Growth hormone secretagogue receptor type 1A (GHSR-1A) is a functional receptor of orexigenic peptide ghrelin and is highly expressed in mesolimbic dopaminergic systems that regulate incentive value of artificial reward in substance abuse. Interestingly, GHSR-1A has also shown ligand-independent constitutive activity. Alcohol use disorder (AUD) is one of the growing concerns worldwide as it involves complex neuro-psycho-endocrinological interactions. Positive correlation of acylated ghrelin and alcohol-induced human brain response in the right and left ventral striatum are evident. In the last decade, the beneficial effects of ghrelin receptor (GHSR-1A) antagonism to suppress artificial reward circuitries and induce self-control for alcohol consumption have drawn significant attention from researchers. In this updated review, we summarize the available recent preclinical, clinical, and experimental data to discuss functional, molecular actions of central ghrelin-GHSR-1A signaling in different craving levels for alcohol as well as to promote \"GHSR-1A antagonism\" as one of the potential therapies in early abstinence.

The review presents data on the expression of ghrelin receptor GHS-R1a in the brain in model animals (Danio rerio, rodents, primates), and in the human brain. Studies show widespread localization of GHS-R1a in the brain, which indicates the involvement of the receptor in many physiological processes. Using various models, information has been obtained regarding the participation of the receptor in the regulation of the pro- and anti-inflammatory response, apoptosis and proliferation. It is known that the ghrelin receptor plays an important role in eating behavior and is also involved in the pathogenetic mechanisms of obesity, drug addiction, and alcoholism. With this in mind, research is underway with the use of various therapeutic agents (receptor agonists and antagonists) that can be used for the pharmacological correction of these pathological conditions. This review also presents hypothetical mechanisms of intracellular signaling, in which GHS-R1a may participate; however, a complete understanding of these mechanisms has not yet been reached. The ghrelin intracellular pathways seem to be specific to brain region and, probably, also depend on the metabolic or stress status of the organism.

Ghrelin, an orexigenic hormone, is a peptide that binds to the growth hormone secretagogue receptor; it is secreted mainly by enteroendocrine cells in the oxyntic glands of the stomach. Ghrelin serves a role in both local and systemic physiological processes, and is implicated in various pathologies, including neoplasia, with tissue expression in several types of malignancies in both in vitro and in vivo studies. However, the precise implications of the ghrelin axis in metastasis, invasion and cancer progression regulation has yet to be established. In the case of gastrointestinal (GI) tract malignancies, ghrelin has shown potential to become a prognostic factor or even a therapeutic target, although data in the literature are inconsistent and unsystematic, with reports untailored to a specific histological subtype of cancer or a particular localization. The evaluation of immunohistochemical expression shows a limited outlook owing to the low number of cases analyzed, and in vivo analyses have conflicting data regarding differences in ghrelin serum levels in patients with cancer. The aim of this review was to examine the relationship between ghrelin and GI tract malignancies to demonstrate the inconsistencies in current results and to highlight its clinical significance in the outcome of these patients.

Sepsis continues to produce widespread inflammation, illness, and death, prompting intensive research aimed at uncovering causes and therapies. In this article, we focus on ghrelin, an endogenous peptide with promise as a potent anti-inflammatory agent. Ghrelin was discovered, tracked, and isolated from stomach cells based on its ability to stimulate release of growth hormone. It also stimulates appetite and is shown to be anti-inflammatory in a wide range of tissues. The anti-inflammatory effects mediated by ghrelin are a result of both the stimulation of anti-inflammatory processes and an inhibition of pro-inflammatory forces. Anti-inflammatory processes are promoted in a broad range of tissues including the hypothalamus and vagus nerve as well as in a broad range of immune cells. Aged rodents have reduced levels of growth hormone (GH) and diminished immune responses; ghrelin administration boosts GH levels and immune response. The anti-inflammatory functions of ghrelin, well displayed in preclinical animal models of sepsis, are just being charted in patients, with expectations that ghrelin and growth hormone might improve outcomes in patients with sepsis.

Ghrelin, which is mainly released from the stomach, is the most important orexigenic regulator of food intake, inducing appetite, enhancing adiposity and releasing growth hormone. Besides the hypothalamus, ghrelin receptors (GHS-R1A) are also expressed in the mesolimbic dopaminergic system, which increases the possibility that ghrelin plays an important role in reward regulation for substance use disorders such as alcohol addiction, especially through activating the cholinergic-dopaminergic reward link. In this review we focus on the impact of ghrelin on the development and maintenance of alcohol addiction/dependence, alcohol consumption, alcohol craving and alcohol withdrawal, attempting to integrate preclinical and clinical studies concerning the intriguing relationship between appetite regulation, reward and alcohol addiction. Integrating the existing preclinical and clinical data on ghrelin antagonism, specifically at the GHS-R1A receptor in mesolimbic dopaminergic pathways, may reveal a new and innovative target for the treatment of alcohol dependence in the future.

Ghrelin receptor agonists have been established to be important in ameliorating the nutritional conditions in patients with malnutrition. However, some studies have reported inconsistent results. We aimed to coalesce the available evidence on the efficacy of ghrelin receptor agonists for the treatment of malnutrition.
We searched PubMed, the Cochrane Central Register of Controlled Trials, and EMBASE for relevant articles published through March 2016. Studies comparing the efficacy of ghrelin receptor agonists versus placebo in malnourished patients were eligible for inclusion.
A total of 12 studies involving 1377 patients were included. Compared with placebo, ghrelin receptor agonists could increase the energy intake (standard mean difference [SMD] 2.67, 95% confidence interval [CI] 1.48 to 3.85, P < 0.001), lean body mass (weighted mean difference [WMD] 0.25 kg, 95% CI 0.07 to 0.42, P = 0.006), fat mass (WMD 0.92 kg, 95% CI 0.05 to 1.8, P = 0.038), and grip strength (WMD 0.31 kg, 95% CI 0.207 to 0.414, P < 0.001) of patients with malnutrition.
Our analysis indicated that ghrelin receptor agonists could improve the poor nutritional state of malnourished patients by increasing their energy intake, ameliorating their irregular body composition and improving their grip strength. However, these results might be less conclusive due to the limited sample sizes and one potential publication that has not been released.

