June 2016

Ipamorelin is a hexapeptide (or six-amino-acid) that was developed to mimic ghrelin and its in vivo properties. Until other similar molecules, such as GHRP-1, -2 and -6, ipamorelin contains synthetic amino acids¹. The main function of ipamorelin is to increase the production of growth hormone (GH) from cells that express the GHS-R receptor (also known as the ghrelin receptor). It may also increase IGF-1 levels in healthy animals². However, other similar molecules, such as those listed above, may be associated with significant increases in ACTH and cortisol, whereas ipamorelin is not¹. Nevertheless, ipamorelin may affect growth and development in a manner similar to GH and other ghrelin mimetics (i.e. the GHRPs). Female rats were treated with comparable doses of GH, GHRP and ipamorelin for eight-weeks. This resulted in similar and significant increases in body weight for all three treatments³. Therefore, ipamorelin may be used as a comparative reagent in the assessment of GHS-R activation and GH release in novel or less-studied species⁴. It may also be applied to studies investigating the effects of GH release on subsequent GH expression in these species. For example, ipamorelin was recently incorporated into a study indicating that GH release does not depend on or is influenced by GH mRNA transcription in the black sea bream⁴. (The expression of GH and GHS-R activation act synergistically, or as a positive feedback loop, in some mammalian species⁴. This can also be confirmed through the use of ipamorelin.) Therefore, ipamorelin may be active at many cell types that release GH in vivo. These include, but are not limited to, pituitary, cardiac and liver cells. GH is also associated with a role in normal bone growth and structure. Therefore, ipamorelin may also have a role in bone formation. A study compared bone mass (measured as bone mineral density) in rats treated with 0.5 mg/kg ipamorelin, 0.5 mg/kg GHRP-6, 3.5 mg/kg GH or a placebo every day for eight weeks. Ipamorelin was associated with significant increases in post mortem bone mineral content scans, although to a lesser extent than GH or GHRP-6, compared to placebo³. However, the total weights of vertebrae from ipamorelin-treated rats were significantly greater than those from rats in the placebo group, and were comparable to those taken from GH- and ghrp-6-treated rats³. Ipamorelin also appears to have beneficial effect in animal models of diabetes, as does ghrelin⁵. The peptide has demonstrated the ability to increase insulin production in the pancreatic tissue of diabetic and non-diabetic rats⁶. Unlike ghrelin, however, ipamorelin appears to elicit these effects via adrenergic receptors and through calcium channel activation⁶. Treatment with ipamorelin also results in significant increases in GH concentrations in diabetic mice when compared to non-diabetic mice². This indicates GH resistance, an indicator of type 1 diabetes. Normal mice treated with ipamorelin exhibited significant increases in hepatic IGF-1 compared to identical controls, whereas diabetic, treated mice showed significantly reduced levels of this protein compared to their healthy counterparts². These results demonstrate how ipamorelin can be used to highlight the abnormal hepatic response to GH in this model of diabetes. References:

1. Raun K, Hansen BS, Johansen NL, et al. Ipamorelin, the first selective growth hormone secretagogue. European journal of endocrinology / European Federation of Endocrine Societies. 1998;139(5):552-561.
2. Johansen PB, Segev Y, Landau D, Phillip M, Flyvbjerg A. Growth hormone (GH) hypersecretion and GH receptor resistance in streptozotocin diabetic mice in response to a GH secretagogue. Experimental diabesity research. 2003;4(2):73-81.
3. Svensson J, Lall S, Dickson SL, et al. The GH secretagogues ipamorelin and GH-releasing peptide-6 increase bone mineral content in adult female rats. The Journal of endocrinology. 2000;165(3):569-577.
4. Chan CB, Fung CK, Fung W, Tse MC, Cheng CH. Stimulation of growth hormone secretion from seabream pituitary cells in primary culture by growth hormone secretagogues is independent of growth hormone transcription. Comparative biochemistry and physiology. Toxicology & pharmacology : CBP. 2004;139(1-3):77-85.
5. Adeghate E, Ponery AS. Ghrelin stimulates insulin secretion from the pancreas of normal and diabetic rats. J Neuroendocrinol. 2002;14(7):555-560.
6. Adeghate E, Ponery AS. Mechanism of ipamorelin-evoked insulin release from the pancreas of normal and diabetic rats. Neuro Endocrinol Lett. 2004;25(6):403-406.

