β-Estradiol, Dehydroepiandrosterone, and Dehydroepiandrosterone Sulfate Protect against N-Methyl-d-aspartate-Induced Neurotoxicity in Rat Hippocampal Neurons by Different Mechanisms
β-Estradiol, Dehydroepiandrosterone, and Dehydroepiandrosterone Sulfate Protect against N-Methyl-d-aspartate-Induced Neurotoxicity in Rat Hippocampal Neurons by Different Mechanisms
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DOI：
10.1124/jpet.104.067629
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发表时间：
2004-10
影响因子：
3.5
通讯作者：
K. Kurata;M. Takebayashi;S. Morinobu;S. Yamawaki
中科院分区：
文献类型：
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作者：
K. Kurata;M. Takebayashi;S. Morinobu;S. Yamawaki
本研究观察了β-雌二醇、脱氢表雄酮（DHEA）和硫酸脱氢表雄酮（DHEA-S）对N-甲基-d-天冬氨酸（NMDA）诱导的原代培养大鼠海马神经元神经毒性的保护作用。所有三种类固醇都表现出神经保护作用。时程研究表明，类固醇共治疗只有15分钟，同时暴露于NMDA，但既不预处理，也不添加类固醇24小时后，NMDA介导的神经保护作用。这表明这些类固醇的短期作用对这一过程至关重要。β-雌二醇急性处理剂量依赖性地抑制NMDA诱导的细胞内Ca 2+升高，这与其通过L型电压门控钙通道的神经保护作用密切相关。DHEA的急性治疗，但不与DHEA-S，显着抑制一氧化氮（NO）的生产和Ca 2+敏感的NO合酶（NOS）活性引起的NMDA刺激。一氧化氮合酶抑制剂，NG-单甲基-L-精氨酸乙酸酯也保护对NMDA诱导的神经毒性。这些数据表明，β-雌二醇可能主要通过减少Ca 2+升高而发挥神经保护作用，而DHEA可能通过抑制NOS活性而起作用。用σ-1受体（Sig-1 R）拮抗剂rimcazole或BD 1063（1-[2-（3，4-二氯苯基）乙基]-4-甲基哌嗪二盐酸盐）处理，部分但显著逆转了DHEA-S对NMDA诱导的神经毒性的神经保护作用，而蝇蕈醇，一种GABA-A受体激动剂，则没有。这表明DHEA-S的神经保护作用可能至少部分通过Sig-1 R介导。总之，我们的数据表明，神经类固醇家族成员β-雌二醇，DHEA和DHEA-S通过不同的非基因组机制发挥神经保护作用。
We examined neuroprotective effects of β-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 β-estradiol dose dependently inhibited NMDA-induced intracellular Ca2+ 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 Ca2+-sensitive NO synthase (NOS) activity caused by NMDA stimulation. An NOS inhibitor, NG-monomethyl-l-arginine acetate was also protective against NMDA-induced neurotoxicity. These data indicate that β-estradiol may exert neuroprotective effects mainly by reducing Ca2+ increases but that DHEA may act by inhibiting NOS activity. Treatment with the σ-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 β-estradiol, DHEA, and DHEA-S exert neuroprotective effects through different nongenomic mechanisms.