Molecular mechanisms mediating the neuroprotective role of the selective estrogen receptor modulator, bazedoxifene, in acute ischemic stroke: A comparative study with 17β-estradiol
Molecular mechanisms mediating the neuroprotective role of the selective estrogen receptor modulator, bazedoxifene, in acute ischemic stroke: A comparative study with 17β-estradiol
复制标题
DOI：
10.1016/j.jsbmb.2017.05.001
复制
发表时间：
2017-07-01
影响因子：
4.1
通讯作者：
Salom, Juan B.
中科院分区：
文献类型：
--
作者：
Jover-Mengual, Teresa;Castello-Ruiz, Maria;Salom, Juan B.
随着对大脑中雌激素系统的了解的增加，为了在脑损伤性疾病中提供进一步的神经保护而对其进行调节的可能性也在增加，我们以前已经证明了选择性雌激素受体调节剂bazedoxifene（BZA）减少实验性缺血性脑损伤的能力。本研究旨在通过以下研究深入了解这种神经保护作用的分子机制：1）卒中诱导的凋亡性细胞死亡; 2）雌激素受体（ER）ER α、ER β和G蛋白偶联雌激素受体（GPER）的表达; 3）MAPK/ERK 1/2和PI 3 K/Akt信号通路的调节。为了进行比较，对17只β-雌二醇（E2）给药动物进行了平行研究。将短暂性右侧大脑中动脉闭塞（tMCAO，管腔内螺纹技术，60 min）的雄性Wistar大鼠分配至溶媒-、BZA-（血浆中为20.7 +/- 2.1 ng/mL）和E2-（血浆中为45.6 +/- 7.8 pg/mL）给药组。在发病后24 h，对脑组织样品进行RT-PCR、Western blot和组织化学分析。缺血再灌注本身增加细胞凋亡的caspase-3活性和TUNEL阳性细胞计数，这是逆转BZA和E2。ER α和ER β的表达，但不是GPER的表达，减少了缺血性损伤。BZA和E2具有不同的作用：BZA增加ER α和E11 β的表达，E2增加ER α的表达，但不改变ER β的表达。缺血条件下MAPK/ERK 1/2和PI 3 K/Akt通路均被激活。虽然BZA强烈降低了增加的p-EFIK 1/2水平，但E2没有。BZA和E2均未改变缺血诱导的p-Akt水平升高。这些结果表明，ER α和ER β表达以及ERK 1/2信号通路的调节至少部分地解释了BZA对中风诱导的凋亡性细胞死亡的抑制作用。这为考虑BZA作为急性缺血性卒中治疗中的潜在神经保护药物提供了机制支持。
As the knowledge on the estrogenic system in the brain grows, the possibilities to modulate it in order to afford further neuroprotection in brain damaging disorders so do it. We have previously demonstrated the ability of the selective estrogen receptor modulator, bazedoxifene (BZA), to reduce experimental ischemic brain damage. The present study has been designed to gain insight into the molecular mechanisms involved in such a neuroprotective action by investigating: 1) stroke-induced apoptotic cell death; 2) expression of estrogen receptors (ER) ER alpha, ER beta and the G-protein coupled estrogen receptor (GPER); and 3) modulation of MAPK/ERK1/2 and PI3K/Akt signaling pathways. For comparison, a parallel study was done with 17 beta-estradiol (E2) treated animals. Male Wistar rats subject to transient right middle cerebral artery occlusion (tMCAO, intraluminal thread technique, 60 min), were distributed in vehicle-,BZA-(20.7 +/- 2.1 ng/mL in plasma) and E2- (45.6 +/- 7.8 pg/mL in plasma) treated groups. At 24 h from the onset of tMCAO, RT-PCR,Western blot and histochemical analysis were performed on brain tissue samples. Ischemia-reperfusion per se increased apoptosis as assessed by both caspase-3 activity and TUNEL-positive cell counts, which were reversed by both BZA and E2. ERa and ER beta expression, but not that of GPER, was reduced by the ischemic insult. BZA and E2 had different effects: while BZA increased both ER alpha and Ell beta expression, E2 increased ERa expression but did not change that of ER beta. Both MAPK/ERK1/2 and PI3K/Akt pathways were stimulated under ischemic conditions. While BZA strongly reduced the increased p-EFIK1/2 levels, E2 did not. Neither BZA nor E2 modified ischemia-induced increase in p-Akt levels. These results show that modulation of ERa and ER beta expression, as well as of the ERK1/2 signaling pathway accounts, at least in part, for the inhibitory effect of BZA on the stroke-induced apoptotic cell death. This lends mechanistic support to the consideration of BZA as a potential neuroprotective drug in acute ischemic stroke treatment.