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peptide science.

Age-related loss of skeletal muscle function; impairment of gene expression.

J Musculoskelet Neuronal Interact

G Goldspink

Mechano Growth Factor (MGF) is derived from the insulin-like growth factor (IGF-I) but its sequence differs from the systemic IGF-I produced by the liver. MGF is expressed by mechanically overloaded muscle and is involved in tissue repair and adaptation. It is expressed as a pulse following muscle damage and involved in the activation of muscle satellite (stem) cells. These donate nuclei to the muscle fibers that are required for repair and for the hypertrophy processes which may have similar regulatory mechanisms. Muscles in the elderly are unable to upregulate MGF in response to exercise. This is also true in certain diseases and this helps to explain muscle loss in those conditions. There is evidence that MGF is a local tissue repair factor as well as a growth factor and that it has an important role in damage limitation and inducing repair in other post-mitotic tissues. As there is no cell replacement in these tissues there has to be an effective local cellular repair mechanism. With advancing years this seems to become deficient and there is an increased chance that the damaged cells will undergo cell death leading to progressive loss of tissue function.

[Ghrelin-related drugs: clinical perspectives].

Nihon Rinsho

Akira Shimatsu

Thymulin and the neuroendocrine system.

Peptides

Rodolfo G Goya, Oscar A Brown, Jean-Marie Pléau +1 more

Thymulin is a thymic hormone exclusively produced by the thymic epithelial cells. It consists of a nonapeptide component coupled to the ion zinc, which confers biological activity to this molecule. After its discovery in the early 1970, thymulin was characterized as a thymic hormone involved in several aspects of intra- and extrathymic T-cell differentiation. Subsequently, it was demonstrated that thymulin production and secretion is strongly influenced by the neuroendocrine system. Conversely, an emerging core of information points to thymulin as a hypophysotropic peptide. Here we review the evidence supporting the hypothesis that thymulin is an important player in the hypophyso-thymic axis.

Hexarelin modulates the expression of growth hormone secretagogue receptor type 1a mRNA at hypothalamic and pituitary sites.

Neuroendocrinology

Elena Bresciani, Ralf Nass, Antonio Torsello +5 more

Ghrelin and the synthetic growth hormone secretagogues (GHSs) activate a G-protein-coupled receptor (GHS-R) originally cloned from the pituitary, but which is also expressed in the hypothalamus, in other areas of the brain and in numerous peripheral tissues. Several studies have shown that growth hormone (GH)-releasing hormone (GHRH) is necessary for GHSs to exert maximal GH release in vivo. The exact mechanism of this synergism is not clear. Previous data suggest that GHSs can affect pituitary GHS-R mRNA expression; however, it is unknown whether this effect is age dependent and whether hypothalamic GHS-Rs are also affected. In this study, we tested whether (a) the synthetic GHS hexarelin regulates mRNA expression of its own receptor at the pituitary and/or hypothalamus and whether this effect is age dependent, and (b) whether short-term treatment with GHRH or, conversely, passive immunization against GHRH affects pituitary GHS-R1a mRNA expression in infant (10 days old) and young adult rats. GHS-R1a mRNA expression was measured with competitive reverse transcriptase-polymerase chain reaction. Hexarelin treatment significantly increased pituitary and hypothalamic GHS-R1a mRNA levels in normal infant rats, but not in normal young adult rats. In addition, hexarelin administration also stimulated pituitary GHS-R1a mRNA in infant as well as in young adult rats passively immunized against GHRH. GHRH treatment significantly enhanced pituitary GHS-R1a mRNA expression in GHRH-deprived young adult rats, though it did not affect the basal levels of GHS-R1a mRNA in normal infant and adult rats. These data further support the hypothesis that GHRH can affect GHS-R1a expression and that hexarelin upregulates the expression of its own receptor at the pituitary as well as the hypothalamus in an age-dependent fashion.

Urocortins: take them to heart.

