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

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2019

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Journal of Steroid Biochemistry and Molecular Biology

ISSN

0960-0760

e-ISSN

—

Svazek periodika

189

Číslo periodika v rámci svazku

May

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

9

Strana od-do

195-203

Kód UT WoS článku

000468711800023

EID výsledku v databázi Scopus

2-s2.0-85063004879