Screening of Novel 3α5β-Neurosteroids for Neuroprotective Activity against Glutamate- or NMDA-Induced Excitotoxicity

Publication date: Available online 11 March 2019Source: The Journal of Steroid Biochemistry and Molecular BiologyAuthor(s): Marketa Smidkova, Miroslav Hajek, Santosh Kumar Adla, Barbora Slavikova, Hana Chodounska, Marika Matousova, Helena Mertlikova-Kaiserova, Eva KudovaAbstractA 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 µM), 7 (IC50 = 12.2 µM), 9 (IC50 = 7.8 µM), 13 (IC50 = 1.1 µM) and 16 (IC50 = 8.2 µM) attenuated glutamate-induced Ca2+ entry more effectively than memantine (IC50 = 18.9 µM). Moreover, compound 13 shows comparable effect with MK-801 (IC50 = 1.2 µM) 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....

Source: The Journal of Steroid Biochemistry and Molecular Biology - March 12, 2019 Category: Biochemistry Source Type: research