Effects of Pregnanolone Glutamate and Its Metabolites on GABAA and NMDA Receptors and Zebrafish Behavior

0572804 - FGÚ 2024 RIV US eng J - Journal Article
Abramová, Vera - Leal Alvarado, Vanessa - Hill, M. - Smejkalová, Tereza - Malý, Michal - Valeš, Karel - Dittert, Ivan - Božíková, Paulina - Kysilov, Bohdan - Hrčka Krausová, Barbora - Vyklický, Vojtěch - Balík, Aleš - Fili, Klevinda - Kořínek, Miloslav - Chodounská, Hana - Kudová, Eva - Číž, D. - Martinovič, J. - Černý, Jiří - Bartůněk, Petr - Vyklický ml., Ladislav
Effects of Pregnanolone Glutamate and Its Metabolites on GABAA and NMDA Receptors and Zebrafish Behavior.
ACS Chemical Neuroscience. Roč. 14, č. 10 (2023), s. 1870-1883. ISSN 1948-7193. E-ISSN 1948-7193
R&D Projects: GA MZd(CZ) EF16_025/0007444; GA MŠMT LM2023052; GA ČR(CZ) GA23-04922S; GA TA ČR(CZ) TN02000109
Research Infrastructure: CZ-OPENSCREEN IV - 90252
Institutional support: RVO:67985823 ; RVO:86652036 ; RVO:61388963 ; RVO:68378050
Keywords : negative allosteric modulator * thigmotaxis * steroid * glutamate * zebrafish
OECD category: Neurosciences (including psychophysiology; Neurosciences (including psychophysiology (UOCHB-X); Biochemistry and molecular biology (UMG-J); Biochemistry and molecular biology (BTO-N)
Impact factor: 5, year: 2022
Method of publishing: Limited access
https://doi.org/10.1021/acschemneuro.3c00131

Multiple molecular targets have been identified to mediate membrane-delimited and nongenomic effects of natural and synthetic steroids, but the influence of steroid metabolism on neuroactive steroid signaling is not well understood. To begin to address this question, we set out to identify major metabolites of a neuroprotective synthetic steroid 20-oxo5 beta-pregnan-3 alpha-yl L-glutamyl 1-ester (pregnanolone glutamate, PAG) and characterize their effects on GABAA and NMDA receptors (GABARs, NMDARs) and their influence on zebrafish behavior. Gas chromatography- mass spectrometry was used to assess concentrations of PAG and its metabolites in the hippocampal tissue of juvenile rats following intraperitoneal PAG injection. PAG is metabolized in the peripheral organs and nervous tissue to 20-oxo-17 alpha-hydroxy-5 beta-pregnan-3 alpha-yl L-glutamyl 1-ester (17-hydroxypregnanolone glutamate, 17-OH-PAG), 3 alpha-hydroxy-5 beta-pregnan-20-one (pregnanolone, PA), and 3 alpha,17 alpha-dihydroxy-5 beta-pregnan-20-one (17-hydroxypregnanolone, 17-OH-PA). Patch-clamp electrophysiology experiments in cultured hippocampal neurons demonstrate that PA and 17-OH-PA are potent positive modulators of GABARs, while PAG and 17-OH-PA have a moderate inhibitory effect at NMDARs. PAG, 17-OH-PA, and PA diminished the locomotor activity of zebrafish larvae in a dose-dependent manner. Our results show that PAG and its metabolites are potent modulators of neurotransmitter receptors with behavioral consequences and indicate that neurosteroid-based ligands may have therapeutic potential.
Permanent Link: https://hdl.handle.net/11104/0343402