Shao Haijun, Zhang Yiying, Dong Yuanlin, Yu Buwei, Xia Weiming, Xie Zhongcong
Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
J Alzheimers Dis. 2014;41(2):499-513. doi: 10.3233/JAD-132792.
There is a need to seek new treatment(s) for Alzheimer's disease (AD). A recent study showed that AD patients may have decreased levels of functional GABA receptors. Propofol, a commonly used anesthetic, is a GABA receptor agonist. We therefore set out to perform a proof of concept study to determine whether chronic treatment with propofol (50 mg/kg/week) can improve cognitive function in both aged wild-type (WT) and AD transgenic (Tg) mice. Propofol was administrated to the WT and AD Tg mice once a week for 8 or 12 weeks, respectively. Morris water maze was used to assess the cognitive function of the mice following the propofol treatment. Activation of caspase-3, caspase-9, and caspase-8 was investigated using western blot analysis at the end of the propofol treatment. In the mechanistic studies, effects of propofol, amyloid-β protein (Aβ), and GABA receptor antagonist flumazenil on caspase-3 activation and opening of the mitochondrial permeability transition pore were assessed in H4 human neuroglioma and mouse neuroblastoma cells by western blot analysis and flow cytometry. Here we showed that the propofol treatment improved cognitive function and attenuated brain caspase-3 and caspase-9 activation in both aged WT and AD Tg mice. Propofol attenuated Aβ-induced caspase-3 activation and opening of the mitochondrial permeability transition pore in the cells, and flumazenil inhibited the propofol's effects. These results suggested that propofol might improve cognitive function via attenuating the Aβ-induced mitochondria dysfunction and caspase activation, which explored the potential that anesthetic propofol could improve cognitive function in elderly and AD patients.
需要寻找治疗阿尔茨海默病（AD）的新方法。最近的一项研究表明，AD患者功能性GABA受体水平可能降低。丙泊酚是一种常用麻醉剂，是一种GABA受体激动剂。因此，我们开展了一项概念验证研究，以确定丙泊酚（50mg/kg/周）长期治疗是否能改善老年野生型（WT）和AD转基因（Tg）小鼠的认知功能。分别每周一次给WT和AD Tg小鼠注射丙泊酚，持续8周或12周。使用莫里斯水迷宫评估丙泊酚治疗后小鼠的认知功能。在丙泊酚治疗结束时，通过蛋白质免疫印迹分析研究caspase-3、caspase-9和caspase-8的激活情况。在机制研究中，通过蛋白质免疫印迹分析和流式细胞术，在H4人神经胶质瘤细胞和小鼠神经母细胞瘤细胞中评估丙泊酚、淀粉样β蛋白（Aβ）和GABA受体拮抗剂氟马西尼对caspase-3激活和线粒体通透性转换孔开放的影响。在此我们表明，丙泊酚治疗改善了老年WT和AD Tg小鼠的认知功能，并减弱了脑内caspase-3和caspase-9的激活。丙泊酚减弱了细胞中Aβ诱导的caspase-3激活和线粒体通透性转换孔的开放，而氟马西尼抑制了丙泊酚的作用。这些结果表明，丙泊酚可能通过减轻Aβ诱导的线粒体功能障碍和caspase激活来改善认知功能，这探索了麻醉剂丙泊酚改善老年人和AD患者认知功能的潜力。
