title: Regulation of N-methyl-D-aspartate cytotoxicity by neuroactive steroids in rat cortical neurons.
abstract: We investigated the effects of neuroactive steroids on N-methyl-D-aspartate (NMDA) cytotoxicity in cultured rat cortical neurons. 3alpha-hydroxy-5beta-pregnan-20-one sulfate (3alpha5betaS) attenuated, whereas pregnenolone sulfate and pregnenolone hemisuccinate exacerbated, NMDA neurotoxicity in cortical slice cultures. These actions of steroids were not affected by inhibition of protein synthesis, by blockade of GABA(A) receptors, or by blockade of sigma receptors. In addition, the actions of steroids were not affected by manipulation of cyclic AMP levels or protein kinase C activity. We found that 3alpha5betaS attenuated and pregnenolone hemisuccinate augmented NMDA-induced currents in cortical neurons, whereas pregnenolone sulfate exerted no significant effect. Fluorometric measurements revealed that 3alpha5betaS attenuated and pregnenolone hemisuccinate augmented glutamate-induced increase in intracellular Ca(2+). Pregnenolone sulfate slowed the decay of Ca(2+) increase induced by glutamate, without significant effect on the peak amplitude of Ca(2+) increase. These results indicate that neuroactive steroids affect NMDA cytotoxicity by modulation of Ca(2+) influx through NMDA receptor-associated channels.
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Shirakawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Katsuki
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kume
authors.forename: Shuji
authors.initials: S
authors.lastname: Kaneko
authors.forename: Juichi
authors.initials: J
authors.lastname: Ito
authors.forename: Akinori
authors.initials: A
authors.lastname: Akaike
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D016202:N-Methylaspartate / Q000633:toxicity*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D011278:Pregnanes / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000502:physiology
chemical_list: D011278:Pregnanes; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate