GHRP-2

Essentially a synthetic version of ghrelin analogue, GHRP-2 stimulates the release of an endogenous growth hormone (GH) within the somatotropes of the anterior pituitary in the animal and human body. Specifically, GHRP-2 will increase the number of somatotropes in a GH pulse by limiting the amount of somatostatin present, while standard GHRH increases the amplitude at which the pituitary cells pulse. Unlike ghrelin, GHRP-2 is not specifically used to increase appetite, but it may have secondary actions that impact hypothalamic neurons. These effects last for approximately an hour after the initial application, which mimics the natural application of GH and consists of an eight hour circulation period.

Background

The most important initial historical time points in the development of the enlarging ghrelin system were 1973, 1976, 1982, 1984, 1990, 1996, 1998, and 1999 during which the following sequentially occurred:1
  • isolation of somatostatin, discovery of unnatural growth-hormone-releasing peptides (GHRPs)
  • isolation of growth-hormone-releasing hormone (GHRH)
  • hypothesis of a new natural GHRP different from GHRH
  • GHRP+GHRH synergism in humans
  • discovery of the growth hormone secretagogue GHS/GHRP receptor
  • cloning of the receptor
  • isolation and identification of the new natural endogenous GHRP ghrelin
Thanks to the assiduousness of talented researchers around the globe, our contemporary understanding of the pharmacology and probably also the physiological regulation of growth hormone secretion, came about after the important discovery that GHRP increased pulsatile GH secretion in not only children, but also within normal younger and older men and women. Even though GHRP alone substantially releases GH from the pituitary in vitro without the addition of GHRH, this rhythmic endogenous secretion does require some GHRH. GHRP was first envisioned to be an analog of GHRH but, from comparison of the activity of GHRH and GHRPs between 1982 and1984, it was hypothesized to reflect the activity of a new hormone regulator of GH secretion yet to be isolated and identified. Intravenous bolus GHRP releases more GH than GHRH in humans, but the reverse occurs in vitro. GHRPs are pleiotropic peptides with major effects on GH, nutrition, and metabolism, especially as an additional hormone in combination with GHRH as a new regulator of pulsatile GH secretion. The first indication of pleiotropism was an increase of food intake by GHRP. A major reason for the prolonged initial interest in the GHRPs has been its similar, yet different and complementary, action with GHRH on GH regulation and secretion. Particularly noteworthy is the variable chemistry of the GHRPs. They consist of three major chemical classes including peptides, partial peptides, and nonpeptides, and all appear to act via the same receptor and cellular mechanisms. Generally, most GHRPs have been active by all routes of administration, namely intravenously (IV), subcutaneously (SC), orally, intranasally, and intracerebroventricularly (IVC), which supports their possible broad future clinical utility. From evolutionary studies starting with the zebrafish, the natural receptor and hormone have been present for hundreds of years, underscoring the fundamental evolutionary and functional importance of the ghrelin system. GHRPs were well established to act directly on both the hypothalamus and pituitary several years before the GHS receptor assay.23 Finally, the ghrelin chemical isolation and identification was accomplished surprisingly from the stomach, which is the major site but not the only site. Ghrelin was isolated and identified.4 A primary action of GHRPs continues to concern GH secretion and regulation, but increasingly this has included direct and indirect effects on nutrition and metabolism, as well as a variety of other actions which may be pharmacological and/or physiological.

Does GHRP-2 Work?

The below study results demonstrate the actions of GHRP-2 and GHRP-6 on GH releases in pituitary cells, and a follow up study which focused on increasing these concentrations to create GH dependency to better understand potential dosing restrictions, should this chemical be used in therapeutic sessions in the future:
  • GHRP-2, GHRP-6 and GRF were applied in increasing concentrations to partially purified sheep somatrophs to cause a release of growth hormone in a dependent manner. GHRP-6 was not found to increase the cAMP levels. Mixtures of GRF and GHRP-2 were found to increase growth hormone and cAMP levels, but a combination of GHRP-2 and GHRP-6 did not.
  • When the cells were pretreated with an adenylyl cyclase inhibitor, they did not see a cAMP increase, though there was a growth hormone increase when GRF or GHRP-2 were applied. This antagonist did not prevent cAMP reactions when a combination of growth hormone and GHRP-6 was applied.
  • When the antagonist was applied to the growth hormone receptor, the GHRP-2 and GRF combination did not increase the cAMP rates, but prevented any release of growth hormone when GRF, GHRP-2, or GHRP-6 were applied.
  • GHRP-2 has been demonstrated to affect the ovine pituitary somatotroph to increase cAMP concentrations in a way similar way that of GRF. However, GHRP-2, GHRP-6, and GRF all act on different receptors which explains why GHRP-6 did not have an effect cAMP levels on the rat pituitary cell cultures.