Curr Med Chem Cardiovasc Hematol Agents

Tiziano Scarabelli, Richard Knight

The urocortins, together with corticotropin releasing hormone (CRH), have a long evolutionary pedigree. In the brain, CRH largely mediates anxiogenic effects associated with the stress response, while the urocortins are concerned with adaptive and coping behaviour. The urocortins, in particular, are also expressed in peripheral sites, including the heart. Here, they may play an autocrine/paracrine role, since CRH-R2 receptor subtypes, which preferentially bind the urocortins, are also expressed in the heart. Endogenous cardiac urocortin expression is enhanced by ischaemia/reperfusion injury in vitro, and addition of exogenous urocortins reduces cell death caused by ischaemia/reperfusion in vitro, ex vivo and in vivo. In the isolated perfused heart, urocortin improves haemodynamic recovery, and partially prevents the reduction in high energy phosphates following ischaemia/reperfusion. Urocortin-mediated cardioprotection involves several mechanisms, including increased expression of Kir6.1 K(ATP) channels and HSP90, although other as yet poorly understood mechanisms have also been implicated. Moreover, there is early data suggesting that urocortin has beneficial haemodynamic effects in an ovine model of heart failure, and further studies of the value of both endogenous and exogenous urocortins in the compromised heart are clearly needed. In man, there is suggestive, though indirect, data, that urocortin may also provide an endogenous myocyte salvage mechanism against iatrogenic ischaemia/reperfusion injury associated with bypass surgery. These experimental studies suggest that assessment of the clinical use of urocortins as direct and/or cardioplegic therapies in ischaemia/reperfusion, and maybe heart failure, should be actively pursued.

Neonatal quinpirole treatment impairs Morris water task performance in early postweanling rats: relationship to increases in corticosterone and decreases in neurotrophic factors.

Biol Psychiatry

Russell W Brown, Timothy J Flanigan, Kimberly N Thompson +3 more

Past studies from this laboratory have shown that quinpirole administration from postnatal day (P) 1-21 produces persistent supersensitization of the dopamine D2 receptor that persists throughout the animal's lifetime.

Elucidation of the effect of brain cortex tetrapeptide Cortagen on gene expression in mouse heart by microarray.

Neuro Endocrinol Lett

Sergey V Anisimov, Vladimir Kh Khavinson, Vladimir N Anisimov

Aging is associated with significant alterations in gene expression in numerous organs and tissues. Anti-aging therapy with peptide bioregulators holds much promise for the correction of age-associated changes, making a screening for their molecular targets in tissues an important question of modern gerontology. The synthetic tetrapeptide Cortagen (Ala-Glu-Asp-Pro) was obtained by directed synthesis based on amino acid analysis of natural brain cortex peptide preparation Cortexin. In humans, Cortagen demonstrated a pronounced therapeutic effect upon the structural and functional posttraumatic recovery of peripheral nerve tissue. Importantly, other effects were also observed in cardiovascular and cerebrovascular parameters.

Corticotrophin releasing factor-induced synaptic plasticity in the amygdala translates stress into emotional disorders.

J Neurosci

Donald G Rainnie, Richard Bergeron, Tammy J Sajdyk +3 more

The amygdala is involved in the associative processes for both appetitive and aversive emotions, and its function is modulated by stress hormones. The neuropeptide corticotrophin releasing factor (CRF) is released during stress and has been linked to many stress-related behavioral, autonomic, and endocrine responses. In the present study, nonanxiety-inducing doses of a potent CRF type 1 and 2 receptor agonist, urocortin (Ucn), was infused locally into the basolateral amygdala (BLA) of rats. After 5 daily injections of Ucn, the animals developed anxiety-like responses in behavioral tests. Intravenous administration of the anxiogenic agent sodium lactate elicited robust increases in blood pressure, respiratory rate, and heart rate. Furthermore, in the absence of any additional Ucn treatment, these behavioral and autonomic responses persisted for >30 d. Whole-cell patch-clamp recordings from BLA neurons of these hyper-reactive animals revealed a pronounced reduction in both spontaneous and stimulation-evoked IPSPs, leading to a hyperexcitability of the BLA network. This Ucn-induced plasticity appears to be dependent on NMDA receptor and subsequent calcium-calmodulin-dependent protein kinase II (CaMKII) activation, because it is blocked by pretreatment with NMDA receptor antagonists and by coadministration of CaMKII inhibitors. Our results show for the first time a stress peptide-induced behavioral syndrome that can be correlated with cellular mechanisms of neural plasticity, a novel mechanism that may explain the etiological role of stress in several chronic psychiatric and medical disorders.

