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Novel neurosteroid pregnanolone pyroglutamate suppresses neurotoxicity syndrome induced by tetramethylenedisulfotetramine but is ineffective in a rodent model of infantile spasms
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SYSNO ASEP 0565558 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Novel neurosteroid pregnanolone pyroglutamate suppresses neurotoxicity syndrome induced by tetramethylenedisulfotetramine but is ineffective in a rodent model of infantile spasms Tvůrce(i) Chern, C. R. (US)
Lauková, M. (SK)
Schonwald, A. (US)
Kudová, Eva (UOCHB-X) RID, ORCID
Chodounská, Hana (UOCHB-X) RID, ORCID
Chern, C. J. (US)
Shakarjian, M. P. (US)
Velíšková, J. (US)
Velíšek, L. (US)Zdroj.dok. Pharmacological Reports. - : Springer - ISSN 1734-1140
Roč. 75, č. 1 (2023), s. 177-188Poč.str. 12 s. Jazyk dok. eng - angličtina Země vyd. PL - Polsko Klíč. slova tetramethylenedisulfotetramine ; neurotoxicity ; severe seizures ; neurosteroids ; antidote Obor OECD Neurosciences (including psychophysiology Způsob publikování Omezený přístup Institucionální podpora UOCHB-X - RVO:61388963 UT WOS 000887877300001 EID SCOPUS 85142421203 DOI 10.1007/s43440-022-00437-1 Anotace Background: Neurosteroids are investigated as effective antidotes for the poisoning induced by tetramethylenedisulfotetramine (TMDT) as well as treatments for epileptic spasms during infancy. Both these conditions are quite resistant to pharmacotherapy, thus, a search for new treatments is warranted. Methods: In this study, we determined the efficacy of two novel neurosteroids, pregnanolone glutamate (PAG) and pregnanolone pyroglutamate (PPG), and tested these drugs in doses of 1-10 mg/kg (ip) against the TMDT syndrome and in our rodent model of infantile spasms. Results: Only PPG in doses 5 and 10 mg/kg suppressed the severity of the TMDT syndrome and TMDT-induced lethality, while the 1 mg/kg dose was without an effect. Interestingly, the 1 mg/kg dose of PPG in combination with 1 mg/kg of diazepam was also effective against TMDT poisoning. Neither PAG nor PPG were effective against experimental spasms in the N-methyl-D-aspartate (NMDA)-triggered model of infantile spasms. Conclusions: While evidence suggests that PAG can act through multiple actions which include allosteric inhibition of NMDA-induced and glycine receptor-evoked currents as well as augmentation of gamma-aminobutyric acid subtype A (GABAA) receptor-induced currents, the agent appears to neither have the appropriate mechanistic signature for activity in the infantile spasm model, nor the adequate potency, relative to PPG, for ameliorating the TMDT syndrome. The full mechanisms of action of PPG, which may become a potent TMDT antidote either alone or in combination with diazepam are yet unknown and thus require further investigation. Pracoviště Ústav organické chemie a biochemie Kontakt asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Rok sběru 2024 Elektronická adresa https://doi.org/10.1007/s43440-022-00437-1
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