title: Pharmacological stimulation of GAL1R but not GAL2R attenuates kainic acid-induced neuronal cell death in the rat hippocampus.
abstract: 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 20years, 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 (125)I-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.
authors.affiliation: Department of Neurochemistry, Stockholm University, Svante Arrheniusv. 16B, SE-10691, Stockholm, Sweden. Electronic address: kristin.webling@neurochem.su.se.
authors.forename: Kristin
authors.initials: K
authors.lastname: Webling
authors.affiliation: Neuroscience Program, Biomedical and Health Science Institute, Department of Psychology, The University of Georgia, Athens, GA, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Groves-Chapman
authors.affiliation: Department of Neurochemistry, Stockholm University, Svante Arrheniusv. 16B, SE-10691, Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Runesson
authors.affiliation: Institute of technology, University of Tartu, Nooruse 1, 50411, Tartu, Estonia.
authors.forename: Indrek
authors.initials: I
authors.lastname: Saar
authors.affiliation: Research Program for Receptorbiochemistry and Tumormetabolism, Laura Bassi Centre of Expertise THERAPEP, Department of Pediatrics/University Hospital Salzburg, Paracelsus Medical University, Müllner Hauptstr. 48, 5020, Salzburg, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Lang
authors.affiliation: Department of Neurochemistry, Stockholm University, Svante Arrheniusv. 16B, SE-10691, Stockholm, Sweden.
authors.forename: Rannar
authors.initials: R
authors.lastname: Sillard
authors.affiliation: Department of Neurochemistry, Stockholm University, Svante Arrheniusv. 16B, SE-10691, Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Jakovenko
authors.affiliation: Research Program for Receptorbiochemistry and Tumormetabolism, Laura Bassi Centre of Expertise THERAPEP, Department of Pediatrics/University Hospital Salzburg, Paracelsus Medical University, Müllner Hauptstr. 48, 5020, Salzburg, Austria.
authors.forename: Barbara
authors.initials: B
authors.lastname: Kofler
authors.affiliation: Neuroscience Program, Biomedical and Health Science Institute, Department of Psychology, The University of Georgia, Athens, GA, USA.
authors.forename: Philip V
authors.initials: PV
authors.lastname: Holmes
authors.affiliation: Department of Neurochemistry, Stockholm University, Svante Arrheniusv. 16B, SE-10691, Stockholm, Sweden; Institute of technology, University of Tartu, Nooruse 1, 50411, Tartu, Estonia.
authors.forename: Ülo
authors.initials: Ü
authors.lastname: Langel
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism; D019004:Galanin / Q000031:analogs & derivatives* / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D007608:Kainic Acid / Q000633:toxicity; D008024:Ligands; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D010446:Peptide Fragments / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D044091:Receptor, Galanin, Type 1 / Q000819:agonists / Q000378:metabolism*; D044092:Receptor, Galanin, Type 2 / Q000819:agonists / Q000378:metabolism*
chemical_list: D008024:Ligands; C000614146:M1145 peptide; C000614147:M1154 peptide; C000614145:M617 peptide; D010446:Peptide Fragments; D044091:Receptor, Galanin, Type 1; D044092:Receptor, Galanin, Type 2; D019004:Galanin; D000242:Cyclic AMP; D001920:Bradykinin; D007608:Kainic Acid
keywords: Excitotoxicity; GAL(1)R; GAL(2)R; Galanin; Galanin receptor subtype selective ligands; Label-free real-time technology; M1154; XCELLigence