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

0551648 - ÚOCHB 2023 RIV CH eng J - Journal Article
Kudová, Eva - Mareš, Pavel - Hill, M. - Vondráková, Kateřina - Tsenov, Grygoriy - Chodounská, Hana - Kubová, Hana - Valeš, Karel
The Neuroactive Steroid Pregnanolone Glutamate: Anticonvulsant Effect, Metabolites and Its Effect on Neurosteroid Levels in Developing Rat Brains.
Pharmaceuticals. Roč. 15, č. 1 (2022), č. článku 49. E-ISSN 1424-8247
R&D Projects: GA MZd(CZ) EF16_025/0007444; GA MZd(CZ) NU20-04-00389
Institutional support: RVO:61388963 ; RVO:67985823
Keywords : neurosteroids * anticonvulsant * zuranolone * NMDA * GABA * metabolomics
OECD category: Organic chemistry
Impact factor: 4.6, year: 2022
Method of publishing: Open access
https://www.mdpi.com/1424-8247/15/1/49

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.
Permanent Link: http://hdl.handle.net/11104/0326887