Growth hormone releasing peptides (GHRPs) are short molecules developed to mimic the growth hormone secretagogue (GHS, or ghrelin) as the name suggests. Interest in these small sequences began in the early 1980s. At this time, GHRP-6 was regarded as the most potent of these compounds¹. GHRP-6 is active at the GHS receptor (GHS-R) and may therefore activate or regulate a number of different pathways in animal systems. Ghrelin and/or GH may mediate effects on metabolism, appetite, cardiac function and/or protection and cell survival. Therefore, GHRP-6 may be a useful reagent in animal models of various conditions, ranging from ischemia to obesity. GHRP-6 may be administered by injection, topically or orally. However, there are other ghrelin mimetics that may be more effective when administered by the latter route¹. Intranasal delivery systems for this peptide have also been proposed². GHRP-6 has limited stability and availability as a topical treatment, unless modified or conjugated to another small molecule³. One group recently reported improvements in these properties through the conjugation of GHRP-6 to biotin, and that this formulation elicited significantly increased collagen synthesis in cultured skin cells³. The same group then applied this compound to cultured myoblasts, and reported that this treatment resulted in significant increases in their differentiation to myocytes when compared to control cells³. This was thought to be associated with increased collagen-I synthesis³. Treatment with GHRP-6-biotin was also associated with significant increases in intracellular ATP and lactate compared to controls, indicating that treated cells used more energy than non-treated cells³. These findings may align with others that indicate GH may regulate the expression of various genes involved in myoblast differentiation through IGF signaling⁴. Many researchers have concluded that GHS and its mimetics also act to prevent apoptosis in a number of cell types⁵. Apoptosis in pituitary cells, as well as hypothalamic and cerebellar astrocytes, has been observed as a side-effect of diabetes⁵. This condition may also result in a decrease in GH expression⁵. Therefore, GHRP-6 may be used in relevant studies to assess the effects of GH or ghrelin on both diabetes and diabetes-induced cell death. A 2011 study compared a daily regimen of either GHRP-6, (150μg/kg) this dose of the same combined with approximately 8IU insulin, insulin alone or a placebo on apoptosis in rats with experimentally-induced diabetes⁵. Rats with this condition exhibited significantly more apoptosis in the cell types listed above compared to control animals. As individual treatments, GHRP-6 and insulin did not significantly affect cell death after eight weeks. However, the ‘combined’ treatment was associated with significant decreases in apoptosis and in the concentrations of glial fibrillary acidic protein, a marker of nerve cell damage⁵. GHRP-6 may also enhance the survival of heart muscle cells following experimentally-induced cardiac disease⁶. A single treatment of 400μg/kg in an animal model of acute myocardial infarction was associated with significant reductions in cardiac injuries and oxidative stress compared to controls⁶. GHRP-6 may also be used to assess the putative roles of GH in other processes, most notably aging and hormonal dysregulation⁷. References:

1. DeVita RJ. Small molecule mimetics of GHRP-6. Expert opinion on investigational drugs. 1997;6(12):1839-1843.
2. Pontiroli AE. Peptide hormones: Review of current and emerging uses by nasal delivery. Advanced drug delivery reviews. 1998;29(1-2):81-87.
3. Lim CJ, Jeon JE, Jeong SK, et al. Growth hormone-releasing peptide-biotin conjugate stimulates myocytes differentiation through insulin-like growth factor-1 and collagen type I. BMB Reports. 2015;48(9):501-506.
4. Florini JR, Ewton DZ, Coolican SA. Growth hormone and the insulin-like growth factor system in myogenesis. Endocrine reviews. 1996;17(5):481-517.
5. Granado M, Garcia-Caceres C, Tuda M, Frago LM, Chowen JA, Argente J. Insulin and growth hormone-releasing peptide-6 (GHRP-6) have differential beneficial effects on cell turnover in the pituitary, hypothalamus and cerebellum of streptozotocin (STZ)-induced diabetic rats. Molecular and cellular endocrinology. 2011;337(1-2):101-113.
6. 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.
7. Zouboulis CC, Makrantonaki E. Hormonal therapy of intrinsic aging. Rejuvenation research. 2012;15(3):302-312.