Ghrelin is a hormone with multiple physiologic functions, including promotion of growth hormone release, stimulation of appetite and regulation of energy homeostasis. Treatment with ghrelin/ghrelin-receptor agonists is a prospective therapy for disease-related cachexia and malnutrition. In vitro studies have shown high expression of ghrelin in cancer tissue, although its role including its impact in cancer risk and progression has not been established. We performed a systematic literature review to identify peer-reviewed human or animal in vivo original research studies of ghrelin, ghrelin-receptor agonists, or ghrelin genetic variants and the risk, presence, or growth of cancer using structured searches in PubMed database as well as secondary searches of article reference lists, additional reviews and meta-analyses. Overall, 45 (73.8%) of the 61 studies reviewed, including all 11 involving exogenous ghrelin/ghrelin-receptor agonist treatment, reported either a null (no statistically significant difference) or inverse association of ghrelin/ghrelin-receptor agonists or ghrelin genetic variants with cancer risk, presence or growth; 10 (16.7%) studies reported positive associations; and 6 (10.0%) reported both negative or null and positive associations. Differences in serum ghrelin levels in cancer cases vs controls (typically lower) were reported for some but not all cancers. The majority of in vivo studies showed a null or inverse association of ghrelin with risk and progression of most cancers, suggesting that ghrelin/ghrelin-receptor agonist treatment may have a favorable safety profile to use for cancer cachexia. Additional large-scale prospective clinical trials as well as basic bioscientific research are warranted to further evaluate the safety and benefits of ghrelin treatment in patients with cancer.

Prolonged ileus is a common complication following gastrointestinal surgery, with an incidence of up to 40 %. Investigations examining pharmacological treatment of ileus have proved largely disappointing; however, recently, several compounds have been shown to have benefited when used as prophylaxis to prevent ileus.
This review aimed to evaluate the safety and efficacy of compounds which have been recently developed or repurposed to reduce bowel recovery time, thereby preventing ileus.
Data were taken from a systematic review of the MEDLINE, EMBASE and Cochrane Library Databases, in addition to manual searching of reference lists up to April 2015. No limits were applied.
Only randomized trials were eligible for inclusion.
Opioid receptor antagonists, ghrelin receptor agonists and serotonin receptor agonists used for the prevention of postoperative ileus in gastrointestinal surgery.
Outcomes of time to first defecation, first flatus and composite bowel recovery endpoints (GI2 and GI3) were used to determine efficacy. Pooled treatment effects were presented as the standard mean difference or as hazard ratios alongside the corresponding 95 % confidence intervals. Risk of bias was assessed using the Cochrane risk of bias framework.
A total of 17 studies were included in the final analysis. The μ-opioid receptor antagonist alvimopan and serotonin receptor agonists appeared to significantly shorten the duration of ileus. The use of Ghrelin receptor agonists did not appear to have any effect in five trials. No publication bias was detected.
Most of the trials were poorly reported and of mixed quality. Future studies must focus on the development of a set of core outcomes.
There is evidence to make a strong recommendation for the use of alvimopan in major gastrointestinal surgery to reduce postoperative ileus. Further randomized trials are required to establish whether serotonin receptor agonists are of use. Identifying a low-cost compound to promote bowel recovery following surgery could reduce complications and shorten duration of hospital admissions.

Ghrelin, a 28-amino acid hormone produced mainly by the X/A-like endocrine cells in gastric mucosa, has a widespread tissue distribution and diverse physiological functions such as hormonal, orexigenic, metabolic, cardiovascular, neurological, and immunological activities. Considerable evidence has suggested that ghrelin plays an important role in organism senescence or aging. The present review provides a comprehensive picture of this new development. We first reviewed the aging (senescence)-dependent reduction of ghrelin signaling, and then highlighted its relationship with the aging-associated alteration in food intake, energy metabolism, cardiovascular function, neurological activity, and adaptive immunity. Our literature review suggests that ghrelin is an innovative and promising agent in the treatment of these pathophysiological conditions associated with senescence.

BACKGROUND: Over the past 3 years, several patents appeared dealing with the discovery of compounds able to modulate ghrelin actions: agonists for the treatment of cachexia, as diagnostic agents for GH deficiency or for the increase in gastrointestinal motility, antagonists and inverse agonists as anorexigenic agents for the treatment of obesity and type 2 diabetes. This research has been conducted by several pharmaceutical companies and some compounds have entered clinical trials, but, to date, compounds acting on the ghrelin receptor do not represent clinical options yet.
METHODS: A comprehensive description and categorization of patents related to each type of compounds is provided, together with data related to these compounds that appeared in the scientific literature.
CONCLUSIONS: Ghrelin appears to mediate a myriad of actions, and some of these appear to be due to unknown mechanisms (a second putative ghrelin receptor, putative receptors for unacylated ghrelin); several agonists, antagonists and inverse agonists at ghrelin receptor have been developed but their mechanism of action into CNS is poorly understood. The therapeutic potential of compounds acting on ghrelin receptor is still to be fully assessed, but the results obtained to date are encouraging for the successful clinical translation of compounds able to treat several pathologies.