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Galanin receptor ligands: Design, synthesis, characterization and biological effects
Stockholm University, Faculty of Science, Department of Neurochemistry. (Ülo Langel)ORCID iD: 0000-0001-9671-0354
2016 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

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 among species which indicates that the N-terminus is important for receptor recognition and subsequent binding. Galanin exerts its effects by binding to three different G-protein coupled receptors, which all differ in regional distribution, the affinity for shortened galanin fragments, as well as the G-protein signaling cascade used. At the time of publication, 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 and pathological functions, for example epilepsy, food intake and depression.

Determining the specific involvement of the three different galanin receptors in several 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 also known as the galaninergic system.

Paper 1 demonstrates that the neuroprotective effects of galanin in a kainic acid induced excitotoxic animal model was 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 2 presents a series of systemically active galanin receptor 2 selective ligands subsequently evaluated in two different depression-like animal models.

In conclusion, this thesis presents six new galanin ligands, which can be used to evaluate the galaninergic system as well as to investigate the possible use of peptides as pharmaceuticals.

Place, publisher, year, edition, pages
Stockholm: Department of Neurochemistry , 2016. , 60 p.
National Category
Other Chemistry Topics
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
URN: urn:nbn:se:su:diva-125749ISBN: 978-91-7649-338-0OAI: oai:DiVA.org:su-125749DiVA: diva2:895191
Presentation
2016-02-08, Heilbronnsalen, C458, Svante Arrheniusv. 16B, Stockholm, 14:00 (English)
Opponent
Supervisors
Available from: 2016-01-18 Created: 2016-01-18 Last updated: 2016-01-18Bibliographically approved
List of papers
1. Pharmacological stimulation of GAL1R but not GAL2R attenuates kainic acid-induced neuronal cell death in the rat hippocampus
Open this publication in new window or tab >>Pharmacological stimulation of GAL1R but not GAL2R attenuates kainic acid-induced neuronal cell death in the rat hippocampus
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2016 (English)In: Neuropeptides, ISSN 0143-4179, E-ISSN 1532-2785, Vol. 58, 83-92 p.Article in journal (Refereed) Published
Abstract [en]

The neuropeptide galanin is widely distributed in the central and peripheral nervous systems and part of a bigger family of bioactive peptides. Galanin exerts its biological activity through three G-protein coupled receptor subtypes, GAL1–3R. Throughout the last 20 years, data has accumulated that galanin can have a neuroprotective effect presumably mediated through the activation of GAL1R and GAL2R. In order to test the pharmaceutical potential of galanin receptor subtype selective ligands to inhibit excitotoxic cell death, the GAL1R selective ligand M617 and the GAL2R selective ligand M1145 were compared to the novel GAL1/2R ligand M1154, in their ability to reduce the excitotoxic effects of intracerebroventricular injected kainate acid in rats.

The peptide ligands were evaluated in vitro for their binding preference in a competitive 125I-galanin receptor subtype binding assay, and G-protein signaling was evaluated using both classical signaling and a label-free real-time technique. Even though there was no significant difference in the time course or severity of the kainic acid induced epileptic behavior in vivo, administration of either M617 or M1154 before kainic acid administration significantly attenuated the neuronal cell death in the hippocampus. Our results indicate the potential therapeutic value of agonists selective for GAL1R in the prevention of neuronal cell death. 

Keyword
Galanin, Galanin receptor subtype selective ligands, GAL1R, GAL2R, Label-free real-time technology, XCELLigence, Excitotoxicity, M1154
National Category
Biochemistry and Molecular Biology
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-125756 (URN)10.1016/j.npep.2015.12.009 (DOI)
Funder
Swedish Research CouncilStiftelsen Olle Engkvist ByggmästareHelge Ax:son Johnsons stiftelse
Available from: 2016-01-18 Created: 2016-01-18 Last updated: 2016-09-14Bibliographically approved
2. Novel systemically active galanin receptor 2 ligands in depression-like behavior
Open this publication in new window or tab >>Novel systemically active galanin receptor 2 ligands in depression-like behavior
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2013 (English)In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 127, no 1, 114-123 p.Article in journal (Refereed) Published
Abstract [en]

Neuropeptide galanin and its three G-protein coupled receptors, galanin receptor type 1-galanin receptor type 3 (GalR1-GalR3), are involved in the regulation of numerous physiological and disease processes, and thus represent tremendous potential in neuroscience research and novel drug lead development. One of the areas where galanin is involved is depression. Previous studies have suggested that activation of GalR2 leads to attenuation of depression-like behavior. Unfortunately, lack of in vivo usable subtype specific ligands hinders testing the role of galanin in depression mechanisms. In this article, we utilize an approach of increasing in vivo usability of peptide-based ligands, acting upon CNS. Thus, we have synthesized a series of novel systemically active galanin analogs, with modest preferential binding toward GalR2. We have shown that specific chemical modifications to the galanin backbone increase brain levels upon i.v. injection of the peptides. Several of the new peptides, similar to a common clinically used antidepressant medication imipramine, exerted antidepressant-like effect in forced swim test, a mouse model of depression, at a surprisingly low dose range (<0.5mg/kg). We chose one of the peptides, J18, for more thorough study, and showed its efficacy also in another mouse depression model (tail suspension test), and demonstrated that its antidepressant-like effect upon i.v. administration can be blocked by i.c.v. galanin receptor antagonist M35. The effect of the J18 was also abolished in GalR2KO animals. All this suggests that systemically administered peptide analog J18 exerts its biological effect through activation of GalR2 in the brain. The novel galanin analogs represent potential drug leads and a novel pharmaceutical intervention for depression.

Keyword
animal models of depression, depression, galanin, galanin receptor type 2, neuropeptide, tail suspension test
National Category
Biochemistry and Molecular Biology Neurosciences
Identifiers
urn:nbn:se:su:diva-95760 (URN)10.1111/jnc.12274 (DOI)000325007300012 ()
Note

AuthorCount:11;

Available from: 2013-11-05 Created: 2013-11-04 Last updated: 2016-01-18Bibliographically approved

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