Melanocortin 4 receptor-mediated hyperphagia and activation of neuropeptide Y expression in the dorsomedial hypothalamus during lactation.

J Neurosci

Peilin Chen, Sarah M Williams, Kevin L Grove +1 more

In several hyperphagic models, including lactation, in which hypothalamic melanocortin signaling is reduced, a novel expression of NPY mRNA in the dorsomedial hypothalamus (DMH) has been observed, suggesting that melanocortin signaling and the induced NPY in the DMH may constitute unique neurocircuitry in mediating energy balance. Using lactating rats as a model, the present study first showed that in the DMH abundant alpha-MSH and agouti-related protein fibers are in close apposition to NPY-positive cells. However, no NPY and MC4R (a melanocortin receptor) double-labeled neurons were observed. These data suggested that melanocortin input may synapse on presynaptic terminals that then synapse on DMH NPY cells. To study the function of DMH MC4Rs in energy balance, an MC3/4R-selective agonist, melanotan II (MTII), was injected bilaterally into the DMH. MTII injection significantly suppressed feeding induced by 24 hr fasting or suckling-induced hyperphagia. Furthermore, MTII treatment greatly attenuated suckling-induced NPY expression in the DMH. MTII treatment also stimulated uncoupling protein 1 activity in the brown adipose tissue of suckling female rats, indicative of increased sympathetic outflow. In summary, the present study demonstrated that the melanocortin system in the DMH not only plays an important role in inducing NPY expression in the DMH of lactating rats but also in regulating energy homeostasis, at least in part, by modulating appetite and energy expenditure.

Neurotensin, schizophrenia, and antipsychotic drug action.

Int Rev Neurobiol

Becky Kinkead, Charles B Nemeroff

The search for the underlying pathophysiology of schizophrenia has been an active avenue of investigation since the disease was first recognized more than 100 years ago. Although a great deal of the research has been driven by the known pharmacology of effective antipsychotic drugs, i.e., overactivity of the dopamine system, recent advances in neurobiology provide evidence that reduced synaptic connectivity/neurotransmission may play a substantial role in this disorder. One neuropeptide long posited to play a role in the biology of schizophrenia is neurotensin (NT). Central nervous system administration of NT has been shown to produce a wide variety of effects. Because of its close association with the dopamine (DA) system, the role of the NT system in clinical disorders hypothesized to involve DA circuits such as schizophrenia, Parkinson's disease, and drug abuse has been closely scrutinized. In addition, NT neurotransmission has been implicated in regulation of the stress response, stress-induced gastric ulcers, temperature regulation, food consumption, and analgesia. NT also acts as a growth factor in a variety of human cancer cell lines derived from lung, colon, prostate, and pancreas. This review first provides a background of the NT system. Second, data indicating that NT may mediate the effects of antipsychotic drugs are summarized. Third, data implicating NT in the pathophysiology of schizophrenia are described. Finally, evidence suggesting the use of NTergic compounds as novel antipsychotic drugs are presented.

Selank and short peptides of the tuftsin family in the regulation of adaptive behavior in stress.

Neurosci Behav Physiol

M M Kozlovskaya, I I Kozlovskii, E A Val'dman +1 more

White laboratory male rats, inbred male C57BL/6 and Balb/c mice, and male Wistar rats, all previously divided on the basis of the type of emotional reactivity, were used to compare the effects of ten peptide compounds of the tuftsin family and Selank on the behavioral manifestations of emotional stress created by a conflict situation. Peptides were shown to have positive emotional effects and antistress actions. Individual physiologically significant effects were seen, due to the molecular structures of the study peptides and/or their degradation fragments. The results demonstrate the potential for the synthesis of peptide compounds with predictable directions of pharmacological actions and safe for wide use.

Growth hormone secretagogues modulate the electrical and contractile properties of rat skeletal muscle through a ghrelin-specific receptor.

Br J Pharmacol

Sabata Pierno, Annamaria De Luca, Jean-François Desaphy +7 more

(1) Growth hormone secretagogues (GHS) exhibit potent growth hormone (GH)-releasing activity through the activation of a pituitary receptor. Here, we consider the possibility that GHS can target a specific receptor in rat skeletal muscle and have a role in the control of muscle function. (2) By means of the intracellular microelectrode technique, we found that in vitro application of hexarelin and L-163,255 dose dependently reduced resting chloride (gCl) and potassium (gK) conductances in rat skeletal muscle. These effects were prevented by the GHS-receptor antagonist [D-Lys-3]-GHRP-6, and by either phospholipase C or protein kinase C (PKC) inhibitors. Ghrelin, a natural ligand of GHS receptors, also induced a reduction of muscle gCl and gK, which was antagonised by [D-Lys-3]-GHRP-6. (3) Both GHS shifted the mechanical threshold for the contraction of muscle fibres towards more negative voltages. Accordingly, by means of FURA-2 fluorescent measurements, we demonstrated that L-163,255 induced a resting [Ca(2+)](i) increase, which was reversible and not blocked by nifedipine or removal of external Ca(2+). (4) Ageing is a condition characterised by a deficit of GH secretion, which in turn modifies the electrical and contractile properties of skeletal muscle. In contrast to GH, chronic treatment of aged rats with hexarelin or L-163,255 failed to restore the electrical and contractile muscle properties. Moreover, the two GHS applied in vitro were able to antagonise the beneficial effect on gCl and gK obtained through chronic treatment of aged animals with GH. (5) Thus, skeletal muscle expresses a specific GHS receptor able to decrease gCl and gK through a PKC-mediated intracellular pathway. This peripheral action may account for the lack of restoration of skeletal muscle function in long-term GHS-treated aged animals.

Expression and splicing of the insulin-like growth factor gene in rodent muscle is associated with muscle satellite (stem) cell activation following local tissue damage.

J Physiol

Maria Hill, Geoffrey Goldspink

Muscle satellite cells are mononuclear cells that remain in a quiescent state until activated when they proliferate and fuse with muscle fibres to donate nuclei, a process necessary for post-embryonic growth, hypertrophy and tissue repair in this post-mitotic tissue. These processes have been associated with expression of the insulin-like growth factor (IGF-I) gene that can undergo alternative splicing to generate different gene products with varying functions. To gain insight into the cellular mechanisms involved in local tissue repair, the time courses of expression of two IGF-I splice variants produced in muscle were determined together with marker genes for satellite cell activation following local muscle damage. Using real-time RT-PCR with specific primers, the mRNA transcripts in rat tibialis anterior muscles were measured at different time intervals following either mechanical damage imposed by electrical stimulation of the stretched muscle or damage caused by injection with bupivacaine. It was found that the autocrine splice variant mechano growth factor (MGF) was rapidly expressed and then declined within a few days following both types of damage. Systemic IGF-IEa was more slowly upregulated and its increase was commensurate with the rate of decline in MGF expression. Satellite cell activation as measured by M-cadherin and one of the muscle regulatory factors MyoD and the sequence of expression suggests that the initial pulse of MGF is responsible for satellite cell activation, as the systemic IGF-IEa mRNA expression peaks after the expression of these markers, including M-cadherin protein. Later splicing of the IGF-I gene away from MGF but towards IGF-IEa seems physiologically appropriate as IGF-IEa is the main source of mature IGF-I for upregulation of protein synthesis required to complete the repair.

