Screening of novel 3 alpha 5 beta-neurosteroids for neuroprotective activity against glutamate- or NMDA-induced excitotoxicity

0505510 - ÚOCHB 2020 RIV GB eng J - Journal Article
Šmídková, Markéta - Hájek, Miroslav - Adla, Santosh Kumar - Slavíková, Barbora - Chodounská, Hana - Matoušová, Marika - Mertlíková-Kaiserová, Helena - Kudová, Eva
Screening of novel 3 alpha 5 beta-neurosteroids for neuroprotective activity against glutamate- or NMDA-induced excitotoxicity.
Journal of Steroid Biochemistry and Molecular Biology. Roč. 189, May (2019), s. 195-203. ISSN 0960-0760
R&D Projects: GA TA ČR(CZ) TE01020028; GA MŠMT LO1302; GA TA ČR(CZ) TN01000013
Institutional support: RVO:61388963
Keywords : neurosteroids * NMDAR * glutamate excitotoxicity * neuroprotection
OECD category: Biochemistry and molecular biology
Impact factor: 3.813, year: 2019
Method of publishing: Limited access
https://www.sciencedirect.com/science/article/abs/pii/S0960076019300378?via%3Dihub

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.
Permanent Link: http://hdl.handle.net/11104/0296991