Investigational drug therapies for the treatment of gastroparesis

Introduction: Gastroparesis is defined by nausea, vomiting, pain, early satiety and bloating, and characterized by delayed gastric emptying without obvious structural abnormalities. Metoclopramide is widely used, increasing gastric emptying and inhibiting nausea and vomiting. Other drugs are available in certain countries and some are used ‘off-label’ because they increase gastric emptying or inhibit emesis. However, correlation between gastroparesis symptoms and rates of gastric emptying is poor. For anti-emetic drugs, dose-ranging and Phase III trials in gastroparesis are lacking.

Areas covered: Gastric motility may still be disordered, leading to nausea, even though gastric emptying is unchanged. One hypothesis is that interstitial cells of Cajal (ICC) are damaged by diabetes leading to gastric dysrhythmia and nausea. Novel approaches to treatment of nausea also include the use of ghrelin receptor agonists, highlighting a link between appetite and nausea.

Expert opinion: There is an urgent need to diversify away from historical drug targets. In particular, there is a need to control nausea by regulating ICC functions and/or by facilitating appetite via ghrelin receptor agonists. It is also important to note that different upper gastrointestinal disorders (gastroparesis, chronic unexplained nausea and vomiting, functional dyspepsia) are difficult to distinguish apart, suggesting wider therapeutic opportunity.     

Ghrelin and NUCB2/Nesfatin-1 Co-Localization With Digestive Enzymes in the Intestine of Pejerrey (Odontesthes bonariensis)

Ghrelin (orexigenic) and nesfatin-1 (anorexigenic) are two peptides with opposing actions on food intake regulation and are mainly expressed in the hypothalamus and gut of mammals and fish. Both are involved in the regulation of a wide range of physiological processes in vertebrates, including metabolism, growth, and reproduction. However, the anatomical relationship between these peptides and the nutrient assimilation processes are not well understood. Thus, the aim of this work was to determine the localization of ghrelin, nesfatin-1, and several enzymes involved in the digestive process (lipoprotein lipase, aminopeptidase A, trypsin, and sucrase-isomaltase) in the intestine of pejerrey (Odontesthes bonariensis), a species with commercial importance in South America. We observed co-localization of ghrelin and nesfatin-1 in enteroendocrine cells, absorptive cells, and in cells of the lamina propia. Approximately half of the cells displaying ghrelin-like immunoreactivity co-localized the NUCB2/nesfatin-1-like signal. In addition, both peptides showed co-localization with lipoprotein lipase, aminopeptidase A, trypsin, or sucrase-isomaltase. All digestive enzymes except for aminopeptidase A and trypsin, showed high co-localization (68–88%) with both ghrelin-like and NUCB2/nesfatin-1-like signals in absorptive, enteroendocrine, and lamina propria cells. Together, our results provide immunohistochemical evidence supporting a role for both ghrelin and NUCB2/nesfatin-1 in the regulation of nutrient assimilation in fish. Anat Rec, 302:973–982, 2019. © 2018 Wiley Periodicals, Inc.     

Adipocytokines and ghrelin level of bipolar patients from manic episode to euthymic episode

Purpose: Obesity and metabolic syndrome (MeS) are more frequently observed in bipolar patients than the general population. This may result from the differences of adipocytokines and ghrelin levels in bipolar disorder.

Material and methods: We evaluated the leptin, adiponectin, resistin and ghrelin levels in bipolar patients (n?=?30) in manic episode and in a control group (n?=?30). After treatment, the same patients were evaluated again during the euthymic episode. We also measured the insulin, glucose, insulin resistance (HOMA), trygliceride (TG), total cholesterol (TCHOL), high density lipoprotein cholesterol (HDL) and low density lipoprotein cholesterol (LDL) in relation to the (MeS).

