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

Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F19%3A00505510" target="_blank" >RIV/61388963:_____/19:00505510 - isvavai.cz</a>
Result on the web
<a href="https://www.sciencedirect.com/science/article/abs/pii/S0960076019300378?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/abs/pii/S0960076019300378?via%3Dihub</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.jsbmb.2019.03.007" target="_blank" >10.1016/j.jsbmb.2019.03.007</a>

Result language
angličtina
Original language name
Screening of novel 3 alpha 5 beta-neurosteroids for neuroprotective activity against glutamate- or NMDA-induced excitotoxicity
Original language description
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.
Czech name
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Czech description
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Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10608 - Biochemistry and molecular biology

Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year
2019
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

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