Number of the records: 1

The Neuroactive Steroid Pregnanolone Glutamate: Anticonvulsant Effect, Metabolites and Its Effect on Neurosteroid Levels in Developing Rat Brains

SYSNO ASEP	0551648
Document Type	J - Journal Article
R&D Document Type	Journal Article
Subsidiary J	Článek ve WOS
Title	The Neuroactive Steroid Pregnanolone Glutamate: Anticonvulsant Effect, Metabolites and Its Effect on Neurosteroid Levels in Developing Rat Brains
Author(s)	Kudová, Eva (UOCHB-X)_{RID, ORCID} Mareš, Pavel (FGU-C)_{RID, ORCID} Hill, M. (CZ) Vondráková, Kateřina (FGU-C)_{RID, ORCID, SAI} Tsenov, Grygoriy (FGU-C)_{RID, ORCID} Chodounská, Hana (UOCHB-X)_{RID, ORCID} Kubová, Hana (FGU-C)_{RID, ORCID} Valeš, Karel (FGU-C)_{RID, ORCID, SAI}
Article number	49
Source Title	Pharmaceuticals. - : MDPI Roč. 15, č. 1 (2022)
Number of pages	19 s.
Language	eng - English
Country	CH - Switzerland
Keywords	neurosteroids ; anticonvulsant ; zuranolone ; NMDA ; GABA ; metabolomics
OECD category	Organic chemistry
R&D Projects	EF16_025/0007444 GA MZd - Ministry of Health (MZ)
	NU20-04-00389 GA MZd - Ministry of Health (MZ)
Method of publishing	Open access
Institutional support	UOCHB-X - RVO:61388963 ; FGU-C - RVO:67985823
UT WOS	000757087600001
EID SCOPUS	85122128797
DOI	10.3390/ph15010049
Annotation	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 γ-aminobutyric acid receptors (GABAARs). In this study, we addressed the hypothesis that combined GABAAR 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 GABAARs. 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.
Workplace	Institute of Organic Chemistry and Biochemistry
Contact	asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Viktorie Chládková, Tel.: 232 002 434
Year of Publishing	2023
Electronic address	https://www.mdpi.com/1424-8247/15/1/49

Number of the records: 1