2. Academic Validation
  3. Polydatin Improves Sepsis-Associated Encephalopathy by Activating Sirt1 and Reducing p38 Phosphorylation

Polydatin Improves Sepsis-Associated Encephalopathy by Activating Sirt1 and Reducing p38 Phosphorylation

  • J Surg Res. 2022 Aug;276:379-393. doi: 10.1016/j.jss.2022.03.008.
Lin Huang 1,  Jiawei Chen 1,  Xiaojie Li 1,  Mingxin Huang 1,  Jilou Liu 1,  Na Qin 1,  Zhenhua Zeng 2,  Xingmin Wang 3,  Fen Li 4,  Hong Yang 5
Affiliations

Affiliations

  • 1 Department of Critical Care Medicine, The Third Affiliated Hospital of Southern Medical University, Southern Medical University, Guangzhou, China.
  • 2 Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • 3 Department of Pathology, Liuzhou Maternity and Child Healthcare Hospital, Liuzhou, China. Electronic address: [email protected].
  • 4 Department of Critical Care Medicine, The Third Affiliated Hospital of Southern Medical University, Southern Medical University, Guangzhou, China. Electronic address: [email protected].
  • 5 Department of Critical Care Medicine, The Third Affiliated Hospital of Southern Medical University, Southern Medical University, Guangzhou, China; Guangdong Provincial Key Laboratory of Shock and Microcirculation, Southern Medical University, Guangzhou, China. Electronic address: [email protected].
PMID: 35447391 DOI: 10.1016/j.jss.2022.03.008
Abstract

Introduction: 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).

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords

Mitochondrial function; Polydatin; Sepsis-associated encephalopathy; Sirt1; p38.

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