Amyloid ß lowering and cognition enhancing effects of ghrelin receptor analog [D-Lys (3)] GHRP-6 in rat model of obesity.

Obesity arising due to the dietary and life style changes is fast reaching epidemic proportions all over the world. There is increasing evidence that the incidence of Alzheimer disease (AD) is significantly influenced by a cluster of metabolic diseases, including diabetes and obesity. This study was aimed to test the suitability of experimentally-induced obesity in rats as an experimental animal model of AD. We used the procedure of neonatal administration of rats with monosodium L-glutamate (MSG), which generates adult obese animals as our study design and assessed the AD-like changes by measuring amyloid ß (1-42) and acetylcholinesterase (AChE) levels in the hippocampal extracts and cognitive impairments by Barnes maze task. Further, we investigated the influence of anti-obesity substance [D-Lys (3)] GHRP-6 on blood glucose, hippocampal Aß, AChE levels and restoration of cognitive deficits. Results revealed that administration of MSG to neonatal rats exhibited increased body mass index and serum glucose levels over the controls. Measurement of markers for AD-like molecular changes i.e. amyloid ß (Aß) and AChE levels showed marked elevation in these two parameters in the hippocampus of MSG-treated rats. Assessment of cognitive abilities by Barnes maze revealed spatial disorientation characteristic of AD. Administration of ghrelin receptor analog [D-Lys (3)] GHRP-6 to obese rats resulted in significant restoration of serum cholesterol, glucose, leptin and ghrelin levels to that of control with concomitant reduction in hippocampal Aß and AChE levels. In addition, the treated animals exhibited marked improvement in Barne’s maze task. These findings suggest that MSG-induced obese rats may serve as non-transgenic animal model for AD research. Further, the results indicate the potential of [D-Lys (3)] GHRP-6 as a promising anti-Alzheimer candidate.

Novel mechanisms of growth hormone regulation: growth hormone-releasing peptides and ghrelin

Growth hormone secretion is classically modulated by two hypothalamic hormones, growth hormone-releasing hormone and somatostatin. A third pathway was proposed in the last decade, which involves the growth hormone secretagogues. Ghrelin is a novel acylated peptide which is produced mainly by the stomach. It is also synthesized in the hypothalamus and is present in several other tissues. This endogenous growth hormone secretagogue was discovered by reverse pharmacology when a group of synthetic growth hormone-releasing compounds was initially produced, leading to the isolation of an orphan receptor and, finally, to its endogenous ligand. Ghrelin binds to an active receptor to increase growth hormone release and food intake. It is still not known how hypothalamic and circulating ghrelin is involved in the control of growth hormone release. Endogenous ghrelin might act to amplify the basic pattern of growth hormone secretion, optimizing somatotroph responsiveness to growth hormone-releasing hormone. It may activate multiple interdependent intracellular pathways at the somatotroph, involving protein kinase C, protein kinase A and extracellular calcium systems. However, since ghrelin has a greater ability to release growth hormone in vivo, its main site of action is the hypothalamus. In the current review we summarize the available data on the: a) discovery of this peptide, b) mechanisms of action of growth hormone secretagogues and ghrelin and possible physiological role on growth hormone modulation, and c) regulation of growth hormone release in man after intravenous administration of these peptides.