Overview of our recent topics

Impact of stable analogs of prolactin-releasing peptide in obesity and hypertension

Prolactin-releasing peptide (PrPR) is a new anorexigenic neuropeptide; both PrRP and its receptor knock-outs are obese. Anorexigenic neuropeptides are potential anti-obesitics but their peptide character complicates their delivery to brain, necessary for their exclusively central effect. This project aims to select effective PrRP analogs modified with fatty acid that would prolong their half-life and enable them to cross blood brain barrier. PrRP analogs are subjected to binding and functional tests in cells with relevant receptors. The most potent agonists are tested in mice and rats for short-term effect on food intake, and for long-term effects in hypertensive rats with diet-induced obesity. Relationship of PrRP to other peptides involved in food intake regulation are also studied. In parallel, acute and chronic effect of PrRP analogs on blood pressure and its role in major vasoactive systems are tested in rats. Lipidation of PrRP might be an effective way to deliver peripherally peptides with central effects for a potential treatment of metabolic syndrome.

Type 3 diabetes - neuroprotective features of PrRP and ghrelin analogs

Type 3 diabetes is more known as Alzheimer's disease. Alzheimer's disease is the most common form of dementia and despite of the effort of many research groups the mechanism leading to its development still remains unknown. In our group we study the possible connection between Alzheimer's disease development and type 2 diabetes. Type 2 diabetes can cause the resistance to the effect of insulin in brain where insulin is important for memory formation and learning. Insulin resistance then leads to the development of neuropathological changes which are the hallmarks of Alzheimer's disease (for example increased phosphorylation of Tau protein). These pathological changes are studied in mouse and cellular models. We also employ neuropeptides which could attenuate the pathological changes, for instance analogs of prolactin-releasing peptide. We are also interested in the role of ghrelin or its antagonist on the Alzheimer's disease development.

Stable ghrelin analogs in the treatment of cachexia

Ghrelin, a hormone produced predominantly by the stomach, is the only known peripheral hormone stimulating food intake. Ghrelin promotes a state of positive energy balance, increases food intake and body weight and promotes accumulation of adipose tissue. Furthermore, ghrelin has been shown to exert anti-inflammatory effects, it reduces blood pressure and increases cardiac output. Therefore, ghrelin has been considered a potential anti-cachectic agent. Cachexia is a complex metabolic syndrome that accompanies a number of chronic diseases and is characterized by loss of body weight, muscle wasting and eventually loss of fat mass. Ghrelin contains a serine acylated with n-octanoic acid which is necessary for its biological activity. The ester bond can be easily hydrolyzed by esterases and the peptidic chain of the molecule can be cleaved by proteases which makes ghrelin quite unstable in blood. In order to increase stability of the ghrelin molecule, we designed ghrelin analogs with modified amino acid sequence (incorporation of noncoded amino acids). Ghrelin analogs were further modified by shortening the peptide chain, incorporation of the second fatty acid or replacement of the n-octanoyl with longer or unsaturated fatty acid. We characterize the analogs both in vitro and in vivo and examine their anti-cachectic properties in rodent models of cachexia.