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

Pharmaceuticals

卷:15

Martin Hill¹  Eva Kudova²  Hana Chodounska²  Pavel Mares³  Grygoriy Tsenov³  Hana Kubova³  Katerina Vondrakova³  Karel Vales³ 

[1] Institute of Endocrinology, Narodni 8, 11694 Prague, Czech Republic;

[2] Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo namesti 2, 16000 Prague, Czech Republic;

[3] Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, 14220 Prague, Czech Republic;

关键词: neurosteroids;    anticonvulsant;    zuranolone;    NMDA;    GABA;    metabolomics;   

DOI  :  10.3390/ph15010049

来源: DOAJ

【 摘 要 】

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 (GABA_ARs). In this study, we addressed the hypothesis that combined GABA_AR 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_ARs. 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.

【 授权许可】

Unknown