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Article

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

1
Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo namesti 2, 16000 Prague, Czech Republic
2
Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, 14220 Prague, Czech Republic
3
Institute of Endocrinology, Narodni 8, 11694 Prague, Czech Republic
4
Institute of Mental Health, Topolova 748, 25067 Klecany, Czech Republic
5
Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Strada le Grazie 8, 37134 Verona, Italy
*
Authors to whom correspondence should be addressed.
Academic Editors: Lusine Danielyan and Huu Phuc Nguyen
Pharmaceuticals 2022, 15(1), 49; https://doi.org/10.3390/ph15010049
Received: 30 November 2021 / Revised: 21 December 2021 / Accepted: 27 December 2021 / Published: 30 December 2021
(This article belongs to the Special Issue New Drugs and Biologics For Treatment of Central Nervous Dysfunction)
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. View Full-Text
Keywords: neurosteroids; anticonvulsant; zuranolone; NMDA; GABA; metabolomics neurosteroids; anticonvulsant; zuranolone; NMDA; GABA; metabolomics
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MDPI and ACS Style

Kudova, E.; Mares, P.; Hill, M.; Vondrakova, K.; Tsenov, G.; Chodounska, H.; Kubova, H.; Vales, K. The Neuroactive Steroid Pregnanolone Glutamate: Anticonvulsant Effect, Metabolites and Its Effect on Neurosteroid Levels in Developing Rat Brains. Pharmaceuticals 2022, 15, 49. https://doi.org/10.3390/ph15010049

AMA Style

Kudova E, Mares P, Hill M, Vondrakova K, Tsenov G, Chodounska H, Kubova H, Vales K. The Neuroactive Steroid Pregnanolone Glutamate: Anticonvulsant Effect, Metabolites and Its Effect on Neurosteroid Levels in Developing Rat Brains. Pharmaceuticals. 2022; 15(1):49. https://doi.org/10.3390/ph15010049

Chicago/Turabian Style

Kudova, Eva, Pavel Mares, Martin Hill, Katerina Vondrakova, Grygoriy Tsenov, Hana Chodounska, Hana Kubova, and Karel Vales. 2022. "The Neuroactive Steroid Pregnanolone Glutamate: Anticonvulsant Effect, Metabolites and Its Effect on Neurosteroid Levels in Developing Rat Brains" Pharmaceuticals 15, no. 1: 49. https://doi.org/10.3390/ph15010049

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