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GalR2-positive allosteric modulator exhibits anticonvulsant effects in animal models

Academic Article
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Overview

authors

  • Lu, Xiaoying
  • Roberts, Edward
  • Xia, F. C.
  • Sanchez-Alavez, Manuel
  • Liu, T. Y.
  • Baldwin, R.
  • Wu, S.
  • Chang, J.
  • Wasterlain, C. G.
  • Bartfai, Tamas

publication date

  • August 2010

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • Galanin receptors type 1 (GalR1) and/or type 2 (GalR2) represent unique pharmacological targets for treatment of seizures and epilepsy. Previous studies have shown that the endogenous peptide ligand galanin exerts powerful anticonvulsant effect through activation of these two G protein-coupled receptors, which are highly expressed in the temporal lobe of rodent brain. Here we report the characterization of a putative GalR2-positive allosteric modulator CYM2503. CYM2503 potentiated the galanin-stimulated IP1 accumulation in HEK293 cells stably expressing GalR2 receptor, whereas it exhibited no detectable affinity for the (125)I galanin-binding site of GalR2 receptor, an effect consistent with that of a positive allosteric modulator. In the rat Li-pilocarpine status epilepticus model, CYM2503, injected intraperitoneally, increased the latency to first electrographic seizure and the latency to first stage 3 behavioral seizure, decreased the latency to the establishment of status epilepticus, and dramatically decreased the mortality. In a Li-pilocarpine seizure model in mice, CYM2503 increased the latency to first electrographic seizure and decreased the total time in seizure. CYM2503 also attenuated electroshock-induced seizures in mice. Thus, CYM2503 provides a starting point for the development of anticonvulsant therapy using the galanin R2 receptor as target.

subject areas

  • Allosteric Regulation
  • Animals
  • Anticonvulsants
  • Carbamates
  • Cell Line
  • Dipeptides
  • Disease Models, Animal
  • Electroshock
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Pilocarpine
  • Quinolones
  • Rats
  • Rats, Wistar
  • Receptor, Galanin, Type 1
  • Receptor, Galanin, Type 2
  • Recombinant Proteins
  • Seizures
  • Signal Transduction
  • Status Epilepticus
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Research

keywords

  • G protein-coupled receptor
  • galanin
  • seizure
  • status epilepticus
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Identity

PubMed Central ID

  • PMC2930524

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.1008986107

PubMed ID

  • 20660766
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Additional Document Info

start page

  • 15229

end page

  • 15234

volume

  • 107

issue

  • 34

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