Interaction of the novel GH secretagogue hexarelin with GHRH in regulating the secretion of GH by cultured human pituitary somatotrophinomas in vitro.

J Tongji Med Univ

Q Liu, T Lei, K Liu +2 more

The effects of the novel GH-releasing hexapeptide, Hexarelin, on the secretion of GH in cultured human pituitary somatotrophinomas was further investigated. Hexarelin (20 nmol/L) strongly stimulated GH secretion, which could be reduced by phloretin, but not by RP-cAMPS, an inhibitor of protein kinase A (PKA). (Ac-Tyr1,D-Arg2)-GRF(1-29)-NH2 failed to block the effects of Hexarelin but completely abolished the stimulation of GH secretion exerted by GHRH. When added alone to somatotrophinoma cell cultures, Hexarelin had no effect on cAMP levels, but it potentiated the stimulatory effects of GHRH. These results demonstrated that Hexarelin could directly stimulate GH secretion by human pituitary somatotrophs PKC-dependently, which might be contributed to the activation of the PI transduction system. In addition, Hexarelin could interact with GHRH on the adenylyl cyclase system.

Effects of the novel GH secretogogue, hexarelin on GH secretion and phosphatidylinositol hydrolysis by human pituitary somatotrophinomas in cell culture.

J Tongji Med Univ

Q Liu, T Lei, K Liu +2 more

The effects of the novel GH-releasing hexapeptide, Hexarelin, on cultured human pituitary somatotrophinomas were investigated. Hexarelin (0.01-100 nmol/L) dose-dependently stimulated GH secretion up to 4.6-fold. Maximal effects occurred with 10 nmol/L. These effects were very similar to those observed with GHRP-6. The effects of Hexarelin were reduced by phloretin, an inhibitor of protein kinase C (PKC). The rate of phosphatidylinositol (PI) hydrolysis was markedly increased by Hexarelin in a dose-dependent manner. These results demonstrated that Hexarelin could directly stimulate GH secretion by human pituitary somatotrophs in a PKC-dependent manner, probably via activation of the PI transduction system.

Exploring the site of anorectic action of peripherally administered synthetic melanocortin peptide MT-II in rats.

Brain Res

Prashant Trivedi, Michael Jiang, Constantin C Tamvakopoulos +6 more

Melanotan-II (MT-II), a cyclic heptapeptide, is a potent, non-selective melanocortinergic agonist. When administered centrally or systemically, MT-II elicited a profound inhibitory effect on food intake in rodents, presumably via activation of melanocortin-4-receptor (MC4R). In this study, we sought to investigate whether penetration of MT-II and iodo-MT-II into brain parenchyma is required for the anorectic effect following intravenous (IV) administration. Firstly, both MT-II and iodo-MT-II were effective at suppressing appetite in rats following their IV administration. We next surveyed by in vitro autoradiographic studies the distribution of selective (125)I-MT-II binding sites in multiple brain regions including areas important for feeding regulation such as the hypothalamus and caudal brainstem. Upon IV administration of (125)I-MT-II, significant radioactivity could not be detected in various brain regions by autoradiography except for a group of circumventricular organs (CVOs), which are anatomically situated outside the blood-brain barrier (BBB). The most intensely labeled CVOs include the subfornical organ, median eminence, area postrema and choroid plexus, and accumulation of radioactivity at these sites can be blocked by co-injection of excess unlabeled MT-II. Direct measurement of MT-II in the brain and plasma by LC-MS-MS following IV injection confirmed that the degree of MT-II penetration into the brain is negligible. Furthermore, when given peripherally under conditions that suppressed food intake, MT-II did not result in a detectable induction of c-Fos-like immunoreactivity in brain regions where a significantly elevated c-Fos expression was observed following intracerebroventricular injection of this peptide. Our results indicate that MT-II has a very limited brain penetration capability, and its effect on feeding behavior following systemic administration may be mediated by either the brain regions in close proximity to the CVOs or sites outside of the BBB, including CVOs or other peripheral systems.

