Estradiol Protects White Matter of Male C57BL6J Mice against Experimental Chronic Cerebral Hypoperfusion
Estradiol Protects White Matter of Male C57BL6J Mice against Experimental Chronic Cerebral Hypoperfusion
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DOI：
10.1016/j.jstrokecerebrovasdis.2018.01.030
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发表时间：
2018-07-01
影响因子：
2.5
通讯作者：
Mack, William J.
中科院分区：
文献类型：
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作者：
Dominguez, Reymundo;Zitting, Madison;Mack, William J.
背景和目的：雌二醇是一种性类固醇激素，已知可以保护大脑免受短暂性和全脑缺血相关的损伤。在本研究中，我们利用双侧颈动脉狭窄（BCAS）的实验性小鼠模型来检查雌二醇治疗对慢性脑灌注不足的假定效果。我们假设长期雌二醇治疗可以防止白质损伤和与慢性脑灌注不足相关的陈述性记忆缺陷。方法：成年雄性 C57BL/6J 小鼠接受 BCAS 手术或假手术。手术两天后，小鼠每天接受口服雌二醇（Sham+E、BCAS+E）或安慰剂（Sham+P、BCAS+P）治疗，持续 3134 天。所有小鼠在开始口服治疗后 31-34 天接受新物体识别 (NOR) 测试。处死后，收集血液并将大脑固定、切片并准备用于白质损伤和细胞外信号调节激酶（ERK）表达的组织学检查。结果：接受长期口服雌二醇治疗的动物（BCAS-E2 和 Sham-E2）的血浆雌二醇水平高于接受安慰剂治疗的动物（BCAS-P 和 Sham-P）。与 BCAS-P 小鼠相比，BCASE2 小鼠表现出较少的白质损伤（Kluver-Barrera 染色），并且在 NOR 任务中表现更好。与假手术组相比，BCAS 中大脑中的 ERK 表达增加。在 BCAS 小鼠中，BCAS-E2 组的 ERK + 细胞数量较多。结论：本研究证明口服雌二醇治疗在小鼠慢性脑灌注不足继发的白质损伤和陈述性记忆缺陷中具有潜在的保护作用。
Background and Purpose: Estradiol is a sex steroid hormone known to protect the brain against damage related to transient and global cerebral ischemia. In the present study, we leverage an experimental murine model of bilateral carotid artery stenosis (BCAS) to examine the putative effects of estradiol therapy on chronic cerebral hypoperfusion. We hypothesize that long-term estradiol therapy protects against white matter injury and declarative memory deficits associated with chronic cerebral hypoperfusion. Methods: Adult male C57BL/6J mice underwent either surgical BCAS or sham procedures. Two days after surgery, the mice were given oral estradiol (Sham+E, BCAS+E) or placebo (Sham+P, BCAS+P) treatments daily for 3134 days. All mice underwent Novel Object Recognition (NOR) testing 31-34 days after the start of oral treatments. Following sacrifice, blood was collected and brains fixed, sliced, and prepared for histological examination of white matter injury and extracellular signal-regulated kinase (ERK) expression. Results: Animals receiving long-term oral estradiol therapy (BCAS-E2 and Sham-E2) had higher plasma estradiol levels than those receiving placebo treatment (BCAS-P and Sham-P). BCASE2 mice demonstrated less white matter injury (Kluver-Barrera staining) and performed better on the NOR task compared to BCAS-P mice. ERK expression in the brain was increased in the BCAS compared to sham cohorts. Among the BCAS mice, the BCAS-E2 cohort had a greater number of ERK + cells. Conclusion: This study demonstrates a potentially protective role for oral estradiol therapy in the setting of white matter injury and declarative memory deficits secondary to murine chronic cerebral hypoperfusion.