Department of Anaesthesiology, LKS Faculty of Medicine, The University of Hong Kong, Room K424, Queen Mary Hospital, Pokfulam, Hong Kong SAR, China.
Laboratory of Neurodegenerative Diseases, School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Room L4-49, Laboratory Block, Faculty of Medicine Building, 21 Sassoon Road, Pokfulam, Hong Kong SAR, China.
J Neuroinflammation. 2018 May 17;15(1):147. doi: 10.1186/s12974-018-1163-z.
Systemic inflammation induces neuroinflammation and cellular changes such as tau phosphorylation to impair cognitive function, including learning and memory. This study uses a single model, laparotomy without any pathogen, to characterize these changes and their responses to anti-inflammatory treatment in the intermediate term.
In a two-part experiment, wild-type C57BL/6N mice (male, 3 month old, 25 ± 2 g) were subjected to sevoflurane anesthesia alone or to a laparotomy. Cognitive performance, systemic and neuroinflammatory responses, and tau phosphorylation were evaluated on postoperative days (POD) 1, 3, and 14. The effect of perioperative ibuprofen intervention (60 mg/kg) on these changes was then assessed.
Mice in the laparotomy group displayed memory impairment up to POD 14 with initial high levels of inflammatory cytokines in the liver, frontal cortex (IL-1β, IL-6, and TNF-α), and hippocampus (IL-1β and IL-8). On POD 14, although most circulating and resident cytokine levels returned to normal, a significant number of microglia and astrocytes remained activated in the frontal cortex and microglia in the hippocampus, as well as abnormal tau phosphorylation in these two brain regions. Perioperative ibuprofen improved cognitive performance, attenuated systemic inflammation and glial activation, and suppressed the abnormal tau phosphorylation both in the frontal cortex and hippocampus.
Our results suggest that (1) cognitive dysfunction is associated with an unbalanced pro-inflammatory and anti-inflammatory response, tauopathy, and gliosis; (2) cognitive dysfunction, gliosis, and tauopathy following laparotomy can persist well beyond the immediate postoperative period; and (3) anti-inflammatory drugs can act rapidly to attenuate inflammatory responses in the brain and negatively modulate neuropathological changes to improve cognition. These findings may have implications for the duration of therapeutic strategies aimed at curtaining cognitive dysfunction following surgery.
全身炎症会引发神经炎症和细胞变化，如 tau 磷酸化，从而损害认知功能，包括学习和记忆。本研究使用单一模型（无任何病原体的剖腹术）来描述这些变化及其对中期抗炎治疗的反应。
在两部分实验中，将野生型 C57BL/6N 小鼠（雄性，3 个月龄，25±2g）单独用七氟醚麻醉或行剖腹术。术后第 1、3 和 14 天评估认知表现、全身和神经炎症反应以及 tau 磷酸化。然后评估围手术期布洛芬干预（60mg/kg）对这些变化的影响。
剖腹术组的小鼠在术后 14 天出现记忆障碍，肝、额皮质（IL-1β、IL-6 和 TNF-α）和海马（IL-1β 和 IL-8）中的炎症细胞因子水平最初升高。在 POD14 时，尽管大多数循环和固有细胞因子水平恢复正常，但额皮质中的小胶质细胞和星形胶质细胞以及海马中的小胶质细胞仍存在大量激活，这两个脑区也存在异常 tau 磷酸化。围手术期布洛芬可改善认知表现，减轻全身炎症和神经胶质激活，并抑制这两个脑区的异常 tau 磷酸化。
我们的结果表明：（1）认知功能障碍与促炎和抗炎反应失衡、tau 病和神经胶质增生有关；（2）剖腹术后的认知功能障碍、神经胶质增生和 tau 病可能在术后很长时间内持续存在；（3）抗炎药物可迅速作用于减轻大脑中的炎症反应并负性调节神经病理学变化以改善认知。这些发现可能对旨在防止手术后认知功能障碍的治疗策略的持续时间有意义。