Food Intake & GH Release Effects

Research suggests that circulating ghrelin is also implicated in meal to meal regulation, wherein levels increase in anticipation of a meal and are suppressed by food ingestion, though the underlying mechanisms are not known.56 Serum ghrelin levels vary as a function of energy balance. Ghrelin levels are increased in anorexia and decreased in obesity.78 Thus, it is possible that ghrelin may be an important player in food intake behavior and perhaps in chronic over- and under-nutrition as well.9 Because of its dual effects, ghrelin may be a critical hormonal signal of nutritional status to the somatotropic axis, playing a role in integrating energy balance with the growth process.10 Additional studies demonstrate that peripheral administration of GHRP-2 increases food intake in humans. The effect of GHRP-2 is robust and elicited an increase of food intake in all subjects tested, all of which reported being hungrier while receiving GHRP-2. The magnitude of the effect of GHRP-2 on food intake (+35%) is comparable to that of ghrelin, previously shown to increase food intake by 28% in healthy subjects and by 31% in cancer patients.1112 The effect of 1 μg/kg/h of GHRP-2 is comparable to the effect of ghrelin (5 pmol/kg/min) not only on food intake, but also on GH release. In Wren’s study (also in healthy lean subjects), ghrelin raised GH to similar levels (about 35 μg/L).13 Therefore, ghrelin or the ghrelin mimetic GHRP-2, when administered peripherally, is able to induce significant acute changes of similar magnitude in both GH levels and food intake behavior.

Stature/Growth Effects

Many studies have revealed that chronic administration of GHRP-2 to short stature children with various degrees of GH deficiency induces a sustained enhancement in the rate of linear growth.1415 This suggests the possibility that the acute effect of GHRP-2 on food intake observed in some studies might result in a state of positive energy balance, were GHRP-2 administered chronically. Carefully designed and optimized chronic studies, including detailed body composition and food intake monitoring, will help to demonstrate the long-term effects of GHS(s) on food intake and body weight. Although GHRP-2 increased GH significantly, it is unlikely, judging from the results of rhGH alone, that this increase in GH levels is responsible for the acute changes in food intake in these studies.

Anti-Inflammatory Effects

A study focused on the proper administration of GHRP-2 on arthritic rats injected with Freund’s adjuvant, and then given daily exposures to GHRP-2 or ghrelin fifteen days later, returned interesting results:
  • Those exposed to the ghrelin serum saw a decrease in their leptin concentrations
  • Those given GHRP-2 saw ameliorated external symptoms of their arthritis and a decrease in their paw volume
  • GHRP-2 also decreased IL-6 levels when they had originally been increased by the arthritis symptoms.
  • The results of this study help to show that GHRP-2 may have use in managing IL-6 levels affected by arthritis. This further implies that GHRP-2 may have anti-inflammatory properties as the chemical appeared to have a positive effect on managing the ghrelin receptors and immune cells that were affected by the disease. The comparison of GHRP-2 to similar chemicals in a natural setting is ongoing to assist researchers in evaluating the similarities in composition, so the study of this chemical can be expanded to additional animals.

GHRP-6

Essentially a synthetic version of ghrelin analogue, GHRP-6 (like GHRP-2) stimulates the release of an endogenous growth hormone (GH) within the somatotropes of the anterior pituitary in the animal and human body. Specifically, GHRP-6 will increase the number of somatotropes in a GH pulse by limiting the amount of somatostatin present, while standard GHRH increases the amplitude at which the pituitary cells pulse. Unlike ghrelin, GHRP-6 is not specifically used to increase appetite, but it may have secondary actions that impact hypothalamic neurons. These effects last for approximately an hour after the initial application, which mimics the natural application of GH, and consists of an eight hour circulation period. In studies GHRP-6 has shown biological actions similar to the naturally occurring hunger stimulating peptide ghrelin. Its main use is to promote food intake by stimulating hunger and aid in energy metabolism. It can be used in the treatment of GH deficiency as well as cachexia, eating disorders and obesity. GHRP-6 is a synthetic met-enkephalin (a naturally occurring opioid growth factor) analog. GHRP-6 contains D-amino acids that are entirely synthetic, lacks opioid activity, and shares no sequence relation with GHRH. It has also been shown that GHRP-6 can lead to re-stimulation of the natural production of HGH. Studies have shown that GHRP-6 increases the secretion of IGF-1 (InsulinLike Growth Factor 1) by the liver, which is speculated to be a required component in the anabolic mechanisms leading to the action of HGH. It also appears that GHRP-6 has positive implications for the central nervous system, as ghrelin is known to protect neurons. What may be the most interesting aspect of ghrelin (and therefore GHRP-6, it’s synthetic analog) is the huge variety of roles it plays in biological functions. It is involved in processes that include appetite regulation, cardiac functions, gastrointestinal functions, metabolism of carbohydrates, and even has some behavioral effects.

