Tamoxifen mediated estrogen receptor activation protects against early impairment of hippocampal neuron excitability in an oxygen/glucose deprivation brain slice ischemia model.
Tamoxifen mediated estrogen receptor activation protects against early impairment of hippocampal neuron excitability in an oxygen/glucose deprivation brain slice ischemia model.
复制标题
DOI：
10.1016/j.brainres.2008.10.015
复制
发表时间：
2009-01-09
期刊：
影响因子：
2.9
通讯作者：
Zhou M
中科院分区：
文献类型：
--
作者：
Zhang H;Xie M;Schools GP;Feustel PF;Wang W;Lei T;Kimelberg HK;Zhou M
雌激素预处理卵巢切除大鼠显示通过激活雌激素受体（ER）的长期保护。然而，它仍然是未知的激活的ER是否可以提供保护，防止早期神经元损伤时，急性，我们模拟缺血条件下，应用氧和葡萄糖剥夺（OGD）的解决方案，急性雄性大鼠海马脑片和检查神经元电生理变化。锥体神经元和中间神经元表现出时间依赖性的膜电位去极化和减少诱发动作电位的频率和幅度超过10至15分钟的OGD暴露。这些变化在很大程度上被10 μM TAM抑制。TAM效应是神经元特异性的，因为OGD诱导的星形胶质细胞膜电位去极化没有改变。TAM的作用是通过ER激活介导的，因为它可以被17β-雌二醇模拟，并被ER抑制剂ICI 182，780完全抑制，因此是TAM选择性雌激素受体调节剂（SERM）作用的一个例子。我们进一步表明，TAM对OGD诱导的神经元兴奋性损伤的作用主要是由于激活了神经保护性BK通道，因为10 μM的BK通道抑制剂paxilline显著减弱了TAM的作用。TAM还显著降低锥体神经元中AMPA受体介导的自发兴奋性突触后电流（sEPSC）的频率和幅度，这是OGD的早期结果。总之，本研究表明，17β-雌二醇和TAM均通过ER激活介导的BK+通道增强和增强的神经元AMPA/NMDA受体介导的兴奋性毒性的降低来减轻模拟缺血模型中早期的神经元兴奋性损伤。
Pretreatment of ovarectomized rats with estrogen shows long-term protection via activation of the estrogen receptor (ER). However, it remains unknown whether activation of the ER can provide protection against early neuronal damage when given acutely, we simulated ischemic conditions by applying oxygen and glucose deprived (OGD) solution to acute male rat hippocampal slices and examined the neuronal electrophysiological changes. Pyramidal neurons and interneurons showed a time-dependent membrane potential depolarization and reduction in evoked action potential frequency and amplitude over a 10 to 15 minute OGD exposure. These changes were largely suppressed by 10 μM TAM. The TAM effect was neuron-specific as the OGD induced astrocytic membrane potential depolarization was not altered. The TAM effect was mediated through ER activation because it could be simulated by 17β-estradiol and was completely inhibited by the ER inhibitor ICI 182, 780, and is therefore an example of TAM’s selective estrogen receptor modulator (SERM) action. We further show that TAM effects on OGD- induced impairment of neuronal excitability was largely due to activation of neuroprotective BK channels, as the TAM effect was markedly attenuated by the BK channel inhibitor paxilline at10 μM. TAM also significantly reduced the frequency and amplitude of AMPA receptor mediated spontaneous excitatory postsynaptic currents (sEPSCs) in pyramidal neurons which is an early consequence of OGD. Altogether, this study demonstrates that both 17β-estradiol and TAM attenuate neuronal excitability impairment early on in simulated ischemia model via ER activation mediated potentiation of BK K+ channels and reduction in enhanced neuronal AMPA/NMDA receptor-mediated excitotoxicity.
登录
查看更多内容
影响因子：
2.9
作者：
Gong, LW;Gao, TM;Tong, ZQ
通讯作者：
Tong, ZQ
影响因子：
1.7
作者：
Kimelberg, HK;Feustel, PJ;Tranmer, BI
通讯作者：
Tranmer, BI
影响因子：
5.3
作者：
Allen, NJ;Káradóttir, R;Attwell, D
通讯作者：
Attwell, D
影响因子：
2.9
作者：
Onitsuka, M;Mihara, S;Higashi, H
通讯作者：
Higashi, H
影响因子：
3.4
作者：
Benhassine, N;Berger, T
通讯作者：
Berger, T