Jiang Linhao, Dong Rui, Xu Minhui, Liu Yujia, Xu Jiyan, Ma Zhengliang, Xia Tianjiao, Gu Xiaoping
Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, China.
Medical School, Nanjing University, Nanjing, China.
Front Cell Neurosci. 2022 Sep 21;16:992869. doi: 10.3389/fncel.2022.992869. eCollection 2022.
Postoperative cognitive dysfunction (POCD) is a common complication following anesthesia and surgery that might lead to a decline in learning and memory. Oxidative stress damage is one of the pathogenic mechanisms underlying POCD. Recent studies had shown that the integrated stress response (ISR) is closely related to oxidative stress. The core response of the ISR is phosphorylation of eIF2α. Various cellular stress stimuli trigger activation of eIF2α kinases, thus causing phosphorylation of eIF2α. ISR is associated with many neurodegenerative diseases; however, the relationship between POCD and ISR has not been defined. In the present study, the tibias in 4-month-old male C57BL/6 mice were fractured under isoflurane anesthesia to establish the POCD animal model. Cognitive function was assessed by fear conditioning tests and the Y-maze from 3 to 14 days post-surgery. Western blot was used to determine the levels of PeIF2α, eIF2α, ATF4, GADD34, CHOP, BDNF, proBDNF, and p-NR2B expression. The levels of reactive oxygen species (ROS), superoxide dismutase (SOD), and malondialdehyde (MDA) were measured to determine oxidative stress in hippocampal tissues. After tibial fracture surgery in mice, the hippocampus had increased levels of PeIF2α, ATF4, GADD34, and CHOP protein, ROS-positive cells, and average fluorescence intensity, SOD activity was decreased, and the MDA level was increased. The ISR inhibitor, ISRIB, reduced the levels of PeIF2α, ATF4, GADD34, and CHOP protein, and alleviated oxidative stress in the hippocampus of POCD mice. Moreover, ISRIB ameliorated cognitive dysfunction in POCD mice. Our findings suggested that targeting ISR may represent an effective approach to combat POCD.
术后认知功能障碍（POCD）是麻醉和手术后常见的并发症，可能导致学习和记忆能力下降。氧化应激损伤是POCD潜在的致病机制之一。最近的研究表明，整合应激反应（ISR）与氧化应激密切相关。ISR的核心反应是eIF2α的磷酸化。各种细胞应激刺激会触发eIF2α激酶的激活，从而导致eIF2α的磷酸化。ISR与许多神经退行性疾病有关；然而，POCD与ISR之间的关系尚未明确。在本研究中，对4个月大的雄性C57BL/6小鼠在异氟烷麻醉下进行胫骨骨折，以建立POCD动物模型。在手术后3至14天通过恐惧条件反射试验和Y迷宫评估认知功能。采用蛋白质免疫印迹法检测磷酸化eIF2α（PeIF2α）、eIF2α、活化转录因子4（ATF4）、生长停滞和DNA损伤诱导蛋白34（GADD34）、C/EBP同源蛋白（CHOP）、脑源性神经营养因子（BDNF）、前体BDNF和磷酸化NR2B的表达水平。检测活性氧（ROS）、超氧化物歧化酶（SOD）和丙二醛（MDA）水平，以确定海马组织中的氧化应激情况。小鼠胫骨骨折手术后，海马中PeIF2α、ATF4、GADD34和CHOP蛋白水平升高，ROS阳性细胞和平均荧光强度增加，SOD活性降低，MDA水平升高。ISR抑制剂ISRIB降低了POCD小鼠海马中PeIF2α、ATF4、GADD34和CHOP蛋白水平，并减轻了氧化应激。此外，ISRIB改善了POCD小鼠的认知功能障碍。我们的研究结果表明，针对ISR可能是对抗POCD的一种有效方法。
