中国神经再生研究(英文版) ›› 2021, Vol. 16 ›› Issue (10): 2078-2085.doi: 10.4103/1673-5374.308103

• 观点:退行性病与再生 • 上一篇    下一篇

丙戊酸增强雌激素改善去卵巢阿尔茨海默病模型小鼠的认知功能

  

  • 出版日期:2021-10-15 发布日期:2021-03-19
  • 基金资助:

    中国国家自然科学基金项目(81671257,81371221,31600825)

Combined treatment with valproic acid and estrogen has neuroprotective effects in ovariectomized mice with Alzheimer’s disease

Yan-Zhen Li1, #, Yuan-Jie Liu1, 2, #, Wei Zhang1, Shi-Fang Luo1, 2, Xin Zhou3, *, #br# Gui-Qiong He1, 2, *#br#   

  1. 1Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing, China; 2Department of Anatomy, Chongqing Medical University, Chongqing, China; 3Department of Galactophore, Chongqing University Cancer Hospital, Chongqing, China
  • Online:2021-10-15 Published:2021-03-19
  • Contact: Xin Zhou, PhD, zhouxin75324@163.com; Gui-Qiong He, PhD, guiqionghe@cqmu.edu.cn.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, Nos. 81671257, 81371221, 31600825 (all to GQH).

摘要:

前期研究已发现丙戊酸钠对APP/PS1双转基因阿尔茨海默病模型小鼠的神经保护作用具有性别差异,对雄性模型小鼠的保护作用优于雌性,尤其优于老年雌性模型小鼠,为揭示其机制,实验设计了以去除雌性APP/PS1小鼠双侧卵巢以模拟绝经后妇女体内低雌激素水平状态,而后连续4周腹腔注射丙戊酸钠(30 mg/kg, 1次/d)、17β-雌二醇(2.4μg,1次/d)和/或灌胃植物雌激素甘草素(50μg/ kg,1次/d),观察2者联用的效应。(1)与单独雌激素治疗相比,丙戊酸钠联合治疗可更为显著地抑制糖原合成酶激酶3β水平,提高雌激素受体α的表达,降低雌激素受体β-小泛素样修饰因子的修饰,提高雌激素受体β的水平;提升小鼠脑内雌激素受体水平,进而增强对雌激素治疗的敏感性,有效减少脑内Aβ聚集和Tau蛋白异常磷酸化、降低神经元丢失、提高树突棘密度和突触后致密区,同时明显改善小鼠的记忆和学习障碍;(2)丙戊酸钠联合雌激素治疗通过增加糖原合酶激酶3β的活性增强了雌激素受体对雌激素的敏感性,从而改善了去卵巢阿尔茨海默病小鼠认知功能。实验于2013年3月6日经重庆医科大学动物伦理委员会批准。

https://orcid.org/0000-0002-7077-2001 (Gui-Qiong He)

关键词:

痴呆, 绝经, 雌激素受体α, 雌激素受体β, 糖原合成酶激酶3β, 17β-雌二醇, 甘草素, 淀粉样蛋白β, tau, 神经元缺失

Abstract: Postmenopausal women with Alzheimer’s disease (AD) exhibit dramatically reduced sensitivity to estrogen replacement therapy, which is though to be related to an estrogen receptor (ER)α/ERβ ratio imbalance arising from a significantly decreased level of ERs of the brain. The aim of our study was to investigate whether valproic acid (VPA) can enhance the beneficial effects of estrogen on cognitive function through restoration of ERα and ERβ expression in the brain. We removed the ovaries of female APP/PS1 mice to simulate the low estrogen levels present in postmenopausal women and then administered VPA (30 mg/kg, intraperitoneal injection, once daily), 17β-estradiol (E2) (2.4 μg, intraperitoneal injection, once daily), liquiritigenin (LG) (50 μg/kg, intragastric infusion, once daily), VPA + E2, or VPA + LG for 4 successive weeks. Compared with treatment with a single drug, treatment with VPA + E2 or VPA + LG significantly increased the level of glycogen synthase kinase 3β, increased the expression of estrogen receptor α, reduced the expression of small ubiquitin-like modifiers, and increased the level of estrogen receptor β. This resulted in enhanced sensitivity to estrogen therapy, reduced amyloid β aggregation, reduced abnormal phosphorylation of the tau protein, reduced neuronal loss, increased dendritic spine and postsynaptic density, and significantly alleviated memory loss and learning impairment in mice. This study was approved by the Chongqing Medical University Animal Protection and Ethics Committee, China on March 6, 2013. 

Key words: 17β-estradiol, amyloid β, dementia, estrogen receptor α, estrogen receptor β, glycogen synthase kinase-3β, liquiritigenin, menopause, neuron loss, tau

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