Results: When controlling for age, BMI and glucose, leptin levels were higher in the bipolar disorder manic episode group (BD-ME) and bipolar euthymic episode group (BD-EE) than the control group; resistin levels were higher in the BD-ME compared to the control group and it had a positive correlation with Young Mania Rating Scale (YMRS). After treatment, ghrelin levels were higher in the BD-EE compared to the BD-ME group. There was no difference among the groups with respect to adiponectin.

Conclusions: The present results point that high leptin, resistin and ghrelin levels may be involved in the early pathophysiological process which can lead to later obesity and MeS in patients with bipolar disorder.     

Stress and obesity: The ghrelin connection

Ghrelin is a hormone associated with feeding and energy balance. Not surprisingly, this hormone is secreted in response to acute stressors and it is chronically elevated after exposure to chronic stress in tandem with a number of metabolic changes aimed at attaining homeostatic balance. In the present review, we propose that ghrelin plays a key role in these stress‐induced homeostatic processes. Ghrelin targets the hypothalamus and brain stem nuclei that are part of the sympathetic nervous system to increase appetite and energy expenditure and promote the use of carbohydrates as a source of fuel at the same time as sparing fat. Ghrelin also targets mesolimbic brain regions such as the ventral segmental area and the hippocampus to modulate reward processes, to protect against damage associated with chronic stress, as well as to potentially increase resilience to stress. In all, these data support the notion that ghrelin, similar to corticosterone, is a critical metabolic hormone that is essential for the stress response.     

Glucose availability regulates ghrelin‐induced food intake in the ventral tegmental area

Information about metabolic status arrives in the brain in the form of a complex milieu of circulating signalling factors, including glucose and fatty acids, ghrelin, leptin and insulin. The specific interactions between humoural factors, brain sites of action and how they influence behaviour are largely unknown. We have previously observed interactions between glucose availability and the actions of ghrelin mediated via the agouti‐related peptide neurones of the hypothalamus. In the present study, we examine whether these effects generalise to another ghrelin‐sensitive brain nucleus, the ventral tegmental area (VTA). We altered glucose availability by injecting mice with glucose or 2‐deoxyglucose i.p. to induce hyperglycaemia and glucopenia, respectively. Thirty minutes later, we injected ghrelin in the VTA. Glucose administration suppressed intra‐VTA ghrelin‐induced feeding. Leptin, a longer‐term signal of positive energy balance, did not affect intra‐VTA ghrelin‐induced feeding. 2‐Deoxyglucose and ghrelin both increased food intake in their own right and, together, they additively increased feeding. These results add support to the idea that calculation of metabolic need depends on multiple signals across multiple brain regions and identifies that VTA circuits are sensitive to the integration of signals reflecting internal homeostatic state and influencing food intake.     

Temporospatial effects of acyl‐ghrelin on activation of astrocytes after ischaemic brain injury

The protective mechanisms of astrocyte signalling are based on the release of neurotrophic factors and the clearing of toxic substances in the early stages of cerebral ischaemia. However, astrocytes are also responsible for the detrimental effects that occur during the later stages of ischaemia, in which glial scars are formed, thereby impeding neural recovery. Acyl‐ghrelin has been found to be neuroprotective after stroke, although the influence of acyl‐ghrelin on astrocytes after ischaemic injury is yet to be clarified. In the present study, we used permanent middle cerebral arterial occlusion to establish a brain ischaemia model in vivo, as well as oxygen and glucose deprivation (OGD) to mimic ischaemic insults in vitro. We found that acyl‐ghrelin injection significantly increased the number of activated astrocytes in the peri‐infarct area at day 3 after brain ischaemia and decreased the number of activated astrocytes after day 9. Moreover, the expression of fibroblast growth factor 2 (FGF2) in the ischaemic hemisphere increased markedly after day 3, and i.c.v. injection of SU5402, an inhibitor of FGF2 signalling, abolished the suppression effects of acyl‐ghrelin on astrocyte activation in the peri‐infarct region during the later stages of ischaemia. The results from in vitro studies also showed the dual effect of acyl‐ghrelin on astrocyte viability. Acyl‐ghrelin increased the viability of uninjured astrocytes in an indirect way by stimulating the secretion from OGD‐injured astrocytes. It also inhibited the astrocyte viability in the presence of FGF2 in a dose‐dependent manner. Furthermore, the expression of acyl‐ghrelin receptors on astrocytes was increased after acyl‐ghrelin and FGF2 co‐treatment. In conclusion, acyl‐ghrelin promoted astrocyte activation in the early stages of ischaemia but suppressed the activation in later stages of ischaemic injury. These later effects were likely to be triggered by the increased expression of endogenous FGF2 after brain ischaemia.     