BACKGROUND

The most important initial historical time points in the development of the enlarging ghrelin system were 1973, 1976, 1982, 1984, 1990, 1996, 1998, and 1999 during which the following sequentially occurred: isolation of somatostatin; discovery of unnatural growth-hormone-releasing peptides (GHRPs); isolation of growth-hormone-releasing hormone (GHRH); hypothesis of a new natural GHRP different from GHRH; GHRP+GHRH synergism in humans; discovery of the growth hormone secretagogue GHS/GHRP receptor; cloning of the receptor; isolation; and identification of the new natural endogenous GHRP ghrelin.1 Thanks to the assiduousness of talented researchers around the globe, our contemporary understanding of the pharmacology and probably also the physiological regulation of growth hormone secretion, came about after the important discovery that GHRP increased pulsatile GH secretion in not only children, but also within normal younger and older men and women. Even though GHRP alone substantially releases GH from the pituitary in vitro without the addition of GHRH, this rhythmic endogenous secretion does require some GHRH. GHRP was first envisioned to be an analog of GHRH but, from comparison of the activity of GHRH and GHRPs between 1982 and1984, it was hypothesized to reflect the activity of a new hormone regulator of GH secretion, yet to be isolated and identified. Intravenous bolus GHRP releases more GH than GHRH in humans, but the reverse occurs in vitro. GHRPs are pleiotropic peptides with major effects on GH, nutrition, and metabolism, especially as an additional hormone in combination with GHRH as a new regulator of pulsatile GH secretion. The first indication of pleiotropism was an increase of food intake by GHRP. A major reason for the prolonged initial interest in the GHRPs has been its similar, yet different and complementary, action with GHRH on GH regulation and secretion. Of particular note is the variable chemistry of GHRPs, which consist of three major chemical classes including peptides, partial peptides, and nonpeptides, all of which appear to act via the same receptor and cellular mechanisms. Generally, most GHRPs are active by all routes of administration, specifically intravenously (IV), subcutaneously (SC), orally, intranasally, and intracerebroventricularly (IVC), which supports their possible broad future clinical utility. From evolutionary studies starting with the zebrafish, the natural receptor and hormone have been present for hundreds of years, underscoring the fundamental evolutionary and functional importance of the ghrelin system. GHRPs were well established to act directly on both the hypothalamus and pituitary several years before the GHS receptor assay.23 Finally, the ghrelin chemical isolation and identification was accomplished surprisingly from the stomach, which is the major site but not the only site. Ghrelin was isolated and identified.4 A primary action of GHRPs continues to concern GH secretion and regulation, but increasingly this has included direct and indirect effects on nutrition and metabolism, as well as a variety of other actions which may be pharmacological and/or physiological.

DOES GHRP-6 WORK?

The below study results demonstrate the actions of GHRP-2 and GHRP-6 on GH releases in pituitary cells, and a follow up study which focused on increasing these concentrations to create GH dependency to better understand potential dosing restrictions, should this chemical be used in therapeutic sessions in the future:
  • GHRP-2, GHRP-6 and GRF were applied in increasing concentrations to partially purified sheep somatrophs to cause a release of growth hormone in a dependent manner. GHRP-6 was not found to increase the cAMP levels. Mixtures of GRF and GHRP-2 were found to increase growth hormone and cAMP levels, but a combination of GHRP-2 and GHRP-6 did not.
  • When the cells were pretreated with an adenylyl cyclase inhibitor, they did not see a cAMP increase, though there was a growth hormone increase when GRF or GHRP-2 were applied. This antagonist did not prevent cAMP reactions when a combination of growth hormone and GHRP-6 was applied.
  • When the antagonist was applied to the growth hormone receptor, the GHRP-2 and GRF combination did not increase the cAMP rates, but prevented any release of growth hormone when GRF, GHRP-2, or GHRP-6 were applied.
  • GHRP-2 has been demonstrated to affect the ovine pituitary somatotroph to increase cAMP concentrations in a way similar way that of GRF. However, GHRP-2, GHRP-6, and GRF all act on different receptors which explains why GHRP-6 did not have an effect cAMP levels on the rat pituitary cell cultures.
Research suggests that circulating ghrelin is also implicated in meal to meal regulation, wherein levels increase in anticipation of a meal and are suppressed by food ingestion, though the underlying mechanisms are not known.56 Serum ghrelin levels vary as a function of energy balance. Ghrelin levels are increased in anorexia and decreased in obesity.78 Thus, it is possible that ghrelin may be an important player in food intake behavior and perhaps in chronic over- and under-nutrition as well.9 Because of its dual effects, ghrelin may be a critical hormonal signal of nutritional status to the somatotropic axis, playing a role in integrating energy balance with the growth process.10

