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

Kód výsledku v 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>

Nalezeny alternativní kódy

RIV/86652036:_____/23:00572804 RIV/67985823:_____/23:00572804 RIV/68378050:_____/23:00572804 RIV/00216208:11120/23:43925391 a 2 dalších

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30103 - Neurosciences (including psychophysiology)

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2023

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

ACS Chemical Neuroscience

ISSN

1948-7193

e-ISSN

1948-7193

Svazek periodika

14

Číslo periodika v rámci svazku

10

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

14

Strana od-do

1870-1883

Kód UT WoS článku

000984445000001

EID výsledku v databázi Scopus

2-s2.0-85159605177