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Interestingly, hexarelin, a peptide growth hormone secretagogue, has been shown to improve atherosclerotic lesions by its ability to bind the scavenger receptor CD36, preventing the uptake of oxidized low density lipoproteins, one of the earliest steps of fatty streak lesion observed in the pathogenesis of atherosclerosis [30]. Whether ghrelin and CD36 have a connection requires further studies.
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STUDIES
The drug employed by us was Hexarelin (Hex = His-D-2-methyl-Trp-Ala-Trp-D- Phe-Lys-NH2) which was supplied by Dr. R. Deghenghi, (Europeptides, Argenteuil, France). After ascertaining that a bolus intranasal (i.n.) insufflation of 20 μg/kg has an identical efficacy in raising serum hGH as an intravenous (i.v.) bolus of 1 μg/kg in children with familial short stature (12), we proceeded to find a daily dose which will raise and maintain an elevated serum IGF-I (insulin-like growth factor-I) as a marker of linear growth stimulation. Due to the short half-life of the drug, we found that one or two daily intranasal applications were insufficient to raise serum IGF-I. We thus administered the drug three times a day (t.i.d.) (13) (Table 1). As a dose of 40 μg/kg t.i.d. achieved significant but lower than aimed changes, we decided to use 60 μg/kg t.i.d by i.n. spray, a dose, which was well tolerated by the children (14).
Table 1. Effect of various doses of intranasal Hexarelin for 7 days in children with idiopathic short stature on serum IGF-I, and plasma alkaline phosphatase
Patient no. Sex CA y:m Empty Cell IGF-I (nMol/1) Empty Cell Alkaline phospatase (U/L) Empty Cell 20* b.i.d. 20-20-40* 40* t.i.d. Empty Cell 20* b.i.d. 20-20-40* 40* t.i.d. Empty Cell Empty Cell Empty Cell Basal Day 8 Day 8 Day 8 Basal Day 8 Day 8 Day 8 1 M 5:9 5.8 8.3 (−) (−) 135 151 (−) (−) 2 F 5:10 12.75 (−) 13.6 20.7 162 (−) 167 142 3 M 5:10 7.2 6.3 (−) 8.6 189 190 (−) 208 4 M 7:6 14.2 16.9 12.8 16.1 284 259 265 259 5 M 9:1 8.4 10.1 16.65 18.75 213 210 240 241 6 M 9:11 7.1 6.8 9.5 14.25 218 217 254 238 7 M 11:4 15.4 17.4 26.54 22.75 139 143 137 153 p < 0.05 p < 0.05
CA = chronological age; y = years; m = months. Modified from Frenkel et al. (13).
* Daily dose of Hexarelin (μg/kg).
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Intranasal peptide hormones not yet on the market are insulin, glucagon, growth hormone releasing hormone (GHRH) and GHRP, GH and somatostatin, but the scenario is likely to change in a short period of time. Hexarelin seems very effective and is at a promising stage of development; also, glucagon appears mature enough to undergo extensive clinical evaluation and possibly marketing. The concern is why other peptides have not been further evaluated, as is the case for somatostatin and its analogues.
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Impaired cardiac performance is associated with GH-deficiency in the elderly [17] and GH replacement is reported to have beneficial effects on cardiac function [14]. Hexarelin improved cardiac function in rats with experimentally induced myocardial infarction [18]. However, beneficial effects were also observed in hypophysectomized animals [19]. Furthermore, hexarelin prevented endothelial vasodilator dysfunction in aortic rings of hypophysectomized rats [20]. In hypopituitary adults, hexarelin treatment increased the basal left ventricular ejection fraction [21••]. Therefore, the cardioprotective effects of hexarelin are, at least partially, GH-independent. In support of these direct effects of hexarelin, a hexarelin-binding protein (Mr = 84,000) was characterized in rat cardiac membranes. Hexarelin binding was displaced by GHS-R peptide ligands but not by MK-0677, suggesting the involvement of a GHS-R subtype that regulates coronary vascular tone [22].
