The Neuroactive Steroid Pregnanolone Glutamate: Anticonvulsant Effect, Metabolites and Its Effect on Neurosteroid Levels in Developing Rat Brains
Identifikátory výsledku
Kód výsledku v IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00023761%3A_____%2F22%3AN0000009" target="_blank" >RIV/00023761:_____/22:N0000009 - isvavai.cz</a>
Nalezeny alternativní kódy
RIV/61388963:_____/22:00551648 RIV/67985823:_____/22:00551648 RIV/00023752:_____/22:43920803
Výsledek na webu
<a href="https://www.mdpi.com/1424-8247/15/1/49" target="_blank" >https://www.mdpi.com/1424-8247/15/1/49</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.3390/ph15010049" target="_blank" >10.3390/ph15010049</a>
Alternativní jazyky
Jazyk výsledku
angličtina
Název v původním jazyce
The Neuroactive Steroid Pregnanolone Glutamate: Anticonvulsant Effect, Metabolites and Its Effect on Neurosteroid Levels in Developing Rat Brains
Popis výsledku v původním jazyce
Pregnanolone glutamate (PA-G) is a neuroactive steroid that has been previously demonstrated to be a potent neuroprotective compound in several biological models in vivo. Our in vitro experiments identified PA-G as an inhibitor of N-methyl-D-aspartate receptors and a potentiator of gamma-aminobutyric acid receptors (GABA(A)Rs). In this study, we addressed the hypothesis that combined GABA(A)R potentiation and NMDAR antagonism could afford a potent anticonvulsant effect. Our results demonstrated the strong age-related anticonvulsive effect of PA-G in a model of pentylenetetrazol-induced seizures. PA-G significantly decreased seizure severity in 12-day-old animals, but only after the highest dose in 25-day-old animals. Interestingly, the anticonvulsant effect of PA-G differed both qualitatively and quantitatively from that of zuranolone, an investigational neurosteroid acting as a potent positive allosteric modulator of GABA(A)Rs. Next, we identified 17-hydroxy-pregnanolone (17-OH-PA) as a major metabolite of PA-G in 12-day-old animals. Finally, the administration of PA-G demonstrated direct modulation of unexpected neurosteroid levels, namely pregnenolone and dehydroepiandrosterone sulfate. These results suggest that compound PA-G might be a pro-drug of 17-OH-PA, a neurosteroid with a promising neuroprotective effect with an unknown mechanism of action that may represent an attractive target for studying perinatal neural diseases.
Název v anglickém jazyce
The Neuroactive Steroid Pregnanolone Glutamate: Anticonvulsant Effect, Metabolites and Its Effect on Neurosteroid Levels in Developing Rat Brains
Popis výsledku anglicky
Pregnanolone glutamate (PA-G) is a neuroactive steroid that has been previously demonstrated to be a potent neuroprotective compound in several biological models in vivo. Our in vitro experiments identified PA-G as an inhibitor of N-methyl-D-aspartate receptors and a potentiator of gamma-aminobutyric acid receptors (GABA(A)Rs). In this study, we addressed the hypothesis that combined GABA(A)R potentiation and NMDAR antagonism could afford a potent anticonvulsant effect. Our results demonstrated the strong age-related anticonvulsive effect of PA-G in a model of pentylenetetrazol-induced seizures. PA-G significantly decreased seizure severity in 12-day-old animals, but only after the highest dose in 25-day-old animals. Interestingly, the anticonvulsant effect of PA-G differed both qualitatively and quantitatively from that of zuranolone, an investigational neurosteroid acting as a potent positive allosteric modulator of GABA(A)Rs. Next, we identified 17-hydroxy-pregnanolone (17-OH-PA) as a major metabolite of PA-G in 12-day-old animals. Finally, the administration of PA-G demonstrated direct modulation of unexpected neurosteroid levels, namely pregnenolone and dehydroepiandrosterone sulfate. These results suggest that compound PA-G might be a pro-drug of 17-OH-PA, a neurosteroid with a promising neuroprotective effect with an unknown mechanism of action that may represent an attractive target for studying perinatal neural diseases.
Klasifikace
Druh
J<sub>imp</sub> - Článek v periodiku v databázi Web of Science
CEP obor
—
OECD FORD obor
30104 - Pharmacology and pharmacy
Návaznosti výsledku
Projekt
Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.
Návaznosti
N - Vyzkumna aktivita podporovana z neverejnych zdroju
Ostatní
Rok uplatnění
2022
Kód důvěrnosti údajů
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Údaje specifické pro druh výsledku
Název periodika
Pharmaceuticals
ISSN
1424-8247
e-ISSN
1424-8247
Svazek periodika
15
Číslo periodika v rámci svazku
1
Stát vydavatele periodika
CH - Švýcarská konfederace
Počet stran výsledku
19
Strana od-do
Article Number 49
Kód UT WoS článku
000757087600001
EID výsledku v databázi Scopus
2-s2.0-85122128797