Department of Anesthesiology, The Central Hospital of Tongchuan Mining Bureau, Tongchuan, Shaanxi, 727000, China.
Department of Anesthesiology, Shaanxi Provincial People's Hospital, Xi'an, 710068, China.
J Mol Neurosci. 2017 Dec;63(3-4):385-395. doi: 10.1007/s12031-017-0989-7. Epub 2017 Oct 16.
Neuroinflammation and Alzheimer's-related pathology play essential roles in postoperative cognitive dysfunction (POCD). High-mobility group box 1 (HMGB1) is well known as a pivotal mediator in neuroinflammation, and its associations with Alzheimer's-related pathology and POCD have been also revealed. Glycyrrhizin is a nature inhibitor of HMGB1 and is reported with neuroprotective effects through oral administration. Therefore, the present study aims to test the hypothesis that the oral pretreatment of glycyrrhizin prevents POCD by inhibiting HMGB1-induced neuroinflammation and Alzheimer's-related pathology in aged mice. Aged male C57BL/6 mice were subjected to the splenectomy surgery under general anesthesia and the oral pretreatment of glycyrrhizin. The postoperative cognitive changes were evaluated by using Morris water maze (MWM) test. The protein expressions of HMGB1, TLR4, NF-κB, p-Tau, and pro-inflammatory cytokines were determined by Western blot assay. The hippocampal level of β-amyloid (Aβ) was assessed by ELISA assay. We found that the oral pretreatment of glycyrrhizin inhibited HMGB1 cytosolic expression, increased the PSD-95 protein expression, and attenuated the severity of postoperative memory impairment, as indicated by the shorter swimming latency and distance in MWM trials when compared with the mice subjected to the surgery alone. Additionally, the pretreatment of glycyrrhizin reduced the postoperative neuroinflammation (production of pro-inflammatory cytokines including IL-1β, TNF-α, and IL-6 as well as NF-κB nuclear expression) and Alzheimer's-related pathology (Tau phosphorylation at the site of AT-8 and Ser396 as well as Aβ40 and 42 concentrations) in the hippocampus of the aged mice undergoing splenectomy surgery. In conclusion, our results suggest that the oral pretreatment of glycyrrhizin can prevent the postoperative cognitive impairment by reducing neuroinflammation and Alzheimer's-related pathology in the hippocampus of aged mice via HMGB1 inhibition.
神经炎症和与阿尔茨海默病相关的病理学在术后认知功能障碍（POCD）中起着重要作用。高迁移率族蛋白 B1（HMGB1）是神经炎症的关键介质，其与阿尔茨海默病相关病理学和 POCD 的关系也已被揭示。甘草酸是 HMGB1 的天然抑制剂，通过口服给药已被报道具有神经保护作用。因此，本研究旨在通过抑制 HMGB1 诱导的神经炎症和与阿尔茨海默病相关的病理学来检验甘草酸口服预处理可预防老年小鼠 POCD 的假说。雄性 C57BL/6 老年小鼠在全身麻醉下接受脾切除术，并进行甘草酸口服预处理。术后认知变化通过 Morris 水迷宫（MWM）试验进行评估。通过 Western blot 测定 HMGB1、TLR4、NF-κB、p-Tau 和促炎细胞因子的蛋白表达。通过 ELISA 测定海马β-淀粉样蛋白（Aβ）水平。我们发现，与单独接受手术的小鼠相比，甘草酸口服预处理抑制了 HMGB1 胞质表达，增加了 PSD-95 蛋白表达，并减轻了术后记忆障碍的严重程度，表现在 MWM 试验中游泳潜伏期和距离缩短。此外，甘草酸预处理降低了术后神经炎症（包括 IL-1β、TNF-α 和 IL-6 以及 NF-κB 核表达在内的促炎细胞因子的产生）和与阿尔茨海默病相关的病理学（Tau 在 AT-8 和 Ser396 位点以及 Aβ40 和 42 浓度处的磷酸化）在接受脾切除术的老年小鼠海马体中。总之，我们的结果表明，甘草酸口服预处理通过抑制 HMGB1 可减轻老年小鼠海马体中的神经炎症和与阿尔茨海默病相关的病理学，从而预防术后认知障碍。