GHRP-6 is able to stimulate cortisol and ACTH release in patients with Cushing's disease: comparison with DDAVP.

J Endocrinol Invest

J H A Oliveira, J G H Vieira, J Abucham +1 more

It has been shown that hexarelin stimulates ACTH and cortisol secretion in patients with Cushing's disease. The ACTH release induced by this peptide is 7-fold greater than that obtained by hCRH. The mechanism of action of hexarelin on the hypothalamic-pituitary-adrenal axis has not been fully elucidated. Although controversial, there is evidence that it might be mediated by arginine vasopressin (AVP). The aim of this study was to evaluate the ACTH and cortisol releasing effects of GHRP-6 in patients with Cushing's disease and to compare them with those obtained with DDAVP administration. We studied 10 patients with Cushing's disease (8 female, 2 male; age: 36.7 +/- 4.2 yr), 9 with microadenomas, who were submitted to both GHRP-6 (2 microg/kg iv) and DDAVP (10 micro g i.v.) in bolus administration on 2 separate occasions. ACTH was measured by immunochemiluminometric assay and cortisol by radioimmunoassay. The sensitivities of the assays are 0.2 pmol/l for ACTH, and 11 nmol/l for cortisol. GHRP-6 was able to increase significantly both ACTH (pmol/l, mean +/- SE; basal: 15.5 +/- 1.7 vs peak: 45.1 +/- 9.3) and cortisol values (nmol/l, basal: 583.0 +/- 90.8 vs peak: 1013.4 +/- 194.6). ACTH AUC (pmol/l min(-1)) and cortisol AUC (nmol/l min(-1)) values were 1235.4 and 20577.2, respectively. After DDAVP administration there was a significant increase in ACTH (basal: 13.0 +/- 1.4 vs peak: 50.5 +/- 16.2) and cortisol levels (basal: 572.5 +/- 112.7 vs peak: 860.5 +/- 102.8. AUC values for ACTH and cortisol were 1627.6 +/- 639.8 and 18364.7 +/- 5661.4, respectively. ACTH and cortisol responses to GHRP-6 and DDAVP did not differ significantly (peak: 45.1 +/- 9.3 vs 50.5 +/- 16.2; AUC: 1235.4 +/- 424.8 vs 1627.6 +/- 639.8). There was a significant positive correlation between peak cortisol values after GHRP-6 and DDAVP administration (r = 0.87, p = 0.001). Our results show that GHRP-6 is able to stimulate ACTH and cortisol release in patients with Cushing's disease. These responses are similar to those obtained after DDAVP injection. These findings could suggest the hypothesis that both peptides act by similar mechanisms, either at hypothalamic or pituitary level.

GVS-111 prevents oxidative damage and apoptosis in normal and Down's syndrome human cortical neurons.

