| Autor: |
Kudova E; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo namesti 2, 16000 Prague, Czech Republic., Mares P; Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, 14220 Prague, Czech Republic., Hill M; Institute of Endocrinology, Narodni 8, 11694 Prague, Czech Republic., Vondrakova K; Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, 14220 Prague, Czech Republic.; Institute of Mental Health, Topolova 748, 25067 Klecany, Czech Republic., Tsenov G; Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, 14220 Prague, Czech Republic.; Institute of Mental Health, Topolova 748, 25067 Klecany, Czech Republic.; Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Strada le Grazie 8, 37134 Verona, Italy., Chodounska H; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo namesti 2, 16000 Prague, Czech Republic., Kubova H; Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, 14220 Prague, Czech Republic., Vales K; Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, 14220 Prague, Czech Republic.; Institute of Mental Health, Topolova 748, 25067 Klecany, Czech Republic. |
| Abstrakt: |
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 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. |
