Cai Min, Ma Yu-Long, Qin Pei, Li Yan, Zhang Li-Xia, Nie Huang, Peng Zhengwu, Dong Hui, Dong Hai-Long, Hou Wu-Gang, Xiong Li-Ze
Department of Anesthesiology, Xijing hospital, The Fourth Military Medical University, Xi'an 710032, China; Department of Psychosomatic Medicine, Xijing hospital, The Fourth Military Medical University, Xi'an 710032, China.
Department of Anesthesiology, Xijing hospital, The Fourth Military Medical University, Xi'an 710032, China.
Neurosci Lett. 2014 Jan 13;558:115-9. doi: 10.1016/j.neulet.2013.11.007. Epub 2013 Nov 15.
Estrogen has been shown to have neuroprotective effects in numerous experimental studies involving young and adult animals. However, several clinical trials have found that in aged postmenopausal women who received estrogen replacement therapy, there did not appear to be a reduction in the incidence of stroke. The aim of this study was to investigate the effects of physiological dosages of estrogen on aged female mice subjected to ischemia-reperfusion injury. Adult ovariectomized (OVX) female mice and 22-month-old female mice received daily subcutaneous injections of 100 μg/kg or 300 μg/kg 17β-estradiol (E2) at the back of the neck for four weeks, and the expression levels of estrogen receptor (ER) α and β in the cerebral cortex were determined using real-time PCR and Western blotting analyses. To mimic ischemic stroke, the mice received middle cerebral artery occlusion (MCAO) treatment for 1h followed by a 24-h reperfusion period. The mice were then subjected to neurological deficit testing and infarct volume evaluation. The aged mice showed higher neurological deficit scores and larger infarct volumes compared with the adult mice. Both the lower and higher physiological dosages of E2 significantly improved the neurological test scores and decreased the infarct volume in the adult mice; however, E2 showed no neuroprotective effects in the aged mice. Furthermore, the protein expression of ERα and ERβ in the cerebral cortex was significantly decreased in the aged mice compared with the adult mice, and this decrease was not rescued by E2 treatment. These results indicate that the down-regulation of ERα and ERβ in the cerebral cortex may contribute to the loss of estrogen efficacy against ischemic injury in aged females and may point to new therapies for ischemic stroke in aged postmenopausal women.
在涉及幼年和成年动物的众多实验研究中，雌激素已被证明具有神经保护作用。然而，几项临床试验发现，在接受雌激素替代疗法的老年绝经后女性中，中风发病率似乎并未降低。本研究的目的是调查生理剂量的雌激素对遭受缺血再灌注损伤的老年雌性小鼠的影响。成年去卵巢（OVX）雌性小鼠和22月龄雌性小鼠在颈部后侧每日皮下注射100μg/kg或300μg/kg的17β-雌二醇（E2），持续四周，然后使用实时PCR和蛋白质印迹分析来测定大脑皮层中雌激素受体（ER）α和β的表达水平。为模拟缺血性中风，小鼠接受大脑中动脉闭塞（MCAO）治疗1小时，随后进行24小时再灌注期。然后对小鼠进行神经功能缺损测试和梗死体积评估。与成年小鼠相比，老年小鼠表现出更高的神经功能缺损评分和更大的梗死体积。较低和较高生理剂量的E2均显著改善了成年小鼠的神经测试评分并减小了梗死体积；然而，E2在老年小鼠中未显示出神经保护作用。此外，与成年小鼠相比，老年小鼠大脑皮层中ERα和ERβ的蛋白质表达显著降低，并且这种降低并未通过E2治疗得到挽救。这些结果表明，大脑皮层中ERα和ERβ的下调可能导致老年女性雌激素对缺血性损伤的疗效丧失，并可能为老年绝经后女性缺血性中风指明新的治疗方法。
