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TC-G 1008 facilitates epileptogenesis by acting selectively at the GPR39 receptor but non-selectively activates CREB in the hippocampus of pentylenetetrazole-kindled mice

Authors
  • Doboszewska, Urszula
  • Socała, Katarzyna
  • Pieróg, Mateusz
  • Nieoczym, Dorota
  • Sawicki, Jan
  • Szafarz, Małgorzata
  • Gawel, Kinga
  • Rafało-Ulińska, Anna
  • Sajnóg, Adam
  • Wyska, Elżbieta
  • Esguerra, Camila V.
  • Szewczyk, Bernadeta
  • Maćkowiak, Marzena
  • Barałkiewicz, Danuta
  • Mlyniec, Katarzyna
  • Nowak, Gabriel
  • Sowa, Ireneusz
  • Wlaź, Piotr
Type
Published Article
Journal
Cellular and Molecular Life Sciences
Publisher
Springer-Verlag
Publication Date
Apr 25, 2023
Volume
80
Issue
5
Identifiers
DOI: 10.1007/s00018-023-04766-z
PMID: 37185787
PMCID: PMC10130118
Source
PubMed Central
Keywords
Disciplines
  • Original Article
License
Unknown

Abstract

The pharmacological activation of the GPR39 receptor has been proposed as a novel strategy for treating seizures; however, this hypothesis has not been verified experimentally. TC-G 1008 is a small molecule agonist increasingly used to study GPR39 receptor function but has not been validated using gene knockout. Our aim was to assess whether TC-G 1008 produces anti-seizure/anti-epileptogenic effects in vivo and whether the effects are mediated by GPR39. To obtain this goal we utilized various animal models of seizures/epileptogenesis and GPR39 knockout mice model. Generally, TC-G 1008 exacerbated behavioral seizures. Furthermore, it increased the mean duration of local field potential recordings in response to pentylenetetrazole (PTZ) in zebrafish larvae. It facilitated the development of epileptogenesis in the PTZ-induced kindling model of epilepsy in mice. We demonstrated that TC-G 1008 aggravated PTZ-epileptogenesis by selectively acting at GPR39. However, a concomitant analysis of the downstream effects on the cyclic-AMP-response element binding protein in the hippocampus of GPR39 knockout mice suggested that the molecule also acts via other targets. Our data argue against GPR39 activation being a viable therapeutic strategy for treating epilepsy and suggest investigating whether TC-G 1008 is a selective agonist of the GPR39 receptor. Supplementary Information The online version contains supplementary material available at 10.1007/s00018-023-04766-z.

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