GHRP-6’S EFFECTS ON OBESITY

GHRH/GHRP-6 was the first of a family of synthetic peptides that enhance the release of the GH by the pituitary gland in a dose-dependent manner. Since its discovery, it has been used as a benchmark and starting point for many of the research aims to obtain new drugs, but none of its implications are more engaging than the treating of the obesity epidemic. Normal GH secretion, whether spontaneous or evoked by provocative stimuli, is markedly blunted in obese patients who display, as compared to normal weight subjects a reduced: half-life; frequency of secretory episodes; and daily production rate of the hormone. Scacchi, et al found that the combined administration of GHRH and GHRP-6 represented the most powerful GH releasing stimulus among obese patients, which was still less effective than in lean body mass subjects.They concluded that treatment with biosynthetic GH has been shown to improve the body composition, and the metabolic efficacy of lean body mass in obese patients undergoing therapeutic severe caloric restriction. GH and conceivably GHRPs might therefore have a place in the therapy of obesity.11 In a study designed to assess the effect of both the estrogen and GHRP-6 on the cardiovascular and metabolic diseases in ovariectomized (OVX) rats, Elbassuoni, et al found that although GHRP-6 failed to produce significant change in body weight gain and food intake, it clearly reversed the effect of OVX on fasting serum glucose, insulin, insulin resistance, and the assessed lipid fractions. They concluded that the effect of GHRP-6 on improving dyslipidemia after OVX was even more potent than that of estrogen.12 Furthermore, the mechanism of action of GHRP-6 has been more extensively studied in experimental models with obese subjects, and was shown to be a powerful GH releaser in obesity, and to release GH independently of the hypothalamic factors (GHRH and somatostatin).13

What is Ghrelin?

Ghrelin is a 28 amino acid hunger-stimulating peptide and hormone that is produced mainly by P/D1 cells lining the fundus of the human stomach and epsilon cells of the pancreas. Ghrelin together with obestatin is produced from cleavage of the ghrelin/obestatin prepropeptide (also known as the appetite-regulating hormone or growth hormone secretagogue or motilin-related peptide) which in turn is encoded by the GHRL gene. Ghrelin receptors are expressed in a wide variety of tissues, including the pituitary, stomach, intestine, pancreas, thymus, gonads, thyroid, and heart. The diversity of ghrelin receptor locations suggests ghrelin has diverse biological functions.

How does Ghrelin work?

Ghrelin levels increase before meals and decrease after meals. It is considered the counterpart of the hormone leptin, produced by adipose tissue, which induces satiation when present at higher levels. In some bariatric procedures, the level of ghrelin is reduced in patients, thus causing satiation before it would normally occur. Ghrelin is a potent stimulator of growth hormone secretion from the anterior pituitary gland. The ghrelin receptor is a G protein-coupled receptor, known as the growth hormone secretagogue receptor. Ghrelin binds to the GHSR1a splice-variant of this receptor which is present in high density in the hypothalamus, pituitary as well as vagal afferent cell bodies and vagal afferent endings throughout the gastro-intestinal tract. Ghrelin has been linked to inducing appetite and feeding behaviors. Circulating ghrelin levels are the highest right before a meal and the lowest right after. Injections of ghrelin in both humans and rats have been shown to increase food intake in a dose dependent manner. So the more ghrelin that is injected the more food that is consumed. However, ghrelin does not increase meal size, only meal number. Ghrelin injections also increase an animals’ motivation to seek out food, behaviors including increased sniffing, foraging for food, and hoarding food. Ghrelin also readies the body for the incoming nutrients by stimulating gastrointestinal motility and gastric acid secretions. Ready to get started? Click Here!
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