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5β-reduced neuroactive steroids as modulators of growth and viability of postnatal neurons and glia
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SYSNO ASEP 0584427 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title 5β-reduced neuroactive steroids as modulators of growth and viability of postnatal neurons and glia Author(s) Cheema, Marie Munawar (FGU-C)
Kotrbová Macáková, Zuzana (UMG-J)
Hrčka Krausová, Barbora (FGU-C) ORCID, RID
Adla, Santosh Kumar (UOCHB-X) ORCID
Slavíková, Barbora (UOCHB-X) RID, ORCID
Chodounská, Hana (UOCHB-X) RID, ORCID
Kratochvíl, Miroslav (UOCHB-X) ORCID, RID
Vondrášek, Jiří (UOCHB-X) RID, ORCID
Sedlák, David (UMG-J) RID
Balaštík, Martin (FGU-C) RID, ORCID
Kudová, Eva (UOCHB-X) RID, ORCIDNumber of authors 11 Article number 106464 Source Title Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier - ISSN 0960-0760
Roč. 239, May (2024)Number of pages 13 s. Language eng - English Country GB - United Kingdom Keywords neurosteroids ; neuroactive steroids ; neurite growth ; computational analysis ; myelin basic protein ; high-content screening OECD category Clinical neurology R&D Projects LX22NPO5107 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) NV18-04-00085 GA MZd - Ministry of Health (MZ) GA21-24571S GA ČR - Czech Science Foundation (CSF) Research Infrastructure CZ-OPENSCREEN III - 90130 - Ústav molekulární genetiky AV ČR, v. v. i.
CZ-OPENSCREEN II - 90063 - Ústav molekulární genetiky AV ČR, v. v. i.
CCP II - 90126 - Ústav molekulární genetiky AV ČR, v. v. i.Institutional support FGU-C - RVO:67985823 ; UOCHB-X - RVO:61388963 ; UMG-J - RVO:68378050 UT WOS 001171172200001 EID SCOPUS 85185186454 DOI 10.1016/j.jsbmb.2024.106464 Annotation Endogenous neurosteroids (NS) and their synthetic analogs, neuroactive steroids (NAS), are potentially useful drug-like compounds affecting the pathophysiology of miscellaneous central nervous system disorders (e.g. Alzheimer ' s disease, epilepsy, depression, etc.). Additionally, NS have been shown to promote neuron viability and neurite outgrowth upon injury. The molecular, structural and physicochemical basis of the NS effect on neurons is so far not fully understood, and the development of new, biologically relevant assays is essential for their comparative analysis and for assessment of their mechanism of action. Here, we report the development of a novel, plate-based, high-content in vitro assay for screening of NS and newly synthesized, 5 beta-reduced NAS for the promotion of postnatal neuron survival and neurite growth using fluorescent, postnatal mixed cortical neuron cultures isolated from thy1-YFP transgenic mice. The screen allows a detailed time course analysis of different parameters, such as the number of neurons or neurite lengths of 7-day, in vitro neuron cultures. Using the screen, we identify a new NAS, compound 42, that promotes the survival and growth of postnatal neurons significantly better than several endogenous NS (dehydroepiandrosterone, progesterone, and allopregnanolone). Interestingly, we demonstrate that compound 42 also promotes the proliferation of glia (in particular oligodendrocytes) and that the glial function is critical for its neuron growth support. Computational analysis of the biological data and calculated physicochemical properties of tested NS and NAS demonstrated that their biological activity is proportional to their lipophilicity. Together, the screen proves useful for the selection of neuron-active NAS and the comparative evaluation of their biologically relevant structural and physicochemical features. Workplace Institute of Physiology Contact Lucie Trajhanová, lucie.trajhanova@fgu.cas.cz, Tel.: 241 062 400 Year of Publishing 2025 Electronic address https://doi.org/10.1016/j.jsbmb.2024.106464
Number of the records: 1