The common inhalation anesthetic isoflurane induces apoptosis and increases amyloid β protein levels
The common inhalation anesthetic isoflurane induces apoptosis and increases amyloid β protein levels
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DOI：
10.1097/00000542-200605000-00015
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发表时间：
2006-05-01
期刊：
影响因子：
8.8
通讯作者：
Tanzi, RE
中科院分区：
文献类型：
--
作者：
Xie, ZC;Dong, YL;Tanzi, RE
背景 此前已有报道，常见的吸入麻醉剂异氟烷可增强阿尔茨海默病相关淀粉样蛋白 13 蛋白（Aβ）的聚集和细胞毒性，该蛋白是大脑 β-淀粉样蛋白沉积物的主要肽成分。 方法：稳定转染 H4 人神经胶质瘤细胞以表达人全长野生型淀粉样蛋白 前体蛋白（APP）暴露于2%异氟烷6小时。在处理结束时收获细胞和条件培养基。使用定量蛋白质印迹、细胞活力试剂盒和酶联免疫吸附测定夹心法测量 Caspase-3 激活、APP 加工、细胞活力和 Aβ 水平。对照条件由 5% CO2 加 21% O-2 和平衡氮组成，不影响 caspase-3 激活、细胞活力、APP 加工或 A beta 生成。结果：2% 异氟烷导致 H4 人神经胶质瘤细胞系中的细胞凋亡、APP 加工改变和 A beta 产量增加。异氟烷诱导的细胞凋亡与 Aβ 和 APP 全蛋白水平的变化无关。然而，异氟烷诱导的细胞凋亡因 APP C 末端片段水平的增加而增强。结论：临床相关浓度的异氟烷可诱导细胞凋亡、改变 APP 加工并增加人神经胶质瘤细胞系中 Aβ 的产生。由于导致 Aβ 积累的 APP 加工过程改变是阿尔茨海默病发病机制中的一个关键事件，因此这些发现可能会对脑 Aβ 水平过高的个体和术后认知功能障碍风险增加的老年患者使用这种麻醉剂产生影响。
Background The common inhalation anesthetic isoflurane has previously been reported to enhance the aggregation and cytotoxicity of the Alzheimer disease-associated amyloid 13 protein (A beta), the principal peptide component of cerebral beta-amyloid deposits.Methods: H4 human neuroglioma cells stably transfected to express human full-length wild-type amyloid precursor protein (APP) were exposed to 2% isoflurane for 6 h. The cells and conditioned media were harvested at the end of the treatment. Caspase-3 activation, processing of APP, cell viability, and A beta levels were measured with quantitative Western blotting, cell viability kit, and enzyme-linked inummosorbent assay sandwich. The control condition consisted of 5% CO2 plus 21% O-2 and balanced nitrogen, which did not affect caspase-3 activation, cell viability, APP processing, or A beta generation.Results: Two percent isoflurane caused apoptosis, altered processing of APP, and increased production of A beta in H4 human neuroglioma cell lines. Isoflurane-induced apoptosis was independent of changes in A beta and APP holoprotein levels. However, isoflurane-induced apoptosis was potentiated by increased levels of APP C-terminal fragments.Conclusion: A clinically relevant concentration of isoflurane induces apoptosis, alters APP processing, and increases A beta production in a human neuroglioma cell line. Because altered processing of APP leading to accumulation of A beta is a key event in the pathogenesis of Alzheimer disease, these findings may haveimplications for use of this anesthetic agent in individuals with excessive levels of cerebral A beta and elderly patients at increased risk for postoperative cognitive dysfunction.