Abstract
Brain injury is a familiar complication of severe sepsis, in which excessive inflammation and oxidative stress are the main mechanisms leading to acute brain injury. Here, we focus on probing the function and mechanism of Matairesinol (Mat) in sepsis-mediated brain injury. We established a rat sepsis model by cecal ligation and perforation (CLP) and constructed an in vitro sepsis model by treating neurons and microglia with lipopolysaccharide (LPS). Rats and cells were treated with varying concentrations of Mat, and the changes of neural function, neuronal apoptosis, microglial activation, neuroinflammation and the expression of oxidative stress factors in brain tissues were examined. Additionally, the activation of the MAPK, NF-κB and AMPK pathways in brain tissues and cells was evaluated by Western blot (WB) and/or immunohistochemistry (IHC). Our findings illustrated that Mat improved neuronal apoptosis and weakened microglial activation in CLP rats. Meanwhile, Mat hampered the expression of pro-inflammatory factors (TNF-α, IL-1β, IL-6, IFN-γ, IL-8, and MCP1) and facilitated the contents of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) in brain tissues and microglia. Mechanistically, Mat concentration-dependently dampened the phosphorylation of MAPK, JNK and NF-κB in CLP rats and LPS-stimulated microglia and up-regulated Nrf2 and HO-1. Besides, Mat facilitated the AMPK expression. Meanwhile, Compound C, a specific inhibitor of the AMPK pathway, substantially reduced the neuronal protection and anti-inflammatory effects mediated by Mat. Overall, Mat exerts anti-inflammatory and anti-oxidative stress effects by up-regulating AMPK, thereby ameliorating sepsis-mediated brain injury.
Highlights
Sepsis is a frequent infectious disease that was redefined as organ dysfunction infection in 2016 [1]
Brain injury is often observed after sepsis, and it is implicated in the direct damage or secondary/indirect injuries of sepsis to the brain [24]
This study was conducted based on the construction of the LPS-induced cellular sepsis model and cecal ligation and perforation (CLP)-mediated rat sepsis model
Summary
Sepsis is a frequent infectious disease that was redefined as organ dysfunction infection in 2016 [1]. Sepsis is among the prime contributor to death in critically ill patients, affecting approximately more than 30 million people every year globally, according to a WHO report in 2018 [2]. Sepsis causes dysfunction of multiple organs, with the brain being the first to be affected [3]. Microglia are important players in the homeostasis of the mammalian central nervous system, and their dysregulation causes neurodegenerative and neuroinflammatory diseases [5]. Studies have stated that microglia affect the function of the central nervous system by driving synaptogenesis, synaptic pruning, neurogenesis, and neuronal activity [6]. When external stimulation causes neuronal injury, microglia are spurred to secrete various inflammatory factors
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