Department of Critical Care Medicine, The Third Affiliated Hospital of Southern Medical University, Southern Medical University, Guangzhou, China.
Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China.
J Surg Res. 2022 Aug;276:379-393. doi: 10.1016/j.jss.2022.03.008. Epub 2022 Apr 18.
Our previous study confirmed that polydatin (PD) can alleviate sepsis-induced multiorgan dysfunction (in the vascular endothelium, kidney, and small intestine) by activating Sirt1 and that PD protects against traumatic brain injury in rats via increased Sirt1 and inhibition of the p38-mediated mitogen-activated protein kinase (MAPK) pathway. We aim to investigate whether PD may also attenuate sepsis-associated encephalopathy (SAE).
In this study, we constructed an SAE mouse model by cecal ligation and puncture (CLP) and measured Sirt1 protein activity, p38 phosphorylation, brain tissue pathological damage, pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), mitochondrial function (mitochondrial membrane potential, ATP content, and reactive oxygen species), neurological function, and animal survival time. Sirt1 selective inhibitor Ex527 and p38 inhibitor SB203580 were used to explore the possible mechanism of PD in SAE.
We confirmed that PD inhibits neuroinflammation evidenced by reduced proinflammatory cytokines. In addition, PD protects mitochondria as demonstrated by restored mitochondrial membrane potential and adenosine triphosphate (ATP) content, and decreased reactive oxygen species (ROS) level. As we expected, p38 inhibition reduces neuroinflammation and mitochondrial damage. In contrast, Sirt1 inhibition aggravates cerebral cortex mitochondrial damage and neuroinflammation and promotes phosphorylation of p38. Mechanistically, PD treatment suppressed p38 phosphorylation and consequently reduced the neuroinflammatory response, and these effects were blocked by the Sirt selective inhibitor Ex527.
This study, to the best of our knowledge, is the first to demonstrate that PD alleviates SAE, at least partially, by upregulating Sir1-mediated neuroinflammation inhibition and mitochondrial function protection.
我们之前的研究证实，白藜芦醇（PD）可以通过激活 Sirt1 来减轻脓毒症引起的多器官功能障碍（血管内皮、肾脏和小肠），并且 PD 通过增加 Sirt1 和抑制 p38 介导的丝裂原活化蛋白激酶（MAPK）通路来保护大鼠免受创伤性脑损伤。我们旨在研究 PD 是否也可以减轻脓毒症相关脑病（SAE）。
在这项研究中，我们通过盲肠结扎和穿孔（CLP）构建了 SAE 小鼠模型，并测量了 Sirt1 蛋白活性、p38 磷酸化、脑组织病理损伤、促炎细胞因子（TNF-α、IL-1β 和 IL-6）、线粒体功能（线粒体膜电位、ATP 含量和活性氧）、神经功能和动物存活时间。使用 Sirt1 选择性抑制剂 Ex527 和 p38 抑制剂 SB203580 来探讨 PD 在 SAE 中的可能作用机制。
我们证实 PD 通过减少促炎细胞因子来抑制神经炎症。此外，PD 保护线粒体，表现为线粒体膜电位和三磷酸腺苷（ATP）含量恢复，活性氧（ROS）水平降低。正如我们所料，p38 抑制减少了神经炎症和线粒体损伤。相比之下，Sirt1 抑制加重了大脑皮质线粒体损伤和神经炎症，并促进了 p38 的磷酸化。在机制上，PD 治疗抑制了 p38 磷酸化，从而减少了神经炎症反应，而这些作用被 Sirt1 选择性抑制剂 Ex527 阻断。
就我们所知，这项研究首次表明，PD 通过上调 Sir1 介导的神经炎症抑制和线粒体功能保护来缓解 SAE，至少部分缓解 SAE。
