Abstract
The pathogenesis of sepsis-associated encephalopathy (SAE) involves many aspects, including intracellular peroxidative stress damage, mitochondrial dysfunction, and cell apoptosis. In this study, we mainly explored the influence of P2X7R on the cognitive function of SAE and its molecular mechanism. We established a sepsis model using lipopolysaccharide (LPS) stimulation, followed by an assessment of cognitive function using Morris water maze, and then Western Blot was used to analyze the expression of tight junction proteins ZO-1 and Occludin in the hippocampus of mice. TUNEL assay was used to analyze the apoptosis of brain cells in frozen brain slices of mice during sepsis. Human brain microvascular endothelial cells (HBMECs) were used to research the molecular mechanism of brain cell damage induced by P2X7R. The results showed that P2X7R inhibitors dramatically improved the survival rate of mice, relieved the cognitive dysfunction caused by LPS stimulation, and significantly reduced the brain cell apoptosis caused by LPS. In addition, the inhibition of P2X7R can also reduce the production and accumulation of reactive oxygen species (ROS) in HBMECs in vitro and inhibit the apoptosis signaling pathway associated with mitochondrial serine protease Omi/HtrA2 in HBMECs in vitro. These results suggest that P2X7R has strong value as a potential target for the treatment of SAE.
Highlights
sepsis-associated encephalopathy (SAE) is an inflammatory infection that causes systemic sepsis to spread to the brain, but there is no evidence of direct infection in the brain, and this is one reason for long-term and short-term cognitive impairment and high mortality in sepsis patients in the ICU [1, 2]
Many studies have found that cells in the brain undergo apoptosis under the stimulation of inflammatory factors, which is crucial for the pathogenesis of SAE
Since P2X7R is a receptor closely associated with inflammation and amplifies inflammatory damage, we investigated the influence of P2X7R inhibitor A-438079 on cognitive function in mice after severe sepsis was induced by LPS
Summary
SAE is an inflammatory infection that causes systemic sepsis to spread to the brain, but there is no evidence of direct infection in the brain, and this is one reason for long-term and short-term cognitive impairment and high mortality in sepsis patients in the ICU [1, 2]. More and more evidences show that SAE is closely related to peroxidation stress injury of brain cells, mitochondrial dysfunction, and apoptosis. Activation of P2X7R causes a large amount of Ca2+ and Na+ influx and K+ outflow, resulting in the imbalance of intracellular metabolism. P2X7R is primarily expressed on the surface of various brain cells, especially microglia and astrocytes [6, 7].
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