title: beta-estradiol, dehydroepiandrosterone, and dehydroepiandrosterone sulfate protect against N-methyl-D-aspartate-induced neurotoxicity in rat hippocampal neurons by different mechanisms.
abstract: We examined neuroprotective effects of beta-estradiol, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEA-S) against N-methyl-D-aspartate (NMDA)-induced neurotoxicity in primary cultured rat hippocampal neurons. All three steroids demonstrated neuroprotective effects. Time-course studies revealed that steroid cotreatment for only 15 min at the same time as exposure to NMDA, but neither pretreatment nor addition of steroids for 24 h after NMDA-mediated neuroprotective effects. This indicates that short-term actions of these steroids are critical for this process. Acute treatment with beta-estradiol dose dependently inhibited NMDA-induced intracellular Ca(2+) increases, which strongly correlated with its neuroprotective effect via L-type voltage-gated calcium channels. Acute treatment with DHEA, but not with DHEA-S, significantly inhibited nitric oxide (NO) production and Ca(2+)-sensitive NO synthase (NOS) activity caused by NMDA stimulation. An NOS inhibitor, N(G)-monomethyl-L-arginine acetate was also protective against NMDA-induced neurotoxicity. These data indicate that beta-estradiol may exert neuroprotective effects mainly by reducing Ca(2+) increases but that DHEA may act by inhibiting NOS activity. Treatment with the sigma-1 receptor (Sig-1R) antagonists rimcazole or BD1063 (1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine dihydrochloride) partially, but significantly, reversed the neuroprotective effect of DHEA-S against NMDA-induced neurotoxicity, whereas muscimol, a GABA-A-receptor agonist, did not. This suggests that the neuroprotective effect of DHEA-S may be mediated via Sig-1R, at least in part. Together, our data suggest that the neurosteroid family members beta-estradiol, DHEA, and DHEA-S exert neuroprotective effects through different nongenomic mechanisms.
authors.affiliation: Department of Psychiatry and Neurosciences, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Kurata
authors.forename: Minoru
authors.initials: M
authors.lastname: Takebayashi
authors.forename: Shigeru
authors.initials: S
authors.lastname: Morinobu
authors.forename: Shigeto
authors.initials: S
authors.lastname: Yamawaki
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003687:Dehydroepiandrosterone / Q000494:pharmacology; D019314:Dehydroepiandrosterone Sulfate / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004347:Drug Interactions; D004958:Estradiol / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology*; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009543:Nifedipine / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism; D017480:Receptors, sigma / Q000378:metabolism; D000097605:Sigma-1 Receptor
chemical_list: D002118:Calcium; D003687:Dehydroepiandrosterone; D019314:Dehydroepiandrosterone Sulfate; D016291:Dizocilpine Maleate; D004958:Estradiol; D016202:N-Methylaspartate; D018696:Neuroprotective Agents; D009543:Nifedipine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D009599:Nitroprusside; D011963:Receptors, GABA-A; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor