GHRP-6. By Edgar181 (Own work) [Public domain], via Wikimedia Commons

GHRP-6 is a synthetic hexapeptide associated with the secretion of growth hormone in the pituitary glands of humans and animals¹. It is thought to achieve this through increases in intracellular calcium (Ca²⁺), activated PKC and the DAG/IP3 pathway^2,3. There are two main forms of this molecule: GHRP-6 and [D-Lys (3)]GHRP-6. The latter is a ghrelin receptor (GHS-R) antagonist⁴. In other words, it countermands the actions of GHRP-6. This is useful in many studies, as its use can validate a putative effect of GHRP-6; i.e. if GHRP-6 stimulates a particular pathway, this can be confirmed by its inhibition by [D-Lys (3)]GHRP-6. This version of the peptide can also confirm the role of ghrelin in novel applications⁴. [D-Lys (3)]GHRP-6 may also have its own potential in research and medicine. It has been associated with improvements in the biomarkers of obesity (or the metabolic syndrome), including ghrelin levels, leptin levels, blood cholesterol and blood glucose⁵. In addition, the administration of [D-Lys (3)]GHRP-6 may be associated with reductions in body mass⁵.

New applications for GHRP-6

Some researchers have reported novel properties and/or functions of GHRP-6 or[D-Lys (3)]GHRP-6 that may affect how they are used in science and medicine in the near future. Alternatively, these peptides may be used to quantify the putative effects of ghrelin. Ghrelin is thought to have beneficial effects in situations such as adverse cardiac effects, cardiomyopathy, cerebrovascular complications (e.g. stroke), and vascular protection following retinopathy (in which new blood vessels may be abnormal and non-functional)^1,6. Most of these are based on in vitro or in vivo (animal) trials and studies.

Intraperitoneal administration of combined EGF and GHRP-6 reduced clinical signs, and conserved nerve cell density, in an animal model of stroke⁷. GHRP-6 demonstrated the ability to significantly reduce infarct sizes, necrosis and oxidative stress (caused by reactive oxygen species) compared to a control treatment (saline) in an animal model of myocardial infarction. The control treatment was also associated with significant increases in IGF-1 expression compared to GHRP-6¹. This indicates that GHRP-6 initiates cardioprotective mechanisms that are distinct from those associated with IGF-1. Treatment with GHRP-6 significantly conserved vascular density, increased IGF-1 levels and increased VEGF levels in a rat model of retinopathy⁶. The addition of [D-Lys (3)]GHRP-6 negated these effects⁶.

A study using a rat model of Alzheimer's disease found that the relevant markers (acetylcholinesterase and amyloid-beta) were reduced in animals treated with [D-Lys (3)]GHRP-6 compared to controls⁵. Rats treated with this peptide also showed improved performance in a spatial orientation task⁵. Other research indicates that ghrelin anatagonists may reduce alcohol intake behaviours, e.g. preference for this rather than water in animal studies⁸. However, a study randomizing C57BL/6J mice to [D-Lys (3)]GHRP-6 or another ghrelin antagonist (JMV2959) found that [D-Lys (3)]GHRP-6 reduced ethanol intake and preference on the first day of treatment only⁸. JMV2959 reduced this intake at all time-points, but also reduced food and water intake⁸. [D-Lys (3)]GHRP-6 was also used to confirm the role of ghrelin in relaxing the dilator and sphincter muscles of the rabbit iris⁹.

References:

1. Berlanga J, Cibrian D, Guevara L, et al. 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). 2007;112(4):241-250.

2. Bresson-Bepoldin L, Dufy-Barbe L. GHRP6-stimulated hormone secretion in somatotrophs: involvement of intracellular and extracellular calcium sources. Journal of neuroendocrinology. 1996;8(4):309-314.

3. Mau SE, Witt MR, Bjerrum OJ, Saermark T, Vilhardt H. Growth hormone releasing hexapeptide (GHRP-6) activates the inositol (1,4,5)-trisphosphate/diacylglycerol pathway in rat anterior pituitary cells. Journal of receptor and signal transduction research. 1995;15(1-4):311-323.

4. Luque EM, Torres PJ, de Loredo N, et al. Role of ghrelin in fertilization, early embryo development, and implantation periods. Reproduction (Cambridge, England). 2014;148(2):159-167.

5. Madhavadas S, Kutty BM, Subramanian S. Amyloid beta lowering and cognition enhancing effects of ghrelin receptor analog [D-Lys (3)] GHRP-6 in rat model of obesity. Indian journal of biochemistry & biophysics. 2014;51(4):257-262.

6. Zaniolo K, Sapieha P, Shao Z, et al. Ghrelin modulates physiologic and pathologic retinal angiogenesis through GHSR-1a. Investigative ophthalmology & visual science. 2011;52(8):5376-5386.

7. Garcia Del Barco-Herrera D, Martinez NS, Coro-Antich RM, et al. Epidermal growth factor and growth hormone-releasing peptide-6: combined therapeutic approach in experimental stroke. Restorative neurology and neuroscience. 2013;31(2):213-223.

8. Gomez JL, Ryabinin AE. The effects of ghrelin antagonists [D-Lys(3) ]-GHRP-6 or JMV2959 on ethanol, water, and food intake in C57BL/6J mice. Alcoholism, clinical and experimental research. 2014;38(9):2436-2444.

9. Rocha-Sousa A, Saraiva J, Henriques-Coelho T, Falcao-Reis F, Correia-Pinto J, Leite-Moreira AF. Ghrelin as a novel locally produced relaxing peptide of the iris sphincter and dilator muscles. Experimental eye research. 2006;83(5):1179-1187.