Sphingosine-1-phosphate protects against sepsis-associated encephalopathy by suppressing heparanase-mediated endothelial glycocalyx degradation.

Sepsis-associated encephalopathy (SAE) is a severe complication of sepsis, frequently accompanied by disruption of the blood-brain barrier (BBB), neuroinflammation, and cerebral edema. The endothelial glycocalyx, an essential component of the BBB, is vital for preserving vascular homeostasis and integrity. However, the specific contribution of glycocalyx degradation in cerebral endothelial cells to BBB permeability and subsequent brain injury in SAE remains inadequately defined. In this study, we hypothesized that glycocalyx degradation is a pivotal early event in SAE pathogenesis and investigated the protective effects of sphingosine-1-phosphate (S1P) in maintaining glycocalyx integrity. Using intraperitoneal lipopolysaccharide (LPS) to induce sepsis in C57BL/6 mice, we assessed neurological deficits, BBB integrity, cerebral edema, and neuroinflammation 24 h after induction. Our results showed that S1P treatment effectively preserved glycocalyx structure, improved neurological reflex scores, reduced Evans blue extravasation, inhibited overactivation of microglia and astrocytes, and modulated cytokine expression. Mechanistically, S1P downregulated heparanase expression and promoted glycocalyx synthesis, thereby preventing glycocalyx-loss-driven BBB disruption and ultimately improving neurological outcomes. These findings suggest that S1P may protect against SAE by limiting heparanase-mediated glycocalyx degradation. This study supports the therapeutic potential of S1P and provides new insights into strategies for managing SAE.