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Screening of novel 3 alpha 5 beta-neurosteroids for neuroprotective activity against glutamate- or NMDA-induced excitotoxicity
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SYSNO ASEP 0505510 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Screening of novel 3 alpha 5 beta-neurosteroids for neuroprotective activity against glutamate- or NMDA-induced excitotoxicity Author(s) Šmídková, Markéta (UOCHB-X) RID, ORCID
Hájek, Miroslav (UOCHB-X) RID, ORCID
Adla, Santosh Kumar (UOCHB-X) ORCID
Slavíková, Barbora (UOCHB-X) RID, ORCID
Chodounská, Hana (UOCHB-X) RID, ORCID
Matoušová, Marika (UOCHB-X) ORCID
Mertlíková-Kaiserová, Helena (UOCHB-X) RID, ORCID
Kudová, Eva (UOCHB-X) RID, ORCIDSource Title Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier - ISSN 0960-0760
Roč. 189, May (2019), s. 195-203Number of pages 9 s. Language eng - English Country GB - United Kingdom Keywords neurosteroids ; NMDAR ; glutamate excitotoxicity ; neuroprotection Subject RIV CE - Biochemistry OECD category Biochemistry and molecular biology R&D Projects TE01020028 GA TA ČR - Technology Agency of the Czech Republic (TA ČR) LO1302 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) TN01000013 GA TA ČR - Technology Agency of the Czech Republic (TA ČR) Method of publishing Limited access Institutional support UOCHB-X - RVO:61388963 UT WOS 000468711800023 EID SCOPUS 85063004879 DOI 10.1016/j.jsbmb.2019.03.007 Annotation A broad variety of central nervous system diseases have been associated with glutamate induced excitotoxicity under pathological conditions. The neuroprotective effects of neurosteroids can combat this excitotoxicity. Herein, we have demonstrated the neuroprotective effect of novel steroidal N-methyl-D-aspartate receptor inhibitors against glutamate- or NMDA-induced excitotoxicity. Pretreatment with neurosteroids significantly reduced acute L-glutamic acid or NMDA excitotoxicity mediated by Ca2+ entry and consequent ROS (reactive oxygen species) release and caspase-3 activation. Compounds 6 (IC50 = 5.8 mu M), 7 (IC50 = 12.2 mu M), 9 (IC50 = 7.8 mu M), 13 (IC50 = 1.1 mu M) and 16 (IC50 = 8.2 mu M) attenuated glutamate-induced Ca2+ entry more effectively than memantine (IC50 = 18.9 mu M). Moreover, compound 13 shows comparable effect with MK-801 (IC50 = 1.2 mu M) and also afforded significant protection without any adverse effect upon prolonged exposure. This drop in Ca2+ level resulted in corresponding ROS suppression and prevented glutamate-induced caspase-3 activation. Therefore, compound 13 has great potential for development into a therapeutic agent for improving glutamate-related nervous system diseases. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Year of Publishing 2020 Electronic address https://www.sciencedirect.com/science/article/abs/pii/S0960076019300378?via%3Dihub
Number of the records: 1