丙酮酸乙酯在老龄小鼠围手术期神经认知障碍中的作用
| 作者: |
1李瑞琳,
1苗晓蕾,
1王晖,
1魏昌伟,
1吴安石
1 首都医科大学附属北京朝阳医院麻醉科，北京 100020 |
| 通讯: |
吴安石
Email: wuanshimzk@163.com |
| DOI: | 10.3978/j.issn.2095-6959.2022.05.002 |
| 基金: | 国家自然科学基金(81400883)。 |
摘要
目的：评价丙酮酸乙酯(ethyl pyruvate，EP)在小鼠围手术期神经认知障碍(perioperative neurocognitive disorders，PND)中的作用。方法：纳入54只无特定病原体(specific pathogen free，SPF)老年雄性C57BL/6小鼠，14~16月龄，体重38~52 g。将54只小鼠采用随机数字表法分为3组(n=18)：正常对照组(C组)、肝部分切除手术组(S组)、EP组。EP组在异氟醚麻醉下行肝部分切除术，术毕时腹腔注射EP 100 mg/kg，C组和S组腹腔注射等容量平衡盐溶液。在术前30 min行痕迹条件恐惧实验(trace fear conditioning，TFC)训练，于术后3 d进行TFC检测，记录小鼠僵直时间。行为实验测试后处死小鼠取海马组织，采用ELISA法检测白细胞介素-1β(interleukin-1β，IL-1β)含量，采用蛋白质印迹法检测高迁移率族蛋白1(high mobility group box-1，HMGB1)、晚期糖基化终末产物受体(receptor for advanced glycation end products，RAGE)、激活核因子-κB p65(nuclear factor-κB p65，NF-κBp65)、胶质纤维酸性蛋白(glial fibrillary acidic protein，GFAP)、离子钙结合衔接分子1(ionized calcium binding adapter molecule，Iba1)及β-actin蛋白质表达。结果：与C组相比，在术后3 d时，S组TFC僵直时间缩短，海马IL-1β含量升高，海马HMGB1、RAGE、NF-κBp65、GFAP、Iba1蛋白质表达上调。给予EP治疗，缩短了小鼠术后3 d TFC僵直时间，下调了海马HMGB1、RAGE、NF-κBp65、GFAP、Iba1蛋白质表达和IL-1β含量。结论：EP可能是通过抑制HMGB1的分泌和HMGB1/RAGE-NF-κB信号通路改善中枢炎症，从而改善PND。
关键词：
高迁移率族蛋白1；认知障碍；神经炎症
Effect of ethyl pyruvate on perioperative neurocognitive disorders in aged mice
CorrespondingAuthor: WU Anshi Email: wuanshimzk@163.com
DOI: 10.3978/j.issn.2095-6959.2022.05.002
Foundation: This work was supported by the National Natural Science Foundation of China (81400883).
Abstract
Objective: To evaluate the effect of ethyl pyruvate (EP) on perioperative neurocognitive disorders (PND) in mice. Methods: Fifty-four specific pathogen free (SPF) aged male C57BL/6 mice, 14–16 months old, 38–52 g in weight, were used in the study. Fifty-four mice were divided into 3 groups (n=18) using the random number table method: a normal control group (C group), a partial hepatectomy group (S group) and an EP group. Partial hepatectomy was performed under isoflurane anesthesia in the EP group with an intraperitoneal injection of EP 100 mg/kg at the end of the operation, and an equal volume of balanced salt solution in the C and S groups. All animals received trace fear conditioning (TFC) training 30 min prior to surgery. The freezing time of mice was recorded by TFC test on the third days after surgery. The mice were then sacrificed and the hippocampus organization was isolated for Western blot to detect the protein expression of high mobility group box-1 (HMGB1), receptor for advanced glycation end products (RAGE), activation of nuclear factor Son-κB p65 (NF-κBp65), glial fibrillary acidic protein (GFAP) and ionized calcium binding adapter molecule 1 (Iba1) and for ELISA to detect interleukin-1β (IL-1β) contents. Results: Compared with the C group, the freezing time in the TFC was significantly shortened (P<0.01) and the contents of IL-1β were increased at the third day after surgery. The protein expressions of HMGB1, RAGE, NF-κBp65, GFAP, Iba1 in the hippocampus organization were upregulated at the third day after surgery in S group. Compared with the S group, the freezing time in TFC was significantly prolonged at the third day after surgery in EP group (P<0.05). Compared with the S group, the contents of IL-1β and the protein expressions of HMGB1, RAGE, NF-κBp65, GFAP and Iba1 in the hippocampus organization were reduced at 3 days after surgery in EP group. Conclusion: EP showed significant neuroprotection in PND, the mechanism of which might be related to improve neuroinflammation by inhibiting HMGB1 secretion and HMGB1/RAGE-NF-κB signal pathway.
Keywords：
high mobility group box-1; cognition disorders; neuroinflammation