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Pharmacological stimulation of GAL1R but not GAL2R attenuates kainic acid-induced neuronal cell death in the rat hippocampus
Stockholm University, Faculty of Science, Department of Neurochemistry.ORCID iD: 0000-0001-9671-0354
Stockholm University, Faculty of Science, Department of Neurochemistry.
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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. 

Place, publisher, year, edition, pages
2016. Vol. 58, 83-92 p.
Keyword [en]
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: urn:nbn:se:su:diva-125756DOI: 10.1016/j.npep.2015.12.009ISI: 000382414500011OAI: oai:DiVA.org:su-125756DiVA: diva2:895125
Funder
Swedish Research CouncilStiftelsen Olle Engkvist ByggmästareHelge Ax:son Johnsons stiftelse
Available from: 2016-01-18 Created: 2016-01-18 Last updated: 2017-02-20Bibliographically 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
Identifiers
urn:nbn:se:su:diva-125749 (URN)978-91-7649-338-0 (ISBN)
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
2. Design, Synthesis and Characterization of Galanin Receptor Selective Ligands
Open this publication in new window or tab >>Design, Synthesis and Characterization of Galanin Receptor Selective Ligands
2017 (English)Doctoral 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 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.

Place, publisher, year, edition, pages
Stockholm: Department of Neurochemistry, Stockholm University, 2017. 96 p.
Keyword
galanin, GAL1R, GAL2R, depression, epilepsy
National Category
Chemical Sciences Biochemistry and Molecular Biology
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-139880 (URN)978-91-7649-721-0 (ISBN)978-91-7649-722-7 (ISBN)
Public defence
2017-03-31, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 13:00 (English)
Opponent
Supervisors
Available from: 2017-03-08 Created: 2017-02-20 Last updated: 2017-03-06Bibliographically approved

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