjects after the combined administration of GH-releasing hormone and GHRP-6: evidence for a marked somatotroph secretory capability in obesity. J Clin Endocrinol Metab. 1993 Apr;76(4):819-23. doi: 10.1210/jcem.76.4.8473389. PMID: 8473389.
3. Frieboes RM, Murck H, Maier P, Schier T, Holsboer F, Steiger A. Growth hormone-releasing peptide-6 stimulates sleep, growth hormone, ACTH and cortisol release in normal man. Neuroendocrinology. 1995 May;61(5):584-9. doi: 10.1159/000126883. PMID: 7617137.
4. Demers, A., McNicoll, N., Febbraio, M., Servant, M., Marleau, S., Silverstein, R., & Ong, H. (2004). Identification of the growth hormone-releasing peptide binding site in CD36: a photoaffinity cross-linking study. The Biochemical journal, 382(Pt 2), 417–424. https://doi.org/10.1042/BJ20040036
5. Suda, Y., Kuzumaki, N., Sone, T., Narita, M., Tanaka, K., Hamada, Y., Iwasawa, C., Shibasaki, M., Maekawa, A., Matsuo, M., Akamatsu, W., Hattori, N., Okano, H., & Narita, M. (2018). Down-regulation of ghrelin receptors on dopaminergic neurons in the substantia nigra contributes to Parkinson’s disease-like motor dysfunction. Molecular brain, 11(1), 6. https://doi.org/10.1186/s13041-018-0349-8
6. Subirós, N., Pérez-Saad, H. M., Berlanga, J. A., Aldana, L., García-Illera, G., Gibson, C. L., & García-Del-Barco, D. (2016). Assessment of dose-effect and therapeutic time window in preclinical studies of rhEGF and GHRP-6 coadministration for stroke therapy. Neurological research, 38(3), 187–195. https://doi.org/10.1179/1743132815Y.0000000089
7. Huang, C. C., Chou, D., Yeh, C. M., & Hsu, K. S. (2016). Acute food deprivation enhances fear extinction but inhibits long-term depression in the lateral amygdala via ghrelin signaling. Neuropharmacology, 101, 36–45. https://doi.org/10.1016/j.neuropharm.2015.09.018
8. Berlanga, J., Cibrian, D., Guevara, L., Dominguez, H., Alba, J. S., Seralena, A., Guillén, G., López-Mola, E., López-Saura, P., Rodriguez, A., Perez, B., Garcia, D., & Vispo, N. S. (2007). Growth-hormone-releasing peptide 6 (GHRP6) prevents oxidant cytotoxicity and reduces myocardial necrosis in a model of acute myocardial infarction. Clinical science (London, England : 1979), 112(4), 241–250. https://doi.org/10.1042/CS20060103
9. Hyland, L., Rosenbaum, S., Edwards, A., Palacios, D., Graham, M. D., Pfaus, J. G., Woodside, B., & Abizaid, A. (2018). Central ghrelin receptor stimulation modulates sex motivation in male rats in a site dependent manner. Hormones and behavior, 97, 56–66. https://doi.org/10.1016/j.yhbeh.2017.10.012
10. Huang, H. J., Chen, X. R., Han, Q. Q., Wang, J., Pilot, A., Yu, R., Liu, Q., Li, B., Wu, G. C., Wang, Y. Q., & Yu, J. (2019). The protective effects of Ghrelin/GHSR on hippocampal neurogenesis in CUMS mice. Neuropharmacology, 155, 31–43. https://doi.org/10.1016/j.neuropharm.2019.05.013
11. Mendoza Marí, Y., Fernández Mayola, M., Aguilera Barreto, A., García Ojalvo, A., Bermúdez Alvarez, Y., Mir Benítez, A. J., & Berlanga Acosta, J. (2016). Growth Hormone-Releasing Peptide 6 Enhances the Healing Process and Improves the Esthetic Outcome of the Wounds. Plastic surgery international, 2016, 4361702. https://doi.org/10.1155/2016/4361702
12. Fernández-Mayola, M., Betancourt, L., Molina-Kautzman, A., Palomares, S., Mendoza-Marí, Y., Ugarte-Moreno, D., Aguilera-Barreto, A., Bermúdez-Álvarez, Y., Besada, V., González, L. J., García-Ojalvo, A., Mir-Benítez, A. J., Urquiza-Rodríguez, A., & Berlanga-Acosta, J. (2018). Growth hormone-releasing peptide 6 prevents cutaneous hypertrophic scarring: early mechanistic data from a proteome study. International wound journal, 15(4), 538–546. https://doi.org/10.1111/iwj.12895
13. Berlanga-Acosta, J., Vázquez-Blomquist, D., Cibrián, D., Mendoza, Y., Ochagavía, M. E., Miranda, J., … & Guillén-Nieto, G. E. (2012). Growth Hormone Releasing Peptide 6 (GHRP6) reduces liver fibrosis in CCl4 chronically intoxicated rats. Biotecnología Aplicada, 29(2), 60-72.
14. Frago LM, Pañeda C, Dickson SL, Hewson AK, Argente J, Chowen JA. Growth hormone (GH) and GH-releasing peptide-6 increase brain insulin-like growth factor-I expression and activate intracellular signaling pathways involved in neuroprotection. Endocrinology. 2002 Oct;143(10):4113-22. doi: 10.1210/en.2002-220261. PMID: 12239123.