The broad aim of the studies described in this thesis was to evaluate the role of neuropeptide galanin in acute pancreatitis (AP). Treatment of AP is mainly symptomatic and supportive and no definitive pharmacological therapy for this disease is currently available. There are a number of studies in animal models of AP which demonstrate beneficial effect of a pharmacological agent in the management of AP. But most of these studies are limited to single species. The studies presented in the thesis evaluate the role of galanin and several of its antagonists in experimental AP in two different species. The initial part of the experimental work was performed in the possums, using a well established model of AP in the laboratory. Later, the experimental work has been carried out in the mouse. The overall hypothesis was that galanin plays a major role in the onset and/or progression of AP. In Chapter 2, the effect galanin or galantide administration, before and after AP induction on severity of AP in the possum model is described. The studies demonstrated that galantide decreased various indices of AP when administered prophylactically and therapeutically. 2 Chapter 3 outlines studies to determine if administration of galanin or galantide alters pancreatic vascular perfusion (PVP) during AP in the possum model. These studies suggested that in AP there is an initial fall in PVP, which is exacerbated by administration of galanin prior to onset of AP. Conversely, galantide administration prevented this decrease in PVP, and was associated with a rise in PVP through out the duration of the experiment. Chapter 4 describes preliminary studies on effect of galanin and galantide on pancreatic exocrine secretion. These demonstrated that galantide decreased hyperstimulated pancreatic exocrine secretion, but had no effect on the basal secretion. The subsequent studies are carried out using the caerulein mouse model of AP. The hypothesis has been tested in three different strains of mice, including a galanin gene knock-out (KO) strain. Chapter 5 outlines the effect galanin or galantide administration, before and after AP induction on the severity of AP in the caerulein mouse model. These studies revealed that galantide administration both prophylactically and therapeutically decreased the severity of AP in the mouse. In Chapter 6, the galanin gene KO were used to further test the hypothesis. These studies revealed that AP was less severe in the galanin KO mice, thereby suggesting a role for endogenous galanin in the onset and/or progression of AP. 3 Chapter 7 describes the effects of various galanin antagonist on the severity of AP in the caerulein mouse model. These studies revealed that galantide and M35 have beneficial effects in AP, i.e. reduced the indices of AP, whereas C7 and M40 had complex effects. Chapter 8 provides an overview of findings and discussion of their broader ramifications with future recommendations. Overall, the studies have demonstrated that galanin plays a major role in AP and galanin antagonists may be of potential therapeutic value in the management of AP.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 9 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 6 uppsatser.

Diss. (sammanfattning) Stockholm : Stockholms universitet, 2006. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2001. / Härtill 6 uppsatser.

Ulm, Univ. Diss., 2006.

Thesis (Ph. D.)--University of Washington, 2004. / Vita. Includes bibliographical references (leaves 129-156).

Galanin is a 29/30 amino acid long bioactive peptide discovered over 30 years ago when C-terminally amidated peptides were isolated from porcine intestines. The name galanin originates from a combination of the first and last amino acids - G from glycine and the rest from alanine. The first 15 amino acids are highly conserved throughout species, which indicates that the N-terminus is important for receptor recognition and binding. Galanin exerts its effects by binding to three different G protein-coupled receptors, which all differ according to regional distribution, the affinity for shortened galanin fragments, as well as the intracellular G-protein signaling cascade used. When first discovered, galanin was found to cause muscle contraction as well as hyperglycemia.  Over the years, galanin has been reported to be involved in a wide variety of biological functions, for example food intake and neurogenesis, and pathological functions, for example epilepsy and depression. Determining the specific involvement of the three different galanin receptors in biological and pathological processes is limited by the small amount of galanin receptor selective/specific ligands available as research tools. Furthermore, the fast degradation of peptides limits the administration routes in animal studies. This thesis aims at developing new galanin receptor-selective ligands to help delineate the involvement of the three different galanin receptors. Paper 1 presents the shortest galanin fragment with a galanin receptor 2 specific binding preference where only a single amino acid substitution was made, Ala5Ser in galanin (2-11). In addition, G-protein coupled receptor signaling were evaluated through both a classical second messenger assay and a real-time label-free technique in cells overexpressing the receptor as well as low receptor expression. Paper 2 demonstrates that the neuroprotective effects of galanin in a kainic acid-induced excitotoxic animal model were mediated through galanin receptor 1. Furthermore, a new robust protocol for evaluating G-protein signaling using a label-free real time impedance technique was presented and compared to two different classical second-messenger assays. Paper 3 presents a series of systemically active galanin receptor 2 selective ligands subsequently evaluated in two different depression-like animal models. Paper 4 investigates a mutated form of human galanin which was found in epilepsy patients and binding and signaling properties of the mutated associated ligand p.(A39E) was examined. In conclusion, this thesis presents the discovery of eight new galanin ligands, which can be used to evaluate the galaninergic system as well as to help investigate the possible use of peptides as pharmaceuticals in different diseases.

Correct myelin formation and maintenance is essential for normal functioning and is affected in the demyelinating disease, Multiple Sclerosis (MS). To better understand this disease and identify important targets in promoting remyelination, the study of developmental myelination is important. Galanin, a 29 amino acid neuropeptide has been identified as a potentially important modulator in early myelin development. In our Galanin transgenic mouse model, myelin basic protein (MBP) levels are highly elevated at postnatal day 10 compared to the wild type. A preliminary investigation of Galanin’s behavior at various doses in vitro, yielded results that agreed with Galanin’s effect in vivo. Proteolipid protein (PLP) was highly elevated in the 10nM dose in vitro indicating Galanin exerts its effects in a time and dose dependent manner. Overall, this study identifies Galanin as a potentially important modulator of developmental myelination that may become a therapeutic target in future studies of demyelinating diseases.