Department of Anesthesiology, The Second Affiliated Hospital of University of South China, Hengyang, China.
Department of Anesthesiology, The First Hospital of Hunan University of Chinese Medicine, Changsha, China.
World J Biol Psychiatry. 2023 Feb;24(2):149-161. doi: 10.1080/15622975.2022.2082524. Epub 2022 Jun 14.
Hippocampal neurogenesis is closely related to learning and memory, and hippocampal neurogenesis disorders are involved in the development of many neurodegenerative diseases. Mineralocorticoid receptor (MR) plays a vital role in regulating stress response, neuroendocrine and cognitive functions, and is involved in regulating the integrity and stability of neural networks. However, the potential role of MR in the pathogenesis of postoperative cognitive dysfunction (POCD) is unclear. Therefore, this study evaluated the effect and mechanism of MR activation on postoperative hippocampal neurogenesis and cognitive function in aged mice.
18-month-old male Kunming mice were randomly divided into Control group (C group), Surgery group (S group), Surgery+ Aldosterone group (S+Aldo group), Surgery + Wortmannin group (S+Wort group), Surgery + Aldosterone + Wortmannin group (S+Aldo+Wort group). Laparotomy was used to establish an animal model of postoperative cognitive dysfunction. After surgery, mice were intraperitoneally injected with aldosterone (100 ug/kg,150 ug/kg,200 ug/kg) and / or wortmannin (1 mg/kg); One day before the sacrifice, mice were injected intraperitoneally with BrdU (100 mg / kg / time, 3 times in total). Mice were subjected to Morris water maze and field tests at 1, 3, 7, and 14 days after surgery. Immunofluorescence was used to detect the number of BrdU +, Nestin +, BrdU/Nestin + positive cells in the hippocampal dentate gyrus of mice at 1, 3, 7 and 14 days after surgery. Western-blot was used to detect PI3K/Akt/GSK-3β signaling pathway related proteins Akt, p-Akt, GSK-3β, P-GSK-3β expression.
Stress impairs the performance of aged mice in water maze and open field tests, reduces the number of BrdU/Nestin+ cells in the hippocampal dentate gyrus, and inhibits the phosphorylation of Akt and GSK-3β proteins in the hippocampus. Aldosterone treatment promotes P-Akt, P-GSK-3β protein expression and hippocampal neural stem cell proliferation, and improves postoperative cognitive dysfunction. However, wortmannin treatment significantly reversed these effects of aldosterone.
The mineralocorticoid receptor agonist aldosterone promotes the proliferation of hippocampal neural stem cells and improves cognitive dysfunction in aged mice after surgery, and the mechanism may be related to activation of PI3K/Akt/GSK-3β signaling.
海马神经发生与学习记忆密切相关，海马神经发生障碍参与了许多神经退行性疾病的发生发展。盐皮质激素受体（MR）在调节应激反应、神经内分泌和认知功能方面发挥着重要作用，并参与调节神经网络的完整性和稳定性。然而，MR 在术后认知功能障碍（POCD）发病机制中的潜在作用尚不清楚。因此，本研究评估了 MR 激活对老年小鼠术后海马神经发生和认知功能的影响及机制。
将 18 月龄雄性昆明小鼠随机分为对照组（C 组）、手术组（S 组）、手术+醛固酮组（S+Aldo 组）、手术+wortmannin 组（S+Wort 组）、手术+醛固酮+wortmannin 组（S+Aldo+Wort 组）。采用剖腹手术建立术后认知功能障碍动物模型。术后，小鼠腹腔内注射醛固酮（100μg/kg、150μg/kg、200μg/kg）和/或 wortmannin（1mg/kg）；在处死前 1 天，小鼠腹腔内注射 BrdU（100mg/kg/次，共 3 次）。术后 1、3、7、14 天，小鼠行 Morris 水迷宫和旷场实验。免疫荧光法检测术后 1、3、7、14 天小鼠海马齿状回 BrdU+、Nestin+、BrdU/Nestin+阳性细胞数。Western blot 法检测 PI3K/Akt/GSK-3β 信号通路相关蛋白 Akt、p-Akt、GSK-3β、P-GSK-3β的表达。
应激使老年小鼠在水迷宫和旷场实验中的表现受损，减少海马齿状回 BrdU/Nestin+细胞数量，并抑制海马内 Akt 和 GSK-3β 蛋白的磷酸化。醛固酮处理促进 p-Akt、P-GSK-3β 蛋白表达和海马神经干细胞增殖，改善术后认知功能障碍。然而，wortmannin 处理显著逆转了醛固酮的这些作用。
盐皮质激素受体激动剂醛固酮促进老年小鼠术后海马神经干细胞增殖，改善认知功能障碍，其机制可能与激活 PI3K/Akt/GSK-3β 信号有关。
