PUBLICATION
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, U., Socała, K., Pieróg, M., Nieoczym, D., Sawicki, J., Szafarz, M., Gawel, K., Rafało-Ulińska, A., Sajnóg, A., Wyska, E., Esguerra, C.V., Szewczyk, B., Maćkowiak, M., Barałkiewicz, D., Mlyniec, K., Nowak, G., Sowa, I., Wlaź, P.
- ID
- ZDB-PUB-230516-38
- Date
- 2023
- Source
- Cellular and molecular life sciences : CMLS 80: 133133 (Journal)
- Registered Authors
- Esguerra, Camila V., Gawel, Kinga Aurelia
- Keywords
- 6-Hz seizures, BDNF, Maximal electroshock seizures, TrkB, Valproic acid, Zinc chloride
- MeSH Terms
-
- Animals
- Brain-Derived Neurotrophic Factor/metabolism
- Epilepsy*/chemically induced
- Epilepsy*/genetics
- Epilepsy*/metabolism
- Hippocampus/metabolism
- Mice
- Mice, Knockout
- Pentylenetetrazole*/metabolism
- Receptors, G-Protein-Coupled/genetics
- Receptors, G-Protein-Coupled/metabolism
- Zebrafish/metabolism
- PubMed
- 37185787 Full text @ Cell. Mol. Life Sci.
Citation
Doboszewska, U., Socała, K., Pieróg, M., Nieoczym, D., Sawicki, J., Szafarz, M., Gawel, K., Rafało-Ulińska, A., Sajnóg, A., Wyska, E., Esguerra, C.V., Szewczyk, B., Maćkowiak, M., Barałkiewicz, D., Mlyniec, K., Nowak, G., Sowa, I., Wlaź, P. (2023) TC-G 1008 facilitates epileptogenesis by acting selectively at the GPR39 receptor but non-selectively activates CREB in the hippocampus of pentylenetetrazole-kindled mice. Cellular and molecular life sciences : CMLS. 80:133133.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping