Effects of Pregnanolone Glutamate and Its Metabolites on GABAA and NMDA Receptors and Zebrafish Behavior
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F23%3A00572804" target="_blank" >RIV/61388963:_____/23:00572804 - isvavai.cz</a>
Alternative codes found
RIV/86652036:_____/23:00572804 RIV/67985823:_____/23:00572804 RIV/68378050:_____/23:00572804 RIV/00216208:11120/23:43925391 and 2 more
Result on the web
<a href="https://doi.org/10.1021/acschemneuro.3c00131" target="_blank" >https://doi.org/10.1021/acschemneuro.3c00131</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1021/acschemneuro.3c00131" target="_blank" >10.1021/acschemneuro.3c00131</a>
Alternative languages
Result language
angličtina
Original language name
Effects of Pregnanolone Glutamate and Its Metabolites on GABAA and NMDA Receptors and Zebrafish Behavior
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30103 - Neurosciences (including psychophysiology)
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2023
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
ACS Chemical Neuroscience
ISSN
1948-7193
e-ISSN
1948-7193
Volume of the periodical
14
Issue of the periodical within the volume
10
Country of publishing house
US - UNITED STATES
Number of pages
14
Pages from-to
1870-1883
UT code for WoS article
000984445000001
EID of the result in the Scopus database
2-s2.0-85159605177