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Novel systemically active galanin receptor 2 ligands in depression-like behavior
Stockholm University, Faculty of Science, Department of Neurochemistry. University of Tartu, Estonia .
Stockholm University, Faculty of Science, Department of Neurochemistry.
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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.

Place, publisher, year, edition, pages
2013. Vol. 127, no 1, 114-123 p.
Keyword [en]
animal models of depression, depression, galanin, galanin receptor type 2, neuropeptide, tail suspension test
National Category
Biochemistry and Molecular Biology Neurosciences
URN: urn:nbn:se:su:diva-95760DOI: 10.1111/jnc.12274ISI: 000325007300012OAI: diva2:662034


Available from: 2013-11-05 Created: 2013-11-04 Last updated: 2016-01-18Bibliographically approved
In thesis
1. Galanin receptor ligands: Design, synthesis, characterization and biological effects
Open this publication in new window or tab >>Galanin receptor ligands: Design, synthesis, characterization and biological effects
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
urn:nbn:se:su:diva-125749 (URN)978-91-7649-338-0 (ISBN)
2016-02-08, Heilbronnsalen, C458, Svante Arrheniusv. 16B, Stockholm, 14:00 (English)
Available from: 2016-01-18 Created: 2016-01-18 Last updated: 2016-01-18Bibliographically approved

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