Altered leptin,adiponectin, resistin and ghrelin secretion may represent an intrinsic polycystic ovary syndrome abnormality

Abstract

The aim of the study was to investigate whether altered adipose tissue secretion of various adipokines is secondary to obesity, hyperandrogenism, and hyperinsulinemia or intrinsic to polycystic ovary syndrome (PCOS). This cross-sectional study included 151 women diagnosed with PCOS by the Rotterdam criteria and 95 healthy women matched by age, body mass index (BMI), and waist-to-hip ratio (WHR). Clinical, biochemical, and hormonal characteristics were assessed. Serum concentrations of ghrelin and adiponectin were found to be significantly lower and concentrations of leptin and resistin significantly higher in women with PCOS than in healthy women matched by age, BMI, and WHR. A PCOS diagnosis made the largest contribution to predicting serum levels of leptin, adiponectin, resistin, and ghrelin in all stepwise multiple regression models, which included PCOS diagnosis, BMI, WHR, luteinizing hormone, total testosterone, free testosterone and homeostatic model assessment of insulin resistance as independent predictors. Leptin, adiponectin, ghrelin and resistin levels may serve as independent biomarkers for the diagnosis of PCOS.     

Acute ghrelin changes food preference from a high‐fat diet to chow during binge‐like eating in rodents

Ghrelin, an orexigenic hormone released from the empty stomach, provides a gut–brain signal that promotes many appetitive behaviours, including anticipatory and goal‐directed behaviours for palatable treats high in sugar and/or fat. In the present study, we aimed to determine whether ghrelin is able to influence and/or may even have a role in binge‐like eating behaviour in rodents. Accordingly, we used a palatable scheduled feeding (PSF) paradigm in which ad lib. chow‐fed rodents are trained to ‘binge’ on a high‐fat diet (HFD) offered each day for a limited period of 2 hours. After 2 weeks of habituation to this paradigm, on the test day and immediately prior to the 2‐hour PSF, rats were administered ghrelin or vehicle solution by the i.c.v. route. Remarkably and unexpectedly, during the palatable scheduled feed, when rats normally only binge on the HFD, those injected with i.c.v. ghrelin started to eat more chow and chow intake remained above baseline for the rest of the 24‐hour day. We identify the ventral tegmental area (VTA) (a key brain area involved in food reward) as a substrate involved because these effects could be reproduced, in part, by intra‐VTA delivery of ghrelin. Fasting, which increases endogenous ghrelin, immediately prior to a palatable schedule feed also increased chow intake during/after the schedule feed but, in contrast to ghrelin injection, did not reduce HFD intake. Chronic continuous central ghrelin infusion over several weeks enhanced binge‐like behaviour in palatable schedule fed rats. Over a 4‐week period, GHS‐R1A‐KO mice were able to adapt and maintain large meals of HFD in a manner similar to wild‐type mice, suggesting that ghrelin signalling may not have a critical role in the acquisition or maintenance in this kind of feeding behaviour. In conclusion, ghrelin appears to act as a modulating factor for binge‐like eating behaviour by shifting food preference towards a more nutritious choice (from HFD to chow), with these effects being somewhat divergent from fasting.