Int J Dev Neurosci

Alejandra Pelsman, Carlos Hoyo-Vadillo, Tatiana A Gudasheva +3 more

The neuroprotective activity of a novel N-acylprolyl-containing dipeptide analog of the nootropic 2-oxo-1-pyrrolidine acetamide (Piracetam) designated as GVS-111 (DVD-111/Noopept) was tested in two in vitro models of neuronal degeneration mediated by oxidative stress: normal human cortical neurons treated with H(2)O(2), and Down's syndrome (DS) cortical neurons. Incubation of normal cortical neurons with 50 microM H(2)O(2) for 1h resulted in morphological and structural changes consistent with neuronal apoptosis and in the degeneration of more than 60% of the neurons present in the culture. GVS-111 significantly increased neuronal survival after H(2)O(2)-treatment displaying a dose-dependent neuroprotective activity from 10nM to 100 microM, and an IC(50) value of 1.21+/-0.07 microM. GVS-111 inhibited the accumulation of intracellular free radicals and lipid peroxidation damage in neurons treated with H(2)O(2) or FeSO(4), suggesting an antioxidant mechanism of action. GVS-111 exhibited significantly higher neuroprotection compared to the standard cognition enhancer Piracetam, or to the antioxidants Vitamin E, propyl gallate and N-tert-butyl-2-sulpho-phenylnitrone (s-PBN). In DS cortical cultures, chronic treatment with GVS-111 significantly reduced the appearance of degenerative changes and enhanced neuronal survival. The results suggest that the neuroprotective effect of GVS-111 against oxidative damage and its potential nootropic activity may present a valuable therapeutic combination for the treatment of mental retardation and chronic neurodegenerative disorders.

Galanin: a biologically active peptide.

Curr Drug Targets CNS Neurol Disord

Maria E Vrontakis

Galanin is a biologically active neuropeptide, widely distributed in the central and peripheral nervous systems and the endocrine system. The amino acid sequence of galanin is very conserved (almost 90% among species), indicating the importance of the molecule. Galanin has multiple biological effects. In the central nervous system, galanin alters the release of several neurotransmitters. In particular the ability of galanin to inhibit acetylcholine release, along with the observation of hyperinervation of galanin fibres in the human basal forebrain of Alzheimer's disease patients, suggest a possible role for galanin in the cholinergic dysfunction, characteristic of the disease. Moreover, galanin has been suggested to be involved in other neuronal functions, such as learning and memory, epileptic activity, nociception, spinal reflexes and feeding. Galanin has also been shown to increase the levels of growth hormone, prolactin and luteinizing hormone, to inhibit glucose induced insulin release and to affect gastrointestinal motility. The expression of galanin (mRNA and peptide levels) is elevated following estrogen administration, neuronal activation, denervation and/or nerve injury, as well as during development. The spectrum of galanin's activities indicates that galanin is an important messenger for intercellular communication within the nervous system and the neuroendocrine axis. Galanin acts at specific membrane receptors to exert its effects; so far three human and rodent galanin receptor subtypes have been cloned. Galanin agonists have been shown to have therapeutic application in treatment of chronic pain; galanin antagonists have therapeutic potential in treatment of Alzheimer's disease, depression, and feeding disorders.

Ghrelin plays a minor role in the physiological control of cardiac function in the rat.

Endocrinology

Antonio Torsello, Elena Bresciani, Giuseppe Rossoni +7 more

We have previously reported that a 7-d pretreatment with hexarelin, a synthetic ligand of the GH secretagogue receptor (GHS-R), largely prevented damages induced by ischemia and reperfusion in isolated rat hearts. Our aim was to ascertain whether ghrelin, an endogenous ligand of the GHS-R, is physiologically endowed with cardioprotective activity. Hypophysectomized rats were treated in vivo for 7 d with either ghrelin (320 microg/kg) or hexarelin (80 microg/kg), and their hearts were subjected in vitro to the ischemia and reperfusion procedure. Ghrelin was far less effective than hexarelin in preventing increases in left ventricular end-diastolic pressure (15% and 60% protection for ghrelin and hexarelin, respectively), coronary perfusion pressure (10% and 45% reduction), and release of creatine kinase in the heart perfusate (15% and 55% reduction). In the second experiment, normal rats were passively immunized against ghrelin for 21 d before the ischemia and reperfusion procedure. In these isolated hearts, the ischemia-reperfusion damage was not significantly increased compared with control rats. After hypophysectomy, CD36 mRNA levels significantly increased, whereas those of atrial natriuretic factor significantly decreased. We conclude that: 1) ghrelin plays a minor role in the control of heart function; and 2) hexarelin effects are mediated in part by the GHS-R and largely by interactions with the CD36.