The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Department of Anesthesia and Perioperative Medicine, Wenzhou, China; Zhejiang Provincial Key Laboratory of Anesthesiology, Wenzhou Medical University, Wenzhou, China; Key Laboratory of Pediatric Anesthesiology Ministry of Education, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, United States.
Exp Neurol. 2024 Oct;380:114922. doi: 10.1016/j.expneurol.2024.114922. Epub 2024 Aug 12.
Multiple factors contribute to the development of perioperative neurocognitive disorders (PND). This study was designed to investigate whether Histone Deacetylase 6 (HDAC6) was involved in the formation of postoperative cognitive dysfunction in elderly mice by regulating the degree of acetylation of heat shock protein (HSP90) and related protein functions and quantities.
C57BL/6 J male mice were randomly divided into six groups: control naive (group Control), anesthesia (group Anesthesia), splenectomy surgery (group Surgery), splenectomy surgery plus dissolvent (group Vehicles), splenectomy surgery plus the inhibitor ACY-1215 (group Ricolinostat), and splenectomy surgery plus the inhibitor RU-486(group Mifepristone). After the mice were trained for Morris Water Maze (MWM) test for five days, anesthesia and operational surgery were carried out the following day. Cognitive function was assessed on the 1st, 3rd and 7th days post-surgery. The hippocampi were harvested on days 1, 3, and 7 post-surgeries for Western blots and ELISA assays.
Mice with the splenectomy surgery displayed the activation of the hypothalamic-pituitary-adrenal axis (HPA-axis), marked an increase in adrenocorticotropic hormone (ACTH), glucocorticoid, mineralocorticoid at the molecular level and impaired spatial memory in the MWM test. The hippocampus of surgical groups showed a decrease in acetylated HSP90, a rise in glucocorticoid receptor (GR)-HSP90 association, and an increase in GR phosphorylation and translocation. HDAC6 was increased after the surgical treated. Using two specific inhibitors, HDAC6 inhibitor Ricolinostat (ACY-1215) and GR inhibitor Mifepristone (RU-486), can partially mitigate the effects caused by surgical operation.
Abdominal surgery may impair hippocampal spatial memory, possibly through the HDAC6-triggered increase in the function of HSP90, consequently strengthening the negative role of steroids in cognitive function. Targeting HDAC6- HSP90/GR signaling may provide a potential avenue for the treatment of the impairment of cognitive function after surgery.
多种因素导致围手术期神经认知障碍（PND）的发生。本研究旨在通过调节热休克蛋白（HSP90）和相关蛋白功能和数量的乙酰化程度，探讨组蛋白去乙酰化酶 6（HDAC6）是否通过调节热休克蛋白（HSP90）和相关蛋白的功能和数量参与老年小鼠术后认知功能障碍的形成。
将 C57BL/6J 雄性小鼠随机分为 6 组：对照组（Control）、麻醉组（Anesthesia）、脾切除术组（Surgery）、溶媒组（Vehicles）、抑制剂 ACY-1215 组（Ricolinostat）和抑制剂 RU-486 组（Mifepristone）。小鼠在进行 Morris 水迷宫（MWM）测试训练 5 天后，次日进行麻醉和手术。术后第 1、3、7 天进行认知功能评估。术后第 1、3、7 天取海马组织进行 Western blot 和 ELISA 检测。
脾切除术组小鼠下丘脑-垂体-肾上腺轴（HPA 轴）激活，促肾上腺皮质激素（ACTH）、糖皮质激素、盐皮质激素水平明显升高，MWM 测试空间记忆受损。手术组海马乙酰化 HSP90 减少，糖皮质激素受体（GR）-HSP90 结合增加，GR 磷酸化和转位增加。手术组 HDAC6 增加。使用两种特异性抑制剂，HDAC6 抑制剂 Ricolinostat（ACY-1215）和 GR 抑制剂 Mifepristone（RU-486），可以部分减轻手术引起的影响。
腹部手术可能损害海马体空间记忆，可能通过 HDAC6 触发 HSP90 功能增加，从而增强类固醇对认知功能的负面影响。靶向 HDAC6-HSP90/GR 信号通路可能为术后认知功能障碍的治疗提供潜在途径。
