SIRT3 通过激活 AMPK/mTOR 通路介导的自噬增强丙泊酚在术后认知功能障碍中的保护作用。

SIRT3 Enhances the Protective Role of Propofol in Postoperative Cognitive Dysfunction via Activating Autophagy Mediated by AMPK/mTOR Pathway.

机构信息

Department of Anesthesiology, Peking University People's Hospital, 100044 Beijing, China.

Department of Anesthesiology, Peking University Hospital of Stomatology, 100081 Beijing, China.

出版信息

Front Biosci (Landmark Ed). 2022 Nov 8;27(11):303. doi: 10.31083/j.fbl2711303.

DOI:10.31083/j.fbl2711303

PMID:36472103

Abstract

BACKGROUND

Postoperative cognitive dysfunction (POCD) is a common complication after surgery and anesthesia. In this study, we aimed to determine the neuroprotective mechanism of Sirtuin 3 (SIRT3) and propofol in POCD.

METHODS

The cognitive dysfunction models in C57BL/6J mice were induced and treated, then cognitive function of mice were tested using morris water maze and novel object recognition tests. Primary neurons were stimulated by lipopolysaccharide (LPS) to mimic neuroinflammation during POCD. Meanwhile, cells were treated with propofol. 3-methyladenine (3-MA) was administrated to inhibit autophagy in neurons. SIRT3 overexpression vector was constructed to upregulate SIRT3. Biomarker changes in inflammation, oxidative stress and autophagy were determined and .

RESULTS

Propofol enhanced the spatial cognitive ability and novel objective recognition of POCD mice. Inflammation and oxidative stress were observed in the hippocampus, which were inhibited by propofol treatment. During POCD, SIRT3 expression and autophagy in the hippocampus was decreased; propofol activated autophagy and upregulated SIRT3. In LPS-stimulated neurons, SIRT3 upregulation enhanced the anti-inflammation and anti-oxidative stress roles of propofol; SIRT3 elevated propofol-activated autophagy in neurons undergoing LPS administration. Moreover, 3-MA reversed propofol-induced biomarker changes in inflammation, oxidative stress and autophagy in LPS-stimulated neurons. In POCD mice, SIRT3 upregulation enhanced the cognitive function during propofol treatment; SIRT3 overexpression elevated the inhibitory role of propofol in inflammation, oxidative stress and autophagy. AMPK/mTOR pathway was activated in response to propofol treatment and SIRT3 enhanced the signaling activation.

CONCLUSIONS

SIRT3 enhances the protective effect of propofol on POCD by triggering autophagy that eliminates oxidative stress and inhibits the production of pro-inflammatory cytokines.

摘要

背景

术后认知功能障碍（POCD）是手术和麻醉后常见的并发症。在这项研究中，我们旨在确定 Sirtuin 3（SIRT3）和异丙酚在 POCD 中的神经保护机制。

方法

通过给予 C57BL/6J 小鼠认知功能障碍模型并进行处理，然后使用 Morris 水迷宫和新物体识别测试来测试小鼠的认知功能。用脂多糖（LPS）刺激原代神经元以模拟 POCD 期间的神经炎症。同时，用异丙酚处理细胞。用 3-甲基腺嘌呤（3-MA）抑制神经元中的自噬。构建 SIRT3 过表达载体以上调 SIRT3。测定炎症、氧化应激和自噬的生物标志物变化。

结果

异丙酚增强了 POCD 小鼠的空间认知能力和新物体识别能力。在海马区观察到炎症和氧化应激，异丙酚处理可抑制其发生。在 POCD 期间，海马区 SIRT3 表达和自噬减少；异丙酚激活自噬并上调 SIRT3。在 LPS 刺激的神经元中，SIRT3 上调增强了异丙酚的抗炎和抗氧化应激作用；SIRT3 提高了 LPS 处理的神经元中异丙酚激活的自噬作用。此外，3-MA 逆转了 LPS 刺激的神经元中异丙酚诱导的炎症、氧化应激和自噬的生物标志物变化。在 POCD 小鼠中，SIRT3 上调增强了异丙酚治疗期间的认知功能；SIRT3 过表达提高了异丙酚在炎症、氧化应激和自噬中的抑制作用。异丙酚处理激活了 AMPK/mTOR 通路，而 SIRT3 增强了信号的激活。