Department of Neurology, Hebei Medical University, Shijiazhuang, 050017, China.
Department of Gynecology, Hebei General Hospital, Shijiazhuang, 050051, China.
Neurochem Res. 2020 Sep;45(9):2100-2112. doi: 10.1007/s11064-020-03072-5. Epub 2020 Jul 27.
Vascular dementia (VD) is a clinical syndrome of acquired cognitive dysfunction caused by various cerebrovascular factors. Estrogen is a steroid hormone involved in promoting neuronal survival and in regulating many signaling pathways. However, the mechanism by which it confers neuroprotective effects in VD remains unclear. Here, we aimed to investigate the effect of estrogen on neuronal injury and cognitive impairment in VD rats. Adult female rats were randomly divided into four groups (sham, model, estrogen early and estrogen later treatment) and received sham surgery or bilateral ovariectomy and permanent occlusion of bilateral common carotid arteries (BCCAO). The early treatment group received daily intraperitoneal injections of 17β-estradiol (100 µg/kg/day) for 8 weeks starting the day after BCCAO. The later treatment group was administered the same starting 1 week after BCCAO. Learning and memory functions were assessed using the Morris water maze. Morphological changes within the hippocampal CA1 region were observed by hematoxylin/eosin staining and electron microscopy. Expression of proteins associated with autophagy and signaling were detected by immunohistochemical staining and Western blot. We found that estrogen significantly alleviated cognitive damage and neuronal injury and reduced the expression of Beclin1 and LC3B, indicating a suppression of autophagy. Moreover, estrogen enhanced expression of β-catenin and Cyclin D1, while reducing glycogen synthase kinase 3β, suggesting activation of Wnt/β-catenin signaling. These results indicate that estrogen ameliorates learning and memory deficiencies in VD rats, and that this neuroprotective effect may be explained by the suppression of autophagy and activation of Wnt/β-catenin signaling.
血管性痴呆（VD）是一种由多种脑血管因素引起的获得性认知功能障碍的临床综合征。雌激素是一种参与促进神经元存活和调节多种信号通路的类固醇激素。然而，其在 VD 中发挥神经保护作用的机制尚不清楚。在这里，我们旨在研究雌激素对 VD 大鼠神经元损伤和认知障碍的影响。成年雌性大鼠被随机分为四组（假手术、模型、雌激素早期和雌激素晚期治疗组），并接受假手术或双侧卵巢切除术和双侧颈总动脉永久性闭塞（BCCAO）。早期治疗组在 BCCAO 后第 1 天开始每天腹腔注射 17β-雌二醇（100μg/kg/天）8 周。晚期治疗组在 BCCAO 后 1 周开始给予相同剂量的治疗。使用 Morris 水迷宫评估学习和记忆功能。通过苏木精/伊红染色和电子显微镜观察海马 CA1 区的形态变化。通过免疫组织化学染色和 Western blot 检测与自噬和信号相关的蛋白质表达。我们发现，雌激素显著减轻了认知损伤和神经元损伤，降低了 Beclin1 和 LC3B 的表达，表明自噬受到抑制。此外，雌激素增强了β-连环蛋白和细胞周期蛋白 D1 的表达，同时降低了糖原合成酶激酶 3β的表达，提示 Wnt/β-连环蛋白信号的激活。这些结果表明，雌激素改善了 VD 大鼠的学习和记忆缺陷，这种神经保护作用可能是通过抑制自噬和激活 Wnt/β-连环蛋白信号来解释的。
