NADPH oxidase 2-derived reactive oxygen species in the hippocampus might contribute to microglial activation in postoperative cognitive dysfunction in aged mice
NADPH oxidase 2-derived reactive oxygen species in the hippocampus might contribute to microglial activation in postoperative cognitive dysfunction in aged mice
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DOI：
10.1016/j.bbi.2015.08.002
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发表时间：
2016-01-01
影响因子：
15.1
通讯作者：
Yang, Jian-Jun
中科院分区：
文献类型：
--
作者：
Qiu, Li-Li;Ji, Mu-Huo;Yang, Jian-Jun
小胶质细胞活化在术后认知功能障碍（POCD）的发展中起着关键作用。Nox 2是中枢神经系统中烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶的主要亚型之一，是吞噬细胞（包括小胶质细胞）中活性氧（ROS）过量产生的主要来源。因此，我们假设Nox 2诱导的小胶质细胞活化参与POCD的发展。使16个月大的C57 BL/6小鼠经受用异氟烷麻醉的剖腹探查术以模拟临床人类腹部手术。分别在术后第6天和第7天进行旷场和恐惧条件反射行为测试。分别于术后1 d和7 d检测海马和前额叶皮质中Nox 2、8-羟基-2 '-脱氧鸟苷（8-OH-dG，DNA氧化的标志物）、CD 11b（小胶质细胞活化的标志物）、白细胞介素-1 β（IL-1 β）和脑源性神经营养因子（BDNF）的水平。对于干预性研究，小鼠用NADPH氧化酶抑制剂夹竹桃苷（APO）处理。我们的研究结果表明，剖腹探查术与异氟醚麻醉损害了上下文的恐惧记忆，增加表达的Nox 2，8-OH-dG，CD 11b，和IL-1 β，并下调BDNF的表达在海马在术后7天。手术诱导的小胶质细胞活化和神经炎症持续到术后7 d的海马，但仅在1 d的前额叶皮层。值得注意的是，给予APO可以挽救这些手术引起的认知障碍和相关的脑病理学。总之，我们的数据表明，海马小胶质细胞中Nox 2衍生的ROS至少部分导致老年小鼠手术诱导的神经炎症和认知障碍。(C)2015 Elsevier Inc. All rights reserved.
Microglial activation plays a key role in the development of postoperative cognitive dysfunction (POCD). Nox2, one of the main isoforms of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the central nervous system, is a predominant source of reactive oxygen species (ROS) overproduction in phagocytes including microglia. We therefore hypothesized that Nox2-induced microglial activation is involved in the development of POCD. Sixteen-month-old C57BL/6 mice were subjected to exploratory laparotomy with isoflurane anesthesia to mimic the clinical human abdominal surgery. Behavioral tests were performed at 6 and 7 d post-surgery with open field and fear conditioning tests, respectively. The levels of Nox2, 8-hydroxy-2'-deoxyguanosine (8-OH-dG, a marker of DNA oxidation), CD11b (a marker of microglial activation), interleukin-1 beta(IL-1 beta), and brain-derived neurotrophic factor (BDNF) were determined in the hippocampus and prefrontal cortex at 1 d and 7 d post-surgery, respectively. For the interventional study, mice were treated with a NADPH oxidase inhibitor apocynin (APO). Our results showed that exploratory laparotomy with isoflurane anesthesia impaired the contextual fear memory, increased expression of Nox2, 8-OH-dG, CD11b, and IL-1 beta, and down-regulated BDNF expression in the hippocampus at 7 d post-surgery. The surgery-induced microglial activation and neuroinflammation persisted to 7 d after surgery in the hippocampus, but only at 1 d in the prefrontal cortex. Notably, administration with APO could rescue these surgery-induced cognitive impairments and associated brain pathology. Together, our data suggested that Nox2-derived ROS in hippocampal microglia, at least in part, contributes to subsequent neuroinflammation and cognitive impairments induced by surgery in aged mice. (C) 2015 Elsevier Inc. All rights reserved.