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Pharmacological stimulation of galanin receptor 1 but not galanin receptor 2 attenuates kainic acid-induced neuronal cell death in the rat hippocampus
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.ORCID-id: 0000-0001-9671-0354
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
Vise andre og tillknytning
(engelsk)Manuskript (preprint) (Annet vitenskapelig)
Abstract [en]

The neuropeptide galanin is widely distributed in the central and peripheral nervous systems. Galanin is part of a bigger family of bioactive peptides and its biological activity is mediated through three G-protein coupled receptor subtypes, GalR1-3. The last 20 years have provided data supporting a neuroprotective effect of galanin that probably is mediated through the activation of GalR1 and GalR2.

In this study, an additional galanin receptor ligand, M1154, was developed to fully address the pharmaceutical potential of galanin receptor subtype selective ligands to inhibit excitotoxic cell death. We thereafter adapted a single protocol for signaling assay for all three galanin receptors, by utilizing a non-labeled real time instrument, to ease classification of novel ligands according to their ability to activate the different galanin receptor subtypes. M1154 is a GalR1/2 selective ligand in our binding and signaling assays with no detectable interaction with GalR3.

The novel M1154 peptide was compared to earlier published selective ligands, namely M617 and M1145, in its ability to reduce the excitotoxic effects of kainic acid (KA). While no significant difference in the time course or severity of induced seizure activity was observed, administration of either M617 or M1154 before KA administration, significantly attenuated the neuronal cell death in the hippocampus. Our results clearly show the potential therapeutic value of agonists selective for GalR1 as neuroprotective agents for the prevention of excitotoxic neuronal cell death.

Emneord [en]
GPCR, galanin, neuropeptide, galanin receptor, GalR1, label free real time technology, excitotoxicity, M1154
HSV kategori
Forskningsprogram
neurokemi med molekylär neurobiologi
Identifikatorer
URN: urn:nbn:se:su:diva-75087OAI: oai:DiVA.org:su-75087DiVA, id: diva2:514066
Tilgjengelig fra: 2012-04-05 Laget: 2012-04-05 Sist oppdatert: 2018-01-12bibliografisk kontrollert
Inngår i avhandling
1. Delineating Ligand-Receptor Interactions and the Design of Subtype Selective Galanin Receptor Ligands
Åpne denne publikasjonen i ny fane eller vindu >>Delineating Ligand-Receptor Interactions and the Design of Subtype Selective Galanin Receptor Ligands
2012 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

We now celebrate that it is 30 years since galanin was first isolated. During these three decades galanin has been identified in numerous tissues and physiological processes, and in an abundant number of species. In the nervous system galanin primarily displays a modulatory role. The galaninergic system consists of a number of bioactive peptides with a highlyplastic expression pattern and three different receptors, GalR1-GalR3. The lack of receptor subtype selective ligands and antibodies have severely hampered the characterization of this system. Therefore, most of the knowledgehas been drawn from experiments with transgenic animals, which has givensome major conclusions, despite the risk of inducing compensatory effects inthese animal studies. Therefore, the production of subtype selective ligandsis of great importance to delineate the galanin system and slowly experimental data from receptor subtype selective ligand trials is emerging. This thesis aims at studying galanin receptor-ligand interactions and to increase and improve the utilized tools in the galanin research field, especially the development of novel galanin receptor subtype selective ligands. Paper I demonstrates the potential to N-terminally extend galanin analogues and the successful development of a GalR2 selective ligand. In addition, a cell line stably expressing GalR3 was developed to improve and simplify future evaluations of receptor subtype selective galanin ligands. Paper II extends the number of GalR2 selective ligands and shows that i.c.v. administration of galanin receptor ligands stimulates food intake through GalR1. Paper III demonstrates the successful development of a mixed GalR1/GalR2 agonist without any detectable interaction with GalR3. Subsequently, this peptide was used to delineate which receptor subtype mediatesthe neuroprotective effects of galanin in the CA3 region of hippocampus. Furthermore, a robust protocol for detection of receptor activation was developed to ease the detection of the relative potency of novel ligands at the three galanin receptor subtypes. Paper IV describes the finding of several essential amino acids for ligand interaction in GalR3 through the performance of an L-alanine mutagenesis study. A constructed in silico homology model of GalR3 confirmed and extended these findings. In conclusion, this thesis provides a novel design strategy for galanin receptor ligands and increases the understanding of ligand interactions with the GalR3. Furthermore, published ligands together with new galanin analogues have proven to be highly receptor specific, thus implicating that a future delineation of the galaninergic system as a therapeutic target is possible.

sted, utgiver, år, opplag, sider
Stockholm: Department of Neurochemistry, Stockholm University, 2012. s. 96
HSV kategori
Forskningsprogram
neurokemi med molekylär neurobiologi
Identifikatorer
urn:nbn:se:su:diva-75503 (URN)978-91-7447-503-6 (ISBN)
Disputas
2012-06-01, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrheniusväg 16 B, Stockholm, 13:00 (engelsk)
Opponent
Veileder
Merknad

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 3: Manuscript.

Tilgjengelig fra: 2012-05-10 Laget: 2012-04-20 Sist oppdatert: 2019-10-04bibliografisk kontrollert

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