Post-ischemic estradiol treatment reduced glial response and triggers distinct cortical and hippocampal signaling in a rat model of cerebral ischemia.
Post-ischemic estradiol treatment reduced glial response and triggers distinct cortical and hippocampal signaling in a rat model of cerebral ischemia.
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DOI：
10.1186/1742-2094-9-157
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发表时间：
2012-07-02
影响因子：
9.3
通讯作者：
Wandosell F
中科院分区：
文献类型：
--
作者：
Pérez-Álvarez MJ;Maza Mdel C;Anton M;Ordoñez L;Wandosell F
已经显示，在包括脑缺血在内的几种神经退行性疾病中，雌二醇发挥神经保护作用。在啮齿动物模型中，缺血前这种激素的存在减弱了与这些事件相关的损伤（大脑中动脉闭塞（MCAO）），尽管其在缺血后施用时的治疗价值尚未被评估。因此，我们评估了在大鼠中诱导永久性MCAO（pMCAO）后雌二醇治疗的效果，研究了PI 3 K/AKT/GSK 3/β-catenin存活通路和在受pMCAO不同影响的两个脑区（皮质和海马）中SAPK-JNK的活化。此外，我们分析了雌二醇对神经胶质细胞损伤反应的影响。雄性大鼠进行pMCAO和雌二醇（0.04毫克/公斤），手术后6，24和48小时。最后一次治疗后6小时处死动物，并通过免疫组化定量的“反应性胶质增生”使用抗GFAP和Iba 1抗体的脑损伤进行评估。此外，在同侧大脑皮质和海马的蛋白质印迹中测定Akt、磷酸化-AktSer 473、磷酸化-AktThr 308、GSK 3、磷酸化-GSK 3Ser 21/9、β-连环蛋白、SAPK-JNK和pSAPK-JNKThr 183/Tyr 185水平，并通过免疫组织化学测定神经元磷酸化-Akt表达的区域差异。皮质和海马中GFAP-（5.25倍）和Iba 1-（1.8倍）标记细胞百分比的增加表明pMCAO诱导了“反应性胶质化”。缺血后雌二醇治疗可防止这种效应;减少这些细胞的数量，与对照动物相当。pMCAO在皮质和海马中不同程度地下调PI 3 K/AkT/GSK 3/β-catenin存活通路，雌二醇处理在大脑皮质（最受影响的区域）中比在海马中更有效地恢复该通路的活性。诱导pMCAO后54 h，SAPK-JNK的磷酸化水平没有变化，而pMCAO确实显著降低了神经元中磷酸化AktSer 473的水平，这种作用可被雌二醇逆转。本研究表明，pMCAO后雌二醇治疗减轻了神经元和神经胶质的缺血性损伤，其中PI 3 K/AKT/GSK 3/β-连环蛋白通路至少部分参与了该事件。这些发现表明，雌二醇是一种潜在的有用的治疗，以促进人类缺血性中风后的恢复。
Estradiol has been shown to exert neuroprotective effects in several neurodegenerative conditions, including cerebral ischemia. The presence of this hormone prior to ischemia attenuates the damage associated with such events in a rodent model (middle cerebral artery occlusion (MCAO)), although its therapeutic value when administered post-ischemia has not been assessed. Hence, we evaluated the effects of estradiol treatment after permanent MCAO (pMCAO) was induced in rats, studying the PI3K/AKT/GSK3/β-catenin survival pathway and the activation of SAPK-JNK in two brain areas differently affected by pMCAO: the cortex and hippocampus. In addition, we analyzed the effect of estradiol on the glial response to injury. Male rats were subjected to pMCAO and estradiol (0.04 mg/kg) was administered 6, 24, and 48 h after surgery. The animals were sacrificed 6 h after the last treatment, and brain damage was evaluated by immunohistochemical quantification of ‘reactive gliosis’ using antibodies against GFAP and Iba1. In addition, Akt, phospho-AktSer473, phospho-AktThr308, GSK3, phospho-GSK3Ser21/9, β-catenin, SAPK-JNK, and pSAPK-JNKThr183/Tyr185 levels were determined in western blots of the ipsilateral cerebral cortex and hippocampus, and regional differences in neuronal phospho-Akt expression were determined by immunohistochemistry. The increases in the percentage of GFAP- (5.25-fold) and Iba1- (1.8-fold) labeled cells in the cortex and hippocampus indicate that pMCAO induced ‘reactive gliosis’. This effect was prevented by post-ischemic estradiol treatment; diminished the number of these cells to those comparable with control animals. pMCAO down-regulated the PI3K/AkT/GSK3/β-catenin survival pathway to different extents in the cortex and hippocampus, the activity of which was restored by estradiol treatment more efficiently in the cerebral cortex (the most affected region) than in the hippocampus. No changes in the phosphorylation of SAPK-JNK were observed 54 h after inducing pMCAO, whereas pMCAO did significantly decrease the phospho-AktSer473 in neurons, an effect that was reversed by estradiol. The present study demonstrates that post-pMCAO estradiol treatment attenuates ischemic injury in both neurons and glia, events in which the PI3K/AKT/GSK3/β-catenin pathway is at least partly involved. These findings indicate that estradiol is a potentially useful treatment to enhance recovery after human ischemic stroke.
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影响因子：
4.8
作者：
Barreto, George;Santos-Galindo, Maria;Garcia-Segura, Luis M.
通讯作者：
Garcia-Segura, Luis M.
影响因子：
3.5
作者：
Cardona-Gomez, P;Perez, M;Wandosell, F
通讯作者：
Wandosell, F
影响因子：
15.1
作者：
Benakis, Corinne;Bonny, Christophe;Hirt, Lorenz
通讯作者：
Hirt, Lorenz
影响因子：
6.1
作者：
Farr, Tracy D.;Carswell, Hilary V. O.;Macrae, I. Mhairi
通讯作者：
Macrae, I. Mhairi
影响因子：
3.4
作者：
BOVOLENTA, P;WANDOSELL, F;NIETOSAMPEDRO, M
通讯作者：
NIETOSAMPEDRO, M