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1.1.5.2.4(iii)(d) Other transmitters
Morphine microinjections before introduction of an estrous female prevented both noncontact erections and the rise in NO that occurred in control rats (Melis et al., 1999b). Hexarelin analog peptides, which were originally known for their ability to induce growth hormone release, activate specific receptors on OT neurons in the PVN to admit calcium and thereby stimulate NOS in the OT neurons and elicit erections (reviewed in Argiolas and Melis (2005)). A cannabinoid CB1 antagonist, microinjected into the PVN, elicited erections, an effect reduced by CB1 agonists, an NMDA antagonist, and an NOS inhibitor in the PVN, and by an ICV OT antagonist (Melis et al., 2004b). The CB1 receptors in the PVN are mostly on GABAergic terminals, which in turn impinge on both OT and glutamatergic neurons (Castelli et al., 2007). The authors note that one would expect inhibition of the inhibitory CB1 receptors to increase GABA release; however, they suggest that stimulation of CB1 receptors may inhibit GABA reuptake in the PVN; therefore, blocking CB1 receptors would increase GABA reuptake and disinhibit glutamatergic and OT neurons. Thus, the mechanism of CB1 antagonists' effects is not clear. Pro-VGF-derived peptides are cleavage products of VFG, the product of the vgf gene, which is selectively induced by nerve growth factor (see references in Argiolas and Melis (2005)). They may activate OT neurons in the PVN and thereby facilitate erections; their effects are inhibited by both NOS and OT antagonists (reviewed in Argiolas and Melis (2005)).
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Different ghrelin variants might also explain the diverse signalling of the GHS-R. The acylation of ghrelin typically involves an octanoic acid but other types of esterification have also been observed (Chan and Cheng, 2004; Davenport et al., 2005; Kojima et al., 1999; Kojima and Kangawa, 2005). Moreover, novel putative ghrelin transcripts have been described which possibly may be produced independent of preproghrelin and translated into novel peptides (Seim et al., 2007). Some of these and other described ghrelin variants include an exon-4 variant C-peptide and an In2 variant (Jeffery et al., 2005; Kineman et al., 2007; Seim et al., 2007). Another ghrelin form is the mouse ghrelin gene-derived transcript (GGDT), specifically expressed in the testis. Its expression is developmentally regulated and a variant with a unique C-terminus is expressed in multiple tissues (Jeffery et al., 2005; Tanaka et al., 2001). In addition, alternative splicing of preproghrelin gene yields des-Gln ghrelin which lacks Gln at residue 14 (Hosoda et al., 2000). Des-Gln-ghrelin, present in smaller amounts in the blood, has similar potency and efficacy compared to a full-length acyl-ghrelin. In addition, ghrelin and GHS have differential GHS-R1a potencies and efficacies and additional signalling pathways besides Gq have also been reported (Muccioli et al., 2007). Peptidic (GHRP-6, Ghrelin) and non-peptidic molecules (MK-0677) were reported to have differences in binding activities and studies using hexarelin as tracer supports the existence of several receptors (Cassoni et al., 2001). In addition, ligands other than ghrelin might also act on the GHS-R. Indeed, recent data demonstrated the ability of growth-hormone releasing hormone (GHRH) to modulate the ghrelin receptor, demonstrates ligand promiscuity of the GHS-R1a. Even though, the GH secreting activity of GHRH is not dependent on GHS-R expression, GHRH itself is able to bind to the GHS-R and does not compete for binding against ghrelin but increases the affinity of ghrelin to the receptor (Casanueva et al., 2008). Equally, the ghrelin-mediated GH release is independent of GHRH and ghrelin even gives a stronger release of GH compared to GHRH (Takaya et al., 2000). Nevertheless, GHRH increases the maximal response of ghrelin in inositol phosphate turnover assays through Gq-associated signal transduction and also increases the potency in a calcium assay, demonstrating that GHRH acts as an allosteric modulator on the receptor (Casanueva et al., 2008). This might implicate that other endogenous ligands can be promiscuous on the GHS-R receptor and modulate signalling in a similar matter. The existence of additional functional endogenous ghrelin variants or other ligands is very interesting. Different endogenous ligands can have different affinities for their cognate receptors and can mediate distinct effects on receptor signalling (Rashid et al., 2004). They might also induce different rates of desensitization and internalization. Moreover, differential expression of receptor subtypes and ghrelin variants across several tissues might explain the differential ghrelin signalling and the plethora of biological activities of ghrelin. Thus, this new emerging model of GHS-R activation may possibly explain the diverse biological actions of ghrelin and GHS-R by differential signalling of multiple endogenous ligands and receptor subtypes and the differential expression across tissues.
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It has been known since the mid 1980s that intranasal administration of GHRH(1–44) and GHRH(1–29) coupled with a promoter raises serum GH levels, however, with a low bioavailability [10]. It was shown later that GHRH(1–29) raises GH levels in a dose-dependent manner [30], but prolonged administration is prohibited by poor efficacy, poor tolerability and by the appearance of antibodies directed against GHRH [31]. The availability of GH-releasing peptides, a family of peptides that are five to seven amino acids long, has led to a renewal of interest in intranasal administration. After acute administration, bioavailability is around 8% without promoters, and the effect of the hexapeptide on GH release is greater and more reproducible than GHRH(1–29) [32–34]. A six-month trial, with thrice daily administration, has shown the hexapeptide to be effective in increasing serum insulin-growth factor-I (IGF-I) levels and in enhancing growth velocity in children, without causing significant side effects [35]. Chronic, intermittent intranasal administration of hexarelin has been shown to increase IGF and IGF-binding protein 3 (IGFBP3) in elderly subjects, suggesting that this peptide can restore the reduced GH release of these subjects [36].
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1.1.5.2.4(i) Anatomy
The PVN is an important integrative site for endocrine and autonomic functions. It comprises a parvocellular division, which projects to several brain areas and the spinal cord, and a magnocellular division, which releases OT and vasopressin from the posterior pituitary (reviewed in Swanson and Sawchenko (1980)). Axons that project to the spinal cord release OT, vasopressin, somatostatin, DA, and other, undetermined transmitters. Periventricular DA neurons and brainstem NE and 5-HT nuclei provide input to the parvocellular PVN. The PVN is important for noncontact erections and seminal emission, but is less critical for reflexive erections and copulation. DA, glutamate, NO, and hexarelin analog peptides stimulate OTergic neurons that project to several brain areas and the spinal cord (reviewed in Argiolas and Melis (2005)). GABA and opioid peptides inhibit those neurons.
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7 PPARγ and candidate peptides as targets for the development of anticonvulsant drugs
Several endogenous peptides, such as adrenocorticotropic hormone, angiotensin II, cholecystokinin, cortistatin, dynorphin, galanin, ghrelin, neuropeptide Y, neurotensin, somatostatin, and thyrotropin-releasing hormone, seem to suppress epileptic seizures. At variance, other neuropeptides, including arginine-vasopressin peptide, corticotropin-releasing hormone, enkephalin, β-endorphin, pituitary adenylate cyclase-activating polypeptide, and tachykinins have proconvulsive effects (Biagini et al., 2011; Clynen, Swijsen, Raijmakers, Hoogland, & Rigo, 2014; Costa et al., 2022; Giordano et al., 2016; Lucchi et al., 2017). In this paragraph, we will focus on the ghrelin receptor antagonist EP-80317, which displayed anticonvulsant effects in the 6-Hz corneally stimulated mice through PPARγ involvement (Lucchi et al., 2017).
EP-80317 (Haic-D-Mrp-D-Lys-Trp-D-Phe-Lys-NH2) is a hexapeptide with a primary structure similar to that of hexarelin. However, it differs for substitutions in the first and third amino acid residues causing the loss of the growth hormone (GH)-releasing properties possessed by hexarelin (Momany et al., 1981). In our studies, we demonstrated that EP-80317 displays anticonvulsant effects in the pilocarpine model and in the repeated 6-Hz corneal stimulation model (Biagini et al., 2011; Giordano et al., 2016; Lucchi et al., 2017). Moreover, we found that GW9662, an inhibitor of PPARγ activity, is able to limit the beneficial effects of EP-80317 in both the animal models. In addition to this, PPARγ immunoreactivity was transiently increased in pyramidal cells and interneurons belonging to parvalbumin and somatostatin-28 subclasses, in coincidence with the anticonvulsant effects of EP-80317 in the repeated 6-Hz corneal stimulation model. Overall, these findings suggested that PPARγ is able to modulate seizures and mediates the anticonvulsant effects of EP-80317 (Lucchi et al., 2017).
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I Introduction
Growth hormone (GH) secretion from the pituitary gland is under the regulation of two hypothalamic hormones, GH-releasing hormone (GHRH) and somatotropin release-inhibiting factor (SRIF; somatostatin). GHRH stimulates GH release whereas SRIF inhibits GH secretion. Development of synthetic GH-releasing peptides (GHRPs) (i.e., GHRP-6, hexarelin) that stimulate GH secretion through a non-GHRH receptor has led to the hypothesis that there are unique, endogenous GH-releasing peptides distinct from GHRH. This non-GHRH receptor has been determined to be a growth hormone secretagogue receptor. Cloning of a novel G-protein-coupled receptor for the GH-releasing peptides bolstered the hypothesis of unique GH-releasing peptides, and, more recently, the endogenous ligand for the growth hormone secretagogue receptor was cloned. Two separate groups concurrently characterized and named the native ligand, one group calling the peptide ghrelin and the other group naming it motilin-related peptide. Ghrelin is the name used in this article.
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