Guo Jin-Min, Shu He, Wang Lei, Xu Jian-Jiang, Niu Xue-Cai, Zhang Li
Department of Pharmacology, Jinan Military General Hospital, Jinan, Shandong, China.
Department of Orthopaedics, Jinan Military General Hospital, Jinan, Shandong, China.
CNS Neurosci Ther. 2017 Apr;23(4):360-369. doi: 10.1111/cns.12686. Epub 2017 Mar 2.
Stroke is a major cause of mortality and disability, especially for postmenopausal women. In view of the protective action of estrogen, hormone therapy remains the only effective way to limit this risk. The objective of this study was to investigate the efficiency and underlying mechanisms of estrogen neuroprotection.
Subcutaneous injection of 17β-estradiol in rats after ovariectomy (OVX) was used to manipulate estrogen level and explore the effects of estrogen in cerebral ischemic damage both in vivo and in vitro. Silent mating type information regulation 2 homolog 1 (SIRT1) knockout mice and adenosine monophosphate (AMP)-activated kinase (AMPK) inhibitor Compound C were also used to investigate the underlying pathway of estrogen.
Estrogen deficiency induced by OVX aggravated brain infarction in experimentally induced cerebral ischemia rats, whereas estrogen pretreatment reduced ischemia-induced cerebral injuries. Neurons of estrogen deficiency models were susceptible to apoptosis under oxygen-glucose deprivation (OGD). In contrast, neurons with estrogen-supplemented serum exhibited restored resistance to cell apoptosis. In OGD neurons, estrogen promoted AMPK activation through estrogen receptor α, and neuroprotection of estrogen was prevented by AMPK inhibition. Estrogen increased SIRT1 expression and activation, and estrogen-induced AMPK activation disappeared in SIRT1 knockout neurons. Moreover, estrogen-induced neuroprotection was abolished in SIRT1 knockout mice and AMPK-inhibited rats.
Our data support that estrogen protects against ischemic stroke through preventing neuron death via the SIRT1-dependent AMPK pathway.
中风是导致死亡和残疾的主要原因，对绝经后女性而言尤其如此。鉴于雌激素的保护作用，激素疗法仍然是降低这种风险的唯一有效方法。本研究的目的是探讨雌激素神经保护作用的有效性及潜在机制。
采用去卵巢（OVX）大鼠皮下注射17β-雌二醇的方法来调控雌激素水平，探讨雌激素在体内和体外对脑缺血损伤的影响。还利用沉默交配型信息调节2同源物1（SIRT1）基因敲除小鼠和单磷酸腺苷（AMP）激活的蛋白激酶（AMPK）抑制剂Compound C来研究雌激素的潜在作用途径。
OVX诱导的雌激素缺乏加重了实验性脑缺血大鼠的脑梗死，而雌激素预处理减轻了缺血诱导的脑损伤。雌激素缺乏模型的神经元在氧糖剥夺（OGD）条件下易发生凋亡。相反，补充雌激素血清的神经元对细胞凋亡的抵抗能力得以恢复。在OGD神经元中，雌激素通过雌激素受体α促进AMPK激活，而AMPK抑制可阻断雌激素的神经保护作用。雌激素增加SIRT1的表达和激活，且雌激素诱导的AMPK激活在SIRT1基因敲除神经元中消失。此外，雌激素诱导的神经保护作用在SIRT1基因敲除小鼠和AMPK抑制的大鼠中被消除。
我们的数据支持雌激素通过SIRT1依赖的AMPK途径预防神经元死亡，从而对缺血性中